Reimbursement Review

Blinatumomab (Blincyto)

Sponsor: Amgen Canada Inc.

Therapeutic area: B-cell precursor acute lymphoblastic leukemia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Acute lymphoblastic leukemia (ALL) is a rare and aggressive hematologic malignancy of undifferentiated lymphoid precursors characterized by the proliferation of immature and abnormal lymphoid cells in the bone marrow and peripheral blood.¹ In 2019 alone, 440 new cases of ALL were diagnosed in Canada (excluding Quebec).² From 2015 to 2017, the 5-year net survival rate for patients in Canada aged 15 to 99 years was 47%.³ While ALL is the least common type of leukemia in adults, it is the most prevalent cancer among children and young adults.⁴ B-lymphoblastic (B-cell) phenotype is the most common type of ALL, accounting for approximately 85% of pediatric ALL cases and around 75% of adult ALL cases.^5,6 The leukemia cells in many patients with B-cell ALL have chromosomal abnormalities, with 1 of the most prevalent abnormalities occurring in the Philadelphia chromosome (Ph) (occurring in 1% to 3% of childhood ALL cases and 11% to 29% of adult ALL cases).⁷ Determining the ALL subtype and presence of chromosomal abnormalities is critical for understanding the disease status, risk factors, and treatment planning. In addition, minimal residual disease (MRD) assessments provide information on the prognosis and chance of relapse, with higher MRD levels indicating greater chances of relapse.⁸ MRD testing by flow cytometry is widely available in Canada and recommended for ALL. In the pediatric ALL population, MRD testing is part of the standard of care and is publicly funded. In the adult ALL population, while it is routinely performed, funding for MRD testing is not uniform across Canada.

While conventional regimens differ in terms of specific drug selection, dosing, and duration, they all typically include 3 phases: induction, consolidation (sometimes called “intensification”), and maintenance; during these phases, intensive multidrug chemotherapy protocols are used.⁴ However, not all patients respond to available conventional treatments, relapse remains a substantial risk, and many patients experience toxicity-related adverse events (AEs). Further, patients with ALL experience a variety of symptoms, including fatigue, dry mouth, lack of appetite, irritability, and nervousness.⁹ These symptoms, coupled with disease outlook, treatment modalities, side effects, and other comorbidities common in ALL highlight the substantial unmet need. The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of blinatumomab, 28 mcg/day for adult patients weighing 45 kg or more and 15 mcg/m² per day for adult patients weighing less than 45 kg, and pediatric patients, lyophilized powder for solution, IV infusion by infusion pump in the treatment of Ph-negative CD19-positive B-cell precursor ALL in the consolidation phase of multiphase chemotherapy in the frontline setting.

Blinatumomab has previously been reviewed by Canada’s Drug Agency (CDA-AMC) for the treatment of pediatric and adult patients with Ph-negative B-cell precursor ALL in the relapse or refractory setting, adult patients with relapsed or refractory Ph-positive B-cell precursor ALL, and patients with Ph-negative CD19-positive B-cell precursor ALL in first or second hematologic complete remission (CR) with MRD greater than or equal to 0.1%. All final CDA-AMC recommendations were to reimburse with clinical criteria and/or conditions.

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from clinical expert(s) consulted for the purpose of this review.

Patient Input

CDA-AMC received 2 inputs for this submission. The first input, provided by the Leukemia & Lymphoma Society of Canada (LLSC), included survey results of adult patients with ALL and their caregivers. The second input was a joint submission provided by LLSC, Advocacy for Canadian Childhood Oncology Research Network (Ac2orn), Ontario Parents Advocating for Children with Cancer (OPACC), and Childhood Cancer Canada and was based on interviews with 3 caregivers of pediatric patients with B-cell ALL who received blinatumomab treatment. The patient group input for pediatric patients was supplemented with information on disease experience and experience with currently available treatments, gathered from previous patient group submissions to CDA-AMC for blinatumomab for pediatric patients with Ph-negative B-cell precursor ALL in the relapsed or refractory setting (pan-Canadian Oncology Drug Review [pCODR] 10099 Blinatumomab ALL for pediatrics in 2017 and PX0367 Blinatumomab for ALL for pediatrics in 2024).

LLSC is a national charitable organization dedicated to finding a cure for blood cancers and improving the quality of life of people affected by blood cancers and their families by funding research and providing educational resources, services, and support. Ac2orn is a national organization committed to advocating translational research and effective treatments to realize the goal of curing cancers in children, adolescents, and young adults. OPACC advocates for families and organizations navigating the childhood cancer journey. Childhood Cancer Canada supports children diagnosed with cancer and their families.

Input received for adults with ALL is summarized first, followed by patient input from caregivers of pediatric patients with ALL.

LLSC conducted a survey in October and November 2024. The respondents were patients with ALL (69%) and their caregivers (28%). Out of 103 respondents providing their age, 9% were aged 0 to 17 years and were disqualified from the survey. The survey respondents included 49% aged 18 to 39 years, 32% aged 40 to 64 years, 8% aged 65 to 74 years, and 3% aged 75 years or older. Among 82 adults providing responses, most were from Canada, 1 was from the US, and 1 was international. A negative to very negative impact on personal or home life due to ALL was reported by 82% of respondents. When considering their social life, 75% of respondents reported negative to very negative impacts due to ALL. Low energy, fear of infections, frequent hospital visits, depression and/or anxiety, ALL symptom burden, and inadequate nutrition were reported as factors contributing to negative impacts of ALL. Eighteen respondents had experience with blinatumomab. Among all other types of treatment, chemotherapy was the most commonly reported type of ALL treatment (98% of respondents), followed by stem cell transplantation (SCT) (48% of respondents), radiation therapy (45% of respondents), immunotherapy (27% of respondents), targeted therapy (7% of respondents), chimeric antigen receptor (CAR) T-cell therapy (5% of respondents), and other types (16% of respondents; included natural medicine, Chinese medicine, sound baths, meditation, transfusions steroids, and antiemetics). Fatigue and neutropenia were reported by the respondents as the most severe side effects of current treatments (excluding blinatumomab), followed by thrombocytopenia, infections, nausea, vomiting, diarrhea, anemia, fever, peripheral edema, headaches, infusion reactions, neurologic symptoms, and cytokine release syndrome. These side effects had substantial impacts on patients’ lives, including frequent hospitalizations and lower functionality. LLSC added that the most important outcomes for patients include longer remission with consideration of side effects, quality of life, and financial costs.

According to LLSC, 18 respondents stated that they or the person they care or cared for were treated with blinatumomab for ALL. The methods of access were primarily through clinical trials (33%) and compassionate use programs (27%); the remainder of patients accessed blinatumomab through private insurance, Régie de l’assurance maladie du Québec (RAMQ) — Quebec socialized health care, government funding, or they did not know. Out of 15 respondents, 67%, 20%, and 13% of respondents believed that their ALL completely, partially, or did not respond to blinatumomab, respectively. Respondents were asked to rate the severity of the side effects of blinatumomab (from 1 — did not experience to 4 — severe). Among 15 respondents, the highest-rated side effects, as measured by weighted averages, were neutropenia (2.29), fatigue or weakness (2.27), and fever (2), followed by anemia (1.71), thrombocytopenia (1.71), infections (1.64), headaches (1.57), neurologic symptoms (i.e., confusion, seizures, difficulty speaking; 1.53), cytokine release syndrome (1.5), diarrhea (1.47), peripheral edema (1.47), nausea or vomiting (1.4), and infusion reactions (i.e., chills, rash, difficulty breathing; 1.27). In terms of comparing blinatumomab to other treatments, among 15 respondents, 40% felt it was as difficult to tolerate as other treatments, 27% felt it was less or much less difficult, and 7% felt it was more difficult to tolerate. Additionally, out of 15 respondents, 40% strongly agreed, 20% agreed, 33% felt neutral, and 7% disagreed that blinatumomab improved their quality of life compared to other treatments. Most patients indicated that they were likely to take blinatumomab again or recommend it to other patients.

The joint patient group input for pediatric patients gathered information through interviews with 3 caregivers of pediatric patients with B-cell ALL. According to this patient group submission, to avoid repetitive questioning and to minimize emotional strain and undue harm, the interviews focused on experiences and quality of life associated with blinatumomab treatment. For all other information, this patient group input referred to previous LLSC-Ac2orn-OPACC joint submissions to CDA-AMC for relapsed or refractory ALL in children. First, the following section presents the disease experience and experience with currently available treatments gathered from previous patient input submissions. Second, it summarizes patients’ and caregivers’ experience with blinatumomab treatment and patients’ quality of life during blinatumomab treatment compared to their experience with prior treatments for pediatric ALL, based on the joint patient group submission for this current review.

Based on input gathered in previous patient input submissions to CDA-AMC for pediatric patients with relapsed or refractory ALL, children may experience a variety of symptoms, including severe fatigue, pain, high fever, bleeding, bruising, bone pain, and swollen lymph nodes. However, the impacts of pediatric cancer relapse on the child and their family extend beyond physical symptoms. It was highlighted in the patient group submissions that relapse and immunosuppression severely limit children’s ability to engage in normal activities, placing a significant emotional and physical burden on both the child and their family. Families experience intense stress, financial strain, and disrupted daily routines, with caregivers often facing severe impacts on their mental health. It was explained in the patient group submissions that the standard of care for treating relapsed or refractory pediatric ALL typically involves a combination of strategies, including drug therapy and radiation. For patients with refractory disease, these aggressive treatments often result in serious side effects, such as immunosuppression, severe pain, infections, anemia, and organ damage, which can significantly impact the child's quality of life. There is a significant unmet need for more effective, less toxic therapies that improve quality of life by reducing treatment burden and minimizing the need for frequent hospital visits. Outpatient treatment options that decrease hospital stays was also cited as crucial for maintaining normalcy and reducing stress for both patients and their families. In terms of improved outcomes, it was noted in the patient group submissions that patients and their families are looking for options that are not only effective but also gentle on their children. They seek innovative therapies that can provide significant benefits without causing undue harm or severe side effects. Additionally, having these treatments covered by drug plans is crucial, as coverage alleviates the financial burden on families.

In the 3 caregiver interviews conducted by the joint patient group submission for this present review, 2 of the caregivers had children who were 2 years old, and 1 had a child who was 10 years old at diagnosis. Two caregivers were residents of Ontario, and 1 resided in British Columbia. The input focused on patients’ and caregivers’ experiences with administering blinatumomab treatment at home, as well as on comparing their quality of life during blinatumomab treatment to their experiences with prior treatments for pediatric ALL. According to the joint submission, the current conventional therapy for pediatric patients with B-cell ALL living in Canada is chemotherapy infusions, which are often accompanied by serious side effects, negative impact on patients’ physical health, and long hospital stays. Based on the joint input, all 3 caregivers mentioned that they and the patients had overall positive experiences with blinatumomab, especially in comparison to chemotherapy infusion. Because blinatumomab is an outpatient treatment with “gentler” effects, the patients were able to live with family, play with peers, and stay out of the hospital. The 3 caregivers reported that they felt nervous, the child experienced fever, and the child experienced side effects at the start of blinatumomab treatment. According to the patient group input, cognitive testing was done routinely at every blinatumomab bag change to check for neurologic AEs; none of the caregivers reported neurologic AEs as a side effect in the children. Caregivers reported an extra burden because they had to receive a new medication bag of blinatumomab every 4 days and had to visit the medical centre for any glitches in the blinatumomab delivery system. Caregivers noted that, because blinatumomab is a relatively new treatment method, knowledge of blinatumomab’s delivery method was limited among health care professionals. Some caregivers emphasized the need for greater variety for the backpack delivery system for blinatumomab that would be able to accommodate patients of all ages. According to the joint submission, all 3 caregivers related that blinatumomab made a big difference to the quality of life for their patients, themselves, and the rest of their family compared to traditional chemotherapy infusion. Financial stress was experienced by caregivers due to the high cost and lack of public funding for blinatumomab. Finally, the joint submission made the following suggestions for improved outcomes with new therapies:

• Provide caregivers with tips and tools on what to expect with the blinatumomab delivery system and some at-home solutions to help to alleviate practical challenges such as driving to cancer centres at unexpected times.

• Train nurses at local hospitals to administer blinatumomab (to mitigate the requirement of driving to cancer centres).

• Improve blinatumomab knowledge and skills of the nurses at the cancer centres.

• Provide more choices in the delivery system backpacks based on body size and strength of the patient.

Clinician Input

Input From Clinical Experts Consulted for This Review

Two clinical specialists with expertise in the diagnosis and management of Ph-negative B-cell precursor ALL provided input for this review. One of the clinical experts has specific expertise in the diagnosis and management of adults with Ph-negative B-cell precursor ALL, while the other has expertise in pediatric patients with Ph-negative B-cell precursor ALL.

Both clinical experts felt the overarching goal of Ph-negative B-cell precursor ALL treatment is to achieve CR, prevent relapses, and cure the disease (thus providing long-term survival), while minimizing acute and late toxicities. Experts highlighted that not all patients respond to available conventional treatments, relapse remains a substantial risk, and many patients experience toxicity-related AEs. The clinical experts consulted for this review noted that unplanned inpatient admissions due to complications associated with the current conventional treatments are common. Further, as ALL is the most common childhood cancer, the clinical expert with experience treating pediatric patients with ALL highlighted that decreasing relapse rates in ALL would have a significant impact on childhood cancer mortality rates and obviate the need for additional expensive and/or toxic therapies.

Both clinical experts consulted for this review felt that blinatumomab would add an alternative first-line treatment option for patients with Ph-negative B-cell precursor ALL. The experts recommended using 1 to 4 cycles of blinatumomab in sequence with conventional consolidation chemotherapy. Compared to current treatment options, clinical experts noted that blinatumomab’s unique mechanism of action, blocking CD19 antigen expressed on the leukemic blasts, has the potential to improve overall response rate, relapse-free survival (RFS), and overall survival (OS), while decreasing AEs associated with the frequent use of intensive chemotherapy, the potentially improving quality of life for patients with Ph-negative B-cell precursor ALL. If blinatumomab reduces the use of allogeneic SCT by preventing relapse, clinical experts noted that the risk of treatment-related mortality may also decrease.

The clinical experts consulted for this review noted any adult or pediatric patient with Ph-negative B-cell precursor ALL who achieves a CR following induction therapy, regardless of risk (MRD and standard-risk acute lymphoblastic leukemia [SR] with or without high-risk or very high–risk status) and age, would be best suited for first-line consolidation treatment with blinatumomab.

The clinical expert with experience treating pediatric patients noted that the 1 exception may be to exclude pediatric patients from receiving blinatumomab if their expected event-free survival on a particular conventional chemotherapy backbone is expected to be greater than 95% (i.e., those with SR and a favourable risk of relapse [SR-favourable]). However, experts flagged that the molecular characterization of leukemia is rapidly evolving, and the identification of a new high-risk somatic change may alter how patients are currently classified.

The expert felt that adult patients with Ph-negative B-cell precursor ALL who have a poor performance status (PS) (i.e., Eastern Cooperative Oncology Group [ECOG] PS greater than 2) should not be eligible for blinatumomab, while no PS restriction should be made in children, as blinatumomab has been shown to be well tolerated and potentially life-saving. Clinical experts felt there were insufficient data to recommend blinatumomab treatment in patients with acute undifferentiated leukemia and those with Burkitt’s leukemia.

The clinical experts consulted for this review noted that treatment response is based on bone marrow evaluation (including morphological evaluation and MRD assessment) at the end of induction and consolidation treatment. RFS, disease-free survival (DFS), OS, and other survival parameters, such as relapse incidence, are long-term parameters used to assess treatment response in both clinical trials and clinical practice. In both clinical trials and clinical practice, AEs are used to assess treatment benefit. The clinical expert with experience treating adults with ALL noted that, following the completion of maintenance treatment, relapse is assessed every 3 months during the first year, every 6 months during the second year, and then annually between years 3 and 5. The clinical expert with experience treating pediatric patients with ALL noted that, following the completion of maintenance treatment, follow-up practices vary by centre. However, in their clinical practice, relapse is assessed monthly for the first 3 months, then every 3 months during the first year, every 4 months in the second year, every 6 months in the third year, and then annually for the rest of the patient’s life.

The clinical trial, blinatumomab’s label, and the clinical experts consulted for this review noted that blinatumomab should be discontinued in the event of grade 4 cytokine release syndrome, grade 4 neurotoxicity and/or psychiatric events, and grade 4 thrombosis. Other grade 4 toxicities that are deemed clinically significant may require discontinuation of blinatumomab. Toxicities that require dose interruption of blinatumomab and that do not return to grade 1 or less by 14 days (or, in the case of neurotoxicity, by 7 days) necessitate discontinuation of blinatumomab. Recurrent toxicities leading to dose interruption of blinatumomab also require permanent discontinuation of blinatumomab.

The clinical expert with experience treating adult patients with ALL noted that patients who develop any debilitating conditions (such as ECOG PS of greater than 2) should discontinue blinatumomab treatment.

While the clinical experts agreed with these discontinuation criteria, the benefits of treatment, availability of alternative treatments, risks of discontinuation, and patients’ willingness to continue treatment must also be taken into account before making a final discontinuation decision. In adult patients, the expert felt that blinatumomab should be discontinued in the event of disease progression and relapse or upon the patient’s request.

Both clinical experts indicated that treatment with blinatumomab should be initiated on an inpatient basis (3 days for the first infusion and 2 days for subsequent infusions) and, if the drug is well tolerated, that subsequent infusions can be performed in an outpatient clinic.¹⁰ Given the pharmacy, nursing, and monitoring requirements for blinatumomab infusions, specialist care at an oncology centre is required. Both clinical experts consulted for this review felt that any conventional chemotherapy used for ALL treatment can be combined with blinatumomab. They also felt that clinicians should have the ability to adjust the dosage, number of cycles, and cycle length based on toxicity and individual patient’s needs.

The clinical expert with experience treating adults noted that at least 2 cycles of blinatumomab should be given before SCT to deepen the patient’s remission. SCT would likely be required in adult patients in their second CR (regardless of MRD status) or in first CR with continuous MRD positivity and would be considered in adult patients in first CR with MRD-negative status after initially presenting with the highest risk disease of relapse.

Clinician Group Input

Three clinician groups each submitted inputs to CDA-AMC: Ontario Health — Cancer Care Ontario (OH-CCO) Hematology Cancer Drug Advisory Committee (with input from 6 clinicians); Pediatric Oncology Group of Ontario (POGO) (input from 11 clinicians); and Canadian Leukemia Study Group (CLSG) — Groupe Canadien d’Étude sur la Leucémie (GCEL) (input from 7 clinicians). One group provided input relevant to pediatric patients (POGO) and another for adults (CLSG-GCEL), while the third group did not specify an age group of patients represented.

The clinician groups were generally in agreement with the feedback received from the clinical experts consulted for this review. In terms of the goals of therapy, the clinical experts and clinician groups indicated that the main goals are cure of the disease while minimizing toxicity. Other goals include achieving CR, preventing relapse, and avoiding need for second-line therapies, such as allogenic SCT, or CAR T-cell therapy. In pediatric patients, the POGO group stated that relapse therapies carry significant toxicity that leaves young patients with a wide variety of potential lifelong late effects. In adults, the clinician groups noted the substantial risk of relapse, even in patients who are MRD-negative. Thus, additional treatments are needed to improve survival, CR, and relapse rate, and to minimize or reduce toxicity of treatments (during consolidation and/or later therapies).

All clinician groups agreed that the patient population suitable to receive blinatumomab during consolidation include those newly diagnosed with Ph-negative CD19-positive B-cell precursor ALL, regardless of MRD status. Both the pediatric clinical expert consulted for this review and the POGO group indicated that patients who meet the SR-average or high-risk stratification criteria have less favourable outcomes with chemotherapy alone and are expected to benefit from the addition of blinatumomab during consolidation therapy. Those who meet the SR-favourable stratification criteria have excellent response rates (event-free survival greater than 95%) with chemotherapy alone and may not require blinatumomab therapy. The POGO group noted an unmet need for augmentation therapies that have a tolerable AE profile and may allow for cytotoxic “breaks” in therapy to facilitate recovery from cytotoxic-associated complications, such as fungal infections. According to input from POGO, patients with Ph-positive B-cell precursor ALL may also benefit from blinatumomab therapy. The clinician groups agree that standard response assessment for ALL would be relevant to monitoring the effects of blinatumomab, including MRD status, duration of response, relapse, and OS. The adult clinician groups noted the MRD threshold of 0.1% (≥ 10³) is obsolete, and the current standard is greater than or equal to 0.01% (≥ 10⁴).

The experts consulted and the clinician groups agreed that blinatumomab would be discontinued if the patient experienced disease progression or significant toxicity and that specialist care in an ALL treatment centre is warranted. The POGO group expressed that reimbursement strategies should account for all forms of drug wastage that may occur when pediatric doses are prepared.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC reimbursement review process. Key factors identified that could potentially impact the implementation of the CDA-AMC recommendation for blinatumomab used in the consolidation phase of multiphase chemotherapy were use among those outside of the pivotal trials age range (i.e., among those less than 1 year of age and older than 70 years), use among specific risk categories (including those with ECOG PS of greater than 2), and whether those patients with undifferentiated leukemia and those with Burkitt leukemia should be eligible.

Clinical Evidence

Systematic Review

Description of Studies

One ongoing, phase III, open-label, multicentre, international study (5.9% of the randomized sample was from Canada), the E1910 trial, met the inclusion criteria for the systematic review conducted by the sponsor. A second phase III, open-label, multicentre, international study (6.1% of the randomized sample was from Canada), the AALL1731 trial, was included to inform the reimbursement request among pediatric patients. Throughout the systematic review section, details for the E1910 trial are summarized first, followed by those for the AALL1731 trial.

The E1910 trial was aimed at evaluating the efficacy and safety of blinatumomab used in the consolidation phase of multiphase chemotherapy for the treatment of adult patients with Ph-negative B-cell precursor ALL and MRD-negative status. Secondary outcomes included assessing the efficacy and safety of blinatumomab in patients with MRD-positive status, while post hoc analyses were conducted among an MRD-agnostic cohort. Following confirmation of eligibility, all patients completed induction and intensification treatment. Those achieving a CR or CR with incomplete peripheral blood count recovery (CRi) were then randomized 1:1 using stratified randomization to receive consolidation treatment with blinatumomab plus conventional chemotherapy (blinatumomab plus chemotherapy) or conventional chemotherapy alone (chemotherapy). CR was defined as neutrophil count of 1.0 × 10⁹/L or greater, platelet count of 100 × 10⁹/L or greater, no leukemic blasts present in the peripheral blood, adequate bone marrow cellularity with trilineage hematopoiesis, 5% or less blasts in the bone marrow, and no extramedullary leukemia (e.g., CNS or soft tissue involvement). CRi had the same definition, with the exception of incomplete platelet recovery (i.e., platelets greater than 75 and less than 100 × 10⁹/L) or incomplete neutrophil count recovery (i.e., greater than 0.75 and less than 1 × 10⁹/L). Stratified randomization was based on MRD-positive versus MRD-negative status, aged 30 to 54 years versus 55 years or older, CD20-positive versus CD20-negative status, rituximab use versus no use, and intention to receive allogeneic SCT versus no plan for SCT. Following a protocol amendment related to the approval of blinatumomab therapy for patients with MRD-positive status, these patients were assigned (rather than randomized) to blinatumomab plus chemotherapy. Overall, 286 eligible patients were randomized or assigned to either the blinatumomab plus chemotherapy arm (n = 152) or the chemotherapy arm (n = 134) and included in the Step 3 analysis set. The outcomes relevant to this review include OS, RFS, and harms data collected at the June 23, 2023, data cut-off (DCO) date for the primary analysis.

In the E1910 trial, slightly more patients were female (51.4% versus 48.6% male), the mean age at enrolment was 49.9 years (standard deviation = 11.5 years), and patients were primarily white (79.4%), followed by Black or African American (5.9%), Asian (2.1%), American Indian or Alaska Native (1.0%), Native Hawaiian or other Pacific Islander (0.3%) (groupings from original study), and either not reported or unknown (4.5% and 6.6%, respectively). Most patients had an ECOG PS of 1 (58.7%), and 37.1% of randomized or assigned patients had an ECOG PS of 0. Overall, 224 (78.3%) of the randomized or assigned patients had MRD-negative status and were included in the full analysis set (FAS) (112 [73.7%] in the blinatumomab plus chemotherapy arm and 112 [83.6%] in the chemotherapy arm) and 62 (21.7%) had MRD-positive status and were included in the Step 3 MRD-positive analysis set (40 [26.3%] in the blinatumomab plus chemotherapy arm and 22 [16.4%] in the chemotherapy arm).

The AALL1731 trial was aimed at evaluating the efficacy and safety of blinatumomab for the treatment of pediatric patients with SR B-cell ALL. The primary end point was DFS, and the primary objective was to determine whether the addition of blinatumomab (administered as nonsequential cycles) to conventional chemotherapy would improve DFS in all randomized patients with SR B-cell ALL (patients either had an average or high risk of relapse on the basis of clinical features). A post hoc objective was to determine whether the addition of blinatumomab to conventional chemotherapy would improve OS in all randomized patients. All eligible patients received induction treatment before undergoing assessments for relapse risk and receiving 1 cycle of consolidation treatment. Only those with average (SR-average) and high risk (SR-high) of relapse were randomized 1:1 using stratified randomization (based on SR-average versus SR-high and a diagnosis versus no diagnosis of Down syndrome among those with SR-average risk) to blinatumomab plus conventional chemotherapy or conventional chemotherapy alone. Overall, 1,440 eligible patients were randomized to either the blinatumomab plus chemotherapy arm (n = 718) or the chemotherapy arm (n = 722). The outcomes relevant to this review include OS, DFS, and harms data collected at the interim analysis, with DCO date June 30, 2024.

At the planned interim analysis with the DCO date June 30, 2024, the Data Safety Monitoring Committee recommended that the blinatumomab randomization be permanently closed based on the 3-year DFS estimates of 96.0% (standard error [SE] = 1.2%) for the blinatumomab plus chemotherapy arm versus 87.6% (SE = 2.1%) for the chemotherapy alone arm. The associated hazard ratio (HR) was 0.39 (95% confidence interval [CI], 0.24 to 0.64), which exceeded the prespecified interim efficacy stopping criteria.

In the AALL1731 trial, the median age at randomization was 4.3 years (interquartile range [IQR], 2.8 to 6.4). Slightly more patients were male (52.6% [758 of 1,440] versus 47.5% female) and patients were primarily non-Hispanic white (50.4%), followed by Hispanic (25.8%), non-Hispanic Black (5.6%), non-Hispanic Asian (4.3%), or other or unknown (13.9%). Overall, 835 (58.0%) of randomized patients had SR-average (417 in the blinatumomab plus chemotherapy arm and 417 in the chemotherapy arm) and 605 (42.0%) had SR-high (304 in the blinatumomab plus chemotherapy arm and 301 in the chemotherapy arm).

Efficacy Results

Overall Survival

E1910 Trial

In the E1910 trial, the median duration of OS follow-up was 4.5 years in both arms of the Step 3 analysis set (i.e., the overall cohort randomized or assigned to 1 of the treatment arms), at which point 30 (of 152 patients; 19.7%) deaths had occurred in the blinatumomab plus chemotherapy arm and 53 (of 134 patients 39.6%) in the chemotherapy arm. The Kaplan-Meier (KM) estimate for median OS was NE in both arms, with a stratified HR of 0.47 (95% CI, 0.30 to 0.74). The between-group difference in the probability of survival for the blinatumomab plus chemotherapy arm versus the chemotherapy arm at 3 and 5 years was 16.9% (95% CI, 5.5% to 28.3%) and 20.8% (95% CI, 8.5% to 33.0%), respectively.

In the FAS (i.e., the MRD-negative cohort) of the E1910 trial, the median duration of OS follow-up was 4.5 years in both arms, at which point 19 (of 112 patients; 17.0%) deaths had occurred in the blinatumomab plus chemotherapy arm and 40 (of 112 patients; 35.7%) in the chemotherapy arm. The KM estimate for median OS was NE in both arms, with a stratified HR of 0.44 (95% CI, 0.25 to 0.76). The between-group difference in the probability of survival for the blinatumomab plus chemotherapy arm versus the chemotherapy arm at 3 and 5 years was 15.6% (95% CI, 3.0% to 28.2%) and 19.9% (95% CI, 6.3% to 33.5%), respectively.

In the Step 3 MRD-positive analysis set (i.e., the MRD-positive cohort) of the E1910 trial, the median duration of OS follow-up was 4.6 years in the blinatumomab plus chemotherapy arm and 5.0 years in the chemotherapy arm, at which point 11 (of 40 patients; 27.5%) deaths had occurred in the blinatumomab plus chemotherapy arm and 13 (of 22 patients; 59.1%) in the chemotherapy arm. The KM estimate for median OS was NE in the blinatumomab plus chemotherapy arm and was 1.9 months (95% CI, 0.6 months to NE) in the chemotherapy arm; the stratified HR was 0.40 (95% CI, 0.14 to 1.12). The between-group difference in the probability of survival for the blinatumomab plus chemotherapy arm versus the chemotherapy arm at 3 and 5 years was 31.1% (95% CI, 4.1% to 58.0%) and 32.3% (95% CI, 5.4% to 59.3%), respectively.

AALL1731 Trial

In the AALL1731 trial, the median duration of follow-up was 2.5 years (IQR, 1.6 to 3.2 years). Neither the KM estimate for median OS nor the HR were reported. The probability of survival from randomization to 3 years was 98.4% (SE = 0.8%) in the blinatumomab plus chemotherapy arm and 97.1% (SE = 1.1%) in the chemotherapy arm. Between-group differences were not reported. Subgroup analyses among the cohort with an average risk of relapse (probability of survival from randomization to 3 years was 100.0% [SE = not applicable] in the blinatumomab plus chemotherapy arm and 98.4% [SE = 1.0%] in the chemotherapy arm) and high risk of relapse (probability of survival from randomization to 3 years was 96.1% [SE = 2.0%] and 95.3% [SE = 2.2%], respectively) showed similar results.

Relapse-Free Survival

E1910 Trial

In the E1910 trial, the median duration of RFS follow-up was 4.5 years in both arms of the Step 3 analysis set, at which point 36 patients (of 152; 23.7%) had a relapse event in the blinatumomab plus chemotherapy arm and 56 patients (of 134; 41.8%) in the chemotherapy arm. The KM estimate for median RFS was NE in both arms, with a stratified HR of 0.53 (95% CI, 0.35 to 0.81). The between-group difference in the probability of RFS for the blinatumomab plus chemotherapy arm versus the chemotherapy arm at 1, 3, and 5 years was 12.2% (95% CI, 1.8% to 22.7%), 17.3% (95% CI, 5.6% to 28.9%), and 18.4% (6.3% to 30.6%), respectively.

In the FAS in the E1910 trial, the median duration of RFS follow-up was 4.5 years in both arms, at which point 25 patients (of 112; 22.3%) had a relapse event in the blinatumomab plus chemotherapy arm and 43 patients (of 112; 38.4%) in the chemotherapy arm. The KM estimate for median OS was NE in both arms, with a stratified HR of 0.53 (95% CI, 0.32 to 0.88). The between-group difference in the probability of RFS for the blinatumomab plus chemotherapy arm versus the chemotherapy arm at 1, 3, and 5 years was 8.2% (95% CI, –3.0% to 19.4%), 15.4% (95% CI, 2.3% to 28.4%), and 16.5% (95% CI, 2.6% to 30.3%), respectively.

In the Step 3 MRD-positive analysis set in the E1910 trial, the median duration of RFS follow-up was 4.6 years in the blinatumomab plus chemotherapy arm and 5.0 years in the chemotherapy arm, at which point 11 patients (of 40; 27.5%) had a relapse event in the blinatumomab plus chemotherapy arm and 13 patients (of 22; 59.1%) in the chemotherapy arm. The KM estimate for median OS was NE in the blinatumomab plus chemotherapy arm and was 0.6 months (95% CI, 0.2 months to NE) in the chemotherapy arm; the stratified HR was 0.37 (95% CI, 0.13 to 1.03). The between-group difference in the probability of RFS for the blinatumomab plus chemotherapy arm versus the chemotherapy arm at 1, 3, and 5 years was 38.0% (95% CI, 11.6% to 64.5%), 32.4% (95% CI, 6.1% to 58.7%), and 32.4% (95% CI, 6.1% to 58.7%), respectively.

AALL1731 Trial

RFS was not assessed in the AALL1731 trial.

Disease-Free Survival

E1910 Trial

DFS was not assessed in the E1910 trial.

AALL1731 Trial

In the AALL1731 trial, the median duration of follow-up was 2.5 years (IQR, 1.6 to 3.2 years). The probability of remaining disease-free from randomization to 3 years was 96.0% (SE = 1.2%) in the blinatumomab plus chemotherapy arm and 87.9% (SE = 2.1%) in the chemotherapy arm, and the associated HR was 0.39 (95% CI, 0.24 to 0.64). The between-group differences in the probability of DFS at 3 years and the KM estimate for median DFS were not reported. Subgroup analyses among the cohort with an average risk of relapse (probability of DFS from randomization to 3 years was 97.5% [SE = 1.3%] in the blinatumomab plus chemotherapy arm and 90.2% [SE = 2.3%] in the chemotherapy arm, with an associated HR of 0.33 [95% CI, 0.15 to 0.69]) and high risk of relapse (probability of survival from randomization to 3 years 94.1% [SE = 2.5%] and 84.8% [SE = 3.8%], respectively, with an associated HR of 0.45 [95% CI, 0.24 to 0.85]) showed similar results.

Harms Results

Safety outcomes for the E1910 trial were thoroughly reported in the data provided to the CDA-AMC review team and are summarized in this section. For the AALL1731 trial, only the occurrence of select grade 3 or greater treatment-emergent AEs (TEAEs) was available.

In the E1910 trial, harms data are summarized among the Step 3 safety analysis set, which includes all patients in the Step 3 analysis set who took at least 1 dose of protocol-specified therapies. Similarly, in the AALL1731 trial, harms data are summarized among all patients who underwent randomization, started postconsolidation protocol therapy, and had data submitted.

Treatment-Emergent AEs

E1910 Trial

In the E1910 trial, by the June 23, 2023, DCO, a similar percentage of patients in both treatment arms of the Step 3 safety analysis set experienced a TEAE (145 of 147 [98.6%] in the blinatumomab plus chemotherapy arm and 125 of 128 [97.7%] in the chemotherapy arm). The 3 most common TEAEs in the blinatumomab plus chemotherapy arm were investigations (e.g., blood cell counts; 91.8%), blood and lymphatic system disorders (e.g., anemia; 62.6%), and nervous system disorders (e.g., headache; 57.8%). In the chemotherapy arm, the 3 most common TEAEs were investigations (96.9%), blood and lymphatic system disorders (70.3%), and gastrointestinal disorders (e.g., diarrhea; 44.5%).

AALL1731 Trial

In the AALL1731 trial, TEAEs of any grade were not provided in the materials reviewed by the CDA-AMC review team.

Grade 3 or Greater TEAE

E1910 Trial

In the E1910 trial, a similar percentage of patients in both treatment arms of the Step 3 safety analysis set experienced a grade 3 or greater TEAE (141 of 147 [95.9%] in the blinatumomab plus chemotherapy arm and 125 of 128 [97.7%] in the chemotherapy arm). In the blinatumomab plus chemotherapy arm, the 3 most common grade 3 or higher TEAEs were the same as the 3 most common TEAEs of any grade (i.e., investigations [89.8%], blood and lymphatic system disorders [39.5%], and nervous system disorders [22.4%]). In the chemotherapy arm, the 3 most common grade 3 or higher TEAEs were investigations (96.1%), blood and lymphatic system disorders (57.0%), and infection and infestation (e.g., sepsis; 24.2%).

AALL1731 Trial

In the AALL1731 trial, the reporting of TEAEs was restricted to selected grade 3 or higher ones. Generally, it was reported that the percentage of selected grade 3 or higher TEAEs was well balanced across treatment arms. Notable differences included a higher percentage of patients in the blinatumomab plus chemotherapy arms of both the SR-average (47.0% [165 of 351]) and SR-high (57.1% [156 of 273]) cohorts who experienced febrile neutropenia than in the chemotherapy arm alone (39.6% [149 of 376] and 50.5% [140 of 277], respectively) and a higher percentage of patients in the blinatumomab plus chemotherapy arm in the SR-average cohort who experienced sepsis or catheter-related infection (14.8%) and other infections (32.8%) than in the chemotherapy arm alone (5.1% and 26.3%, respectively). In both SR-average and SR-high cohorts, the 3 most common selected grade 3 or higher TEAEs in the blinatumomab plus chemotherapy arms were febrile neutropenia (47.0% and 57.1%, respectively), other infection (32.8% and 35.2%, respectively), and sepsis or catheter-related infection (14.8% and 20.9%, respectively). In both SR-average and SR-high cohorts, the 3 most common selected grade 3 or higher TEAEs in the chemotherapy arms were febrile neutropenia (39.6% and 50.5%, respectively), other infections (26.3% and 37.9%, respectively), and mucositis (15.4% and 17.7%, respectively).

In both SR-average and SR-high subgroups, 1 patient in the blinatumomab plus chemotherapy group and no patient in the chemotherapy group experienced cytokine release syndrome of grade 3 or higher. In the SR-average subgroup, 3 (0.9%) and 4 (1.1%) patients experienced pancreatis of grade 3 or higher in the blinatumomab plus chemotherapy and chemotherapy groups, respectively. Patients in this subgroup experienced neurotoxic events of grade 3 or higher (seizure: 4 [1.1%] and 7 [1.9%]; all other CNS events: 2 [0.6%] and 3 [0.8%]; and peripheral neuropathy: 2 [0.6%] and 9 [2.4%] in the blinatumomab plus chemotherapy and chemotherapy groups, respectively). In the SR-high subgroup, 11 (4.0%) and 8 (2.9%) of patients experienced pancreatis of grade 3 or higher in the blinatumomab plus chemotherapy and chemotherapy groups, respectively. Patients in this subgroup experienced neurotoxic events of grade 3 or higher (seizure: 10 [3.7%] and 7 [2.5%]; all other CNS events: 3 [1.1%] and 4 [1.4%]; peripheral neuropathy: 6 [2.2%] and 2 [0.7%] in the blinatumomab plus chemotherapy and chemotherapy groups, respectively).

Withdrawals Due to AEs

E1910 Trial

In the E1910 trial, withdrawals due to AEs were not reported among the Step 3 safety analysis set; however, they were available for the Step 3 analysis set. Among patients included in the Step 3 analysis set, 14 of 152 patients (9.2%) in the blinatumomab plus chemotherapy arm discontinued treatment due to AEs, side effects, or complications, compared to 5 of 134 patients (3.7%) discontinuing due to AEs, side effects, or complications in the chemotherapy arm.

AALL1731 trial

In the AALL1731 trial, withdrawals due to AEs were not provided in the materials reviewed by the CDA-AMC team.

Treatment-Emergent Serious AEs

E1910 Trial

In the E1910 trial, a higher percentage of patients in the blinatumomab plus chemotherapy arm of the Step 3 safety analysis set experienced treatment-emergent serious AEs (SAEs) (82 of 147 [55.8%]) than in the chemotherapy arm (36 of 128 [28.1%]). The 3 most common treatment-emergent SAEs in the blinatumomab plus chemotherapy arm were infections and infestations (22.4%), investigations (15.6%), and nervous system disorders (15.0%). In the chemotherapy arm, the 3 most common treatment-emergent SAEs were infections and infestations (14.8%), blood and lymphatic system disorders (11.7%), and investigations (4.7%).

AALL1731 Trial

In the AALL1731 trial, treatment-emergent SAEs were not provided in the materials reviewed by the CDA-AMC team.

Fatal TEAEs

E1910 Trial

In the E1910 trial, a similar percentage of patients in both treatment arms of the Step 3 safety analysis set had a fatal TEAE (3 of 147 [2.0%] in the blinatumomab plus chemotherapy arm and 2 of 128 [1.6%] in the chemotherapy arm). In the blinatumomab plus chemotherapy arm, 2 of the fatal TEAEs were due to sepsis (1.4%) and 1 was due to intracranial hemorrhage (0.7%). In the chemotherapy arm, 1 of the fatal TEAEs was due to sepsis (0.8%) and 1 was due to cardiac arrest (0.8%).

AALL1731 Trial

In the AALL1731 trial, 5 patients had a fatal TEAE while in remission; all of these patients were classified as having high risk of relapse. Two of the patients were in the chemotherapy arm (both deaths were sepsis-related) and 3 patients were in the blinatumomab plus chemotherapy arm (1 death was due to sepsis, 1 was due to multiorgan failure, and 1 was due to hypoxic ischemic encephalopathy). None of the deaths occurred during blinatumomab cycles.

Notable Harms

E1910 Trial

In the E1910 trial, among TEAEs of special interest identified in the blinatumomab product monograph and highlighted as important by clinical experts consulted for this review, tumour lysis syndrome was not reported for the Step 3 safety analysis set. Cytokine release syndrome occurred in a higher percentage of patients in the blinatumomab plus chemotherapy arm (23 of 147 [15.6%]) than in the chemotherapy arm (0 of 128 [0.0%]). While infections were not stratified according to which were deemed serious, any infections and infestations occurred in a higher percentage of patients in the blinatumomab plus chemotherapy (34.7%) than in the chemotherapy arm (27.3%). However, most subcategories of infections of special interest (including Fusarium infection, fungal pneumonia, septic shock, Aspergillus infection, bronchopneumonia, Candida infection, enterococcal bacteremia, Escherichia sepsis, and lung infection) were not reported. Finally, relatively few patients in both treatment arms experienced neurotoxicity (2.4% versus 0.0%, respectively) or pancreatitis (0.0% and 0.8%, respectively).

AALL1731 Trial

In the AALL1731 trial, some of the TEAEs of special interest identified in the product monograph and highlighted as important by clinical experts consulted for this review are covered in the reporting of grade 3 or greater TEAEs. However, data on notable harms of any grade were not available.

Critical Appraisal

The E1910 and AALL1731 trials were both randomized, open-label, phase III studies. The open-label nature of both studies poses a risk of bias from lack of blinding. The risk of bias due to lack of blinding is minimal for objective outcomes such as OS. However, it remains for more subjectively assessed outcomes such as RFS, DFS, and AEs. While central laboratories reviewed and confirmed relapses in both studies to mitigate potential bias for RFS and DFS outcomes, assessment bias remains a risk for AEs.

As none of the analyses in the E1910 and AALL1731 trials were adjusted for multiple testing, there is an increased risk of type I error for statistically significant results.

All results from the E1910 and AALL1731 trials should be interpreted in light of the fact that they are based on interim analyses, which may overestimate the observed treatment effects for blinatumomab plus chemotherapy.¹¹ Additionally, data from both trials remained immature (59 of 94 planned OS events had occurred in the FAS of the E1910 trial and 81 of 194 planned DFS events had occurred in the overall cohort of the AALL1731 trial). Nonetheless, as the clinical experts consulted for this review with experience treating patients with ALL felt the chemotherapy arms in both studies performed as expected, bias resulting from the interim analysis effect and immature data were deemed to be minimal. Further, OS results in the AALL1731 trial and OS and RFS results in the Step 3 analysis set in the E1910 trial must be interpreted in light of the fact that these are from post hoc analyses, which are at risk of data manipulation. However, the results of the post hoc analyses were consistent with those observed for primary and secondary outcomes as well as with the clinical experts’ expectations regarding the performance of the control and intervention arms.

The outcomes measured in the E1910 and AALL1731 trials addressed the key treatment goals identified by patient and clinician group input submitted to CDA-AMC and were deemed to be relevant by the consulted clinical experts.

E1910 Trial

As a result of a protocol amendment in the E1910 trial, patients who were MRD-positive were assigned, rather than randomized, to the blinatumomab plus chemotherapy arm; this occurred as a result of updated evidence suggesting blinatumomab plus chemotherapy should be the new standard of care for MRD-positive patients.^12,13 As a result, a higher percentage of patients in the blinatumomab plus chemotherapy arm were MRD-positive. MRD-positive patients have a higher chance of relapse; however, the direction and magnitude of this potential selection bias is unclear.⁸

Baseline characteristics were generally similar in the Step 3 analysis set and the FAS. However, the distribution of most characteristics was not similar for patients in the Step 3 MRD-positive analysis set. The absence of randomization for the Step 3 MRD-positive analysis set increases the risk of imbalance in measured and unmeasured confounders, although, as mentioned, the magnitude and direction of the potential selection bias is hard to determine.

Stratified Cox proportional hazards models, adjusted for stratification factors, were used to estimate the HRs and CIs for OS and RFS. These models assume proportional hazards across treatment arms. Visual inspection of the KM curves by the CDA-AMC review team revealed the OS and RFS curves for the intervention and comparator treatment arms crossed multiple times and did not separate until approximately 4 and 6 months, respectively. While this suggests that the HRs may not reflect the treatment effect over time, it is more likely a result of variation in effects between the treatment and an active control during the early stages of treatment initiation. The KM curves remained separate for the remainder of the observation period, suggesting that the proportional hazards assumption was adequately met. Additionally, sensitivity analyses in the FAS using restricted mean survival time (RMST), which does not rely on the proportional hazards assumption, supported the results of the Cox proportional hazards models for OS and RFS.

The OS analysis in the Step 3 analysis set, the FAS, and the Step 3 MRD-positive analysis set indicated a survival benefit for the blinatumomab plus chemotherapy arm compared to the chemotherapy arm. However, its internal validity may have been influenced by the potential impact of postrelapse therapies. The OS analysis was based on the intention-to-treat (ITT) approach, which assumes that postrelapse therapies are nondifferentially distributed between groups — a condition that may not hold, given the observed disparities in postrelapse therapy use — and the OS analysis did not control or adjust for subsequent postrelapse therapy. While this approach improves generalizability of the OS results, there is potential for confounding by postrelapse therapy, especially considering the noted differences in the use of efficacious postrelapse therapies. Although the observed OS effect represents the combined impact of frontline blinatumomab plus chemotherapy plus subsequent treatments, the overall effect of the differences in use of postrelapse therapy was more likely to favour the chemotherapy alone arm.

The clinical experts consulted for this review with experience treating adult patients with ALL noted that the modified Dana-Farber Cancer Institute (DFCI) protocol is currently the most commonly used protocol to treat Ph-negative B-cell precursor ALL in Canadian clinical practice. The chemotherapy regimen used in E1910 is built upon the UKALLXII/E2993 chemotherapy regimen with dosing modifications based on the C10403 AYA trial, and no indirect treatment comparison was submitted, thus limiting the generalizability to the Canadian setting. However, the clinical expert consulted for this review with experience treating adult patients with ALL felt the efficacy, based on CR and OS, of the regimen used in E1910 was similar to the modified DFCI regimen.

AALL1731 Trial

Baseline characteristics were generally similar between treatment arms, except for MRD in peripheral blood on day 8 in both the SR-average and SR-high subgroups and for cytogenic risk group in the SR-high subgroup. More patients in the blinatumomab plus chemotherapy arm (41.5% and 40.5%) than patients in the chemotherapy arm (35.2% and 35.2%) in the SR-average and SR-high strata had 1% and greater MRD in peripheral blood on day 8. A smaller percentage of patients with SR-high risk in the blinatumomab plus chemotherapy arm had favourable cytogenetics (23.9% versus 31.6%), and a larger percentage had neutral cytogenetics (54.8% versus 48.7%). Both MRD and cytogenetic risk are well-established prognostic factors in ALL and influence treatment response and outcomes.^14-16 The highlighted differences indicate that a larger percentage of patients in the blinatumomab plus chemotherapy arm would be at higher risk of relapse and reduced survival. These could contribute to bias in the comparative outcomes between the treatment arms, potentially favouring chemotherapy.

Among randomized patients, more patients assigned to the blinatumomab plus chemotherapy arm did not start postconsolidation treatment (n = 55 of patients with SR-average risk and n = 20 of patients with SR-high risk) than in the chemotherapy arm (n = 27 of SR-average patients and n = 13 of SR-high risk). These patients were included in the ITT analyses, which are widely used in clinical trials to preserve randomization and provide an unbiased estimate of the treatment effect. The ability of ITT analyses to handle attrition bias depends on the context and the mechanisms of missing data. ITT analyses typically produce unbiased treatment estimates in situations where data are missing completely at random or missing at random, if appropriate methods are used to impute missing data (e.g., multiple imputation). However, in the case of data missing not at random, the ITT analysis may produce biased estimates. It was reported for the study that substantial or informative missingness was neither anticipated nor planned for, based on experience from a previous Children’s Oncology Group ALL trial. However, this assumption may be unrealistic, as the reasons for not initiating postconsolidation therapy vary across the risk strata and treatment groups, potentially leading to data that is not missing at random. Without additional information or results from analyses to determine whether data were missing not at random, it is not possible to determine the impact of attrition bias, if any. No data on treatment completion, discontinuation, dose modifications, and the use of off-protocol treatments were submitted to CDA-AMC for review. Therefore, a comprehensive assessment of attrition and adherence and their potential impact on outcomes could not be done.

The AALL1731 trial planned to use stratified Cox proportional hazards models, adjusted for stratification factors, to test DFS. Tests of the proportional hazards assumption, including the Schoenfeld residuals test (P = 0.031), a Wald test of time-varying interaction (P = 0.048), and a Kolmogorov-type supremum test (P = 0.068), suggested the assumption may not hold. Visual inspection of the KM curves showed no converging or crossing of the DFS curves but indicated that the treatment effect could have a delay of about 2 months before achieving a separation of the curves. In a sensitivity analysis, DFS was analyzed using the RMST method, which does not rely on the proportional hazards assumption and is an appropriate alternative survival analysis approach. Results for the RMST method, which does not rely on the proportional hazards assumption, supported the results of the Cox proportional hazards models for DFS.

Data completeness and transparency of reporting were limitations of the AALL1731 trial. Detailed patient disposition among randomized patients, the receipt of on- and off-protocol therapy, any TEAEs, withdraws due to AEs, treatment-emergent SAEs, and notable harms were not reported.

External Validity

While the comparators in the E1910 and AALL1731 trials were deemed to be acceptable by the clinical experts consulted for this review, blinatumomab is already publicly reimbursed for patients who are MRD-positive (per PC0204 CDA-AMC reimbursement review). No direct or indirect evidence was provided assessing the comparative efficacy of blinatumomab for the currently funded versus the currently being reviewed indication. The clinical experts consulted for this review indicated that, for MRD-positive patients, it is expected that blinatumomab for indications currently funded and currently being reviewed would have a similar efficacy. According to the clinicians consulted for this review, clinicians would likely prefer prescribing blinatumomab per the current review because of the ability to incorporate blinatumomab with chemotherapy and the lack of a requirement to complete 3 intensive chemotherapy blocks. In addition, clinical experts consulted for this review noted that the current review of blinatumomab adds value for patients who have lower levels of MRD (MRD of 0.01% to less than 0.1%, constituting an estimated 5% to 10% of patients as per clinical experts), who are excluded from the currently funded blinatumomab indication. On the other hand, in situations where pediatric patients cannot tolerate additional cycles of consolidation chemotherapy, blinatumomab per the currently funded indication allows for receipt of multiple cycles of blinatumomab to manage leukemia without requiring alternating treatment with consolidation chemotherapy. According to the clinical experts, the choice between both blinatumomab indications should be left to the treating clinician and the patient.

The evidence under review was restricted to a narrower population than the reimbursement request:

1. Age groups (E1910 and AALL1731 trials): While both trials restricted enrolment based on age (aged 30 to 70 years in the E1910 trial and aged 1 to < 10 years in the AALL1731 trial), the clinical experts consulted for this review felt the results of the AALL1731 trial could be generalized to those younger than 1 year and between 10 and 18 years, while the results of the E1910 trial could be generalized to those aged between 18 and 30 years and older than 70 years.

2. Risk groups (AALL1731 trial): The AALL1731 trial results were restricted to patients with SR B-cell ALL (defined as patients aged 1 year to less than 10 years at diagnosis and a white cell count of less than 50,000/µL) with an average or high risk of relapse after induction therapy. The clinical expert consulted for this review with experience treating pediatric patients with ALL noted that the definition of SR B-cell ALL is well established and felt the results among the cohort with a SR B-cell ALL and high risk of relapse (i.e., SR-high) could be generalized to patients with high-risk and very high–risk B-cell ALL. While no data were available among the cohort with a favourable risk of relapse, the clinical expert noted that these patients may not require treatment with blinatumomab, as the efficacy of chemotherapy in these patients is high. However, the clinical expert consulted for this review felt the decision to treat pediatric patients with SR-favourable risk should be left up to the treating physician.

3. MRD status (AALL1731 trial): Patients with SR-high risk after induction therapy who had MRD of 0.1% or greater were reassessed for MRD at the end of consolidation therapy, which is common practice, according to the clinical expert treating pediatric patients. Patients with an end-of-consolidation MRD of less than 0.1% were randomized; those with MRD of 0.1% to less than 1.0% (n = 14) were nonrandomly assigned to receive blinatumomab plus chemotherapy (results are not available); and those with MRD greater than 1% (n = 7) were removed from the trial. The clinical expert treating children agreed to generalize the results of patients with SR-high risk and MRD of less than 0.1% at the end of consolidation therapy to patients with MRD of 0.1% to less than 1.0%. The clinical expert treating children noted that the patient population with SR-high risk and end-of-consolidation MRD of 1% or greater (n = 7) was removed from the trial, as these patients reflect a rare and very high–risk subgroup with disease that is considered refractory and would be managed differently.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^17,18 Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. While literature-based thresholds were unavailable for the current review, the clinical experts consulted for this review provided estimates for clinically meaningful thresholds for all outcomes assessed using GRADE.

Findings from the E1910 trial were included in the GRADE assessments. Results from the AALL1731 trial were not appraised using GRADE, as only published results, rather than a formal Clinical Study Report, was provided to CDA-AMC, and the data were based on publicly available sources.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• OS (probabilities at 3 and 5 years) and RFS (probabilities at 1, 3, and 5 years) in the overall population (i.e., regardless of MRD status), MRD-negative, and MRD-positive populations

• harms (any grade 3 or greater TEAEs, treatment-emergent SAEs, and fatal AEs) in the overall population.

Table 2 presents the GRADE summary of findings for blinatumomab plus chemotherapy versus chemotherapy for adults with Ph-negative B-cell precursor ALL.

Long-Term Extension Studies

No long-term extension studies were submitted.

Indirect Comparisons

No indirect evidence was submitted.

Studies Addressing Gaps in the Evidence From the Systematic Review

No additional studies to address gaps within the systematic review evidence were submitted.

Table 2: Summary of Findings for Blinatumomab Plus Chemotherapy vs. Chemotherapy for Adults With Ph-Negative CD19-Positive B-Cell Precursor Acute Lymphoblastic Leukemia

CI = confidence interval; DCO = data cut-off; MRD = minimal residual disease; NR = not reported; OS = overall survival; RCT = randomized controlled trial; RFS = relapse-free survival; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aStep 3 analysis set: All 286 Step 3 randomized or registered patients combined, regardless of MRD status (152 patients in the blinatumomab plus chemotherapy arm and 134 patients in the chemotherapy arm).

^bEstimated via median time to KM censoring.

^cThe between-group difference in survival probability was requested from the sponsor to aid in the interpretation of the results for this end point.

^dCertainty was not rated down for indirectness or imprecision. Although limitations regarding internal validity were identified (open-label design, potential selection bias, results from interim analyses, and OS was conducted as a post hoc analysis), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. No empirically derived and validated minimal important difference (MID) was identified for the between-group difference in the probability of survival. The clinical experts consulted for this review suggested that a 5% between-group difference would be clinically meaningful, and this value was used as the threshold.

^eFAS: All 224 Step 3 randomized patients who are assessed as MRD-negative centrally after induction and intensification chemotherapy (112 patients in the blinatumomab plus chemotherapy arm and 112 patients in the chemotherapy arm).

^fCertainty was not rated down for indirectness. Although limitations regarding internal validity were identified (open-label design, results from interim analyses, and OS was conducted as a post hoc analysis), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. Rated down 1 level for imprecision. No empirically derived and validated MID was identified for the between-group difference in the probability of survival. The clinical experts consulted for this review suggested that a 5% between-group difference would be clinically meaningful, and this value was used as the threshold. The point estimate suggests clinically meaningful increases in OS at 3 years, while the lower bound of the 95% CI crosses the between-group difference threshold of 5%.

^gStep 3 MRD-positive analysis set: All 62 patients from Step 3 analysis set who are MRD-positive at Step 3 using the protocol-specified cut-off of 0.01% or less (40 patients in the blinatumomab plus chemotherapy arm and 22 patients in the chemotherapy arm).

^hCertainty was not rated down for indirectness. Although limitations regarding internal validity were identified (open-label design, potential selection bias, results from interim analyses, and OS was conducted as a post hoc analysis), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. Rated down 1 level for imprecision. No empirically derived and validated MID was identified for the between-group difference in the probability of survival. The clinical experts consulted for this review suggested that a 5% between-group difference would be clinically meaningful, and this value was used as the threshold. The point estimate suggests clinically meaningful increases in OS at 3 years, while the lower bound of the 95% CI crosses the between-group difference threshold of 5%. While results are from a relatively small sample (n = 62), certainty was not further rated down due to imprecision as this limitation was determined to have a small or no impact on the results.

ⁱCertainty was not rated down for indirectness or imprecision. Although limitations regarding internal validity were identified (open-label design, results from interim analyses, and OS was conducted as a post hoc analysis), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. No empirically derived and validated MID was identified for the between-group difference in the probability of survival. The clinical experts consulted for this review suggested that a 5% between-group difference would be clinically meaningful, and this value was used as the threshold.

^jCertainty was not rated down for indirectness. Although limitations regarding internal validity were identified (open-label design, potential selection bias, results from interim analyses, and OS was conducted as a post hoc analysis), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. While results are from a relatively small sample (n = 62), certainty was not rated down due to imprecision as the limitations were determined to have a small or no impact on the results. No empirically derived and validated MID was identified for the between-group difference in the probability of survival. The clinical experts consulted for this review suggested that a 5% between-group difference would be clinically meaningful, and this value was used as the threshold.

^kCertainty was not rated down for indirectness. Although limitations regarding internal validity were identified (open-label design, potential selection bias, and results from interim analyses), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. No empirically derived and validated MID was identified for the between-group difference in the probability of remaining relapse-free. The clinical experts consulted for this review suggested that a 5% to 7% between-group difference would be clinically meaningful and this range was used as the threshold. Rated down 1 level for imprecision. The point estimate suggests clinically meaningful increases in RFS at 1 year, while the lower bound of the 95% CI crosses the between-group difference threshold of 5% to 7%.

^lCertainty was not rated down for indirectness. Although limitations regarding internal validity were identified (open-label design and results from interim analyses), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. No empirically derived and validated MID was identified for the between-group difference in the probability of remaining relapse-free. The clinical experts consulted for this review suggested that a 5% to 10% between-group difference would be clinically meaningful, and this range was used as the threshold. Rated down 1 level for imprecision. The point estimate suggests clinically meaningful increases in RFS at 1, 3, and 5 years while the lower bound of the 95% CI crosses the between-group difference threshold of 5% to 10%.

^mCertainty was not rated down for indirectness. Although limitations regarding internal validity were identified (open-label design, potential selection bias, and results from interim analyses), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. No empirically derived and validated MID was identified for the between-group difference in the probability of remaining relapse-free. The clinical experts consulted for this review suggested that a 5% to 10% between-group difference would be clinically meaningful, and this range was used as the threshold. While results are from a relatively small sample (n = 62), certainty was not rated down due to imprecision as this limitation was determined to have a small or no impact on the results.

ⁿCertainty was not rated down for indirectness. Although limitations regarding internal validity were identified (open-label design, potential selection bias, and results from interim analyses), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. No empirically derived and validated MID was identified for the between-group difference in the probability of remaining relapse-free. The clinical experts consulted for this review suggested that a 5% to 7% between-group difference would be clinically meaningful, and this range was used as the threshold. The point estimate and upper bound of the 95% CI suggests clinically meaningful increases in RFS at 3 and 5 years. The lower bound of the 95% CI is higher than the lower limit of the between-group difference threshold (5%), and, thus, certainty was not rated down; however, if the upper limit of the threshold (7%) is used certainty would be rated down due to imprecision.

^oCertainty was not rated down for indirectness. Although limitations regarding internal validity were identified (open-label design, potential selection bias, and results from interim analyses), certainty was not rated down for risk of bias because the limitations were determined to have a small or no impact on the results. No empirically derived and validated MID was identified for the between-group difference in the probability of remaining relapse-free. The clinical experts consulted for this review suggested that a 5% to 10% between-group difference would be clinically meaningful and this range was used as the threshold. The point estimate and upper bound of the 95% CI suggests clinically meaningful increases in RFS at 3 and 5 years. The lower bound of the 95% CI is higher than the lower limit of the between-group difference threshold (5%), and, thus, certainty was not rated down; however, if the upper limit of the threshold (10%) is used certainty would be rated down due to imprecision. While results are from a relatively small sample (n = 62), certainty was not rated down due to imprecision as this limitation was determined to have a small or no impact on the results.

^pStep 3 safety analysis set: All 275 patients in the Step 3 analysis set who took at least 1 dose of protocol-specified therapies (147 patients in the blinatumomab plus chemotherapy arm and 128 patients in the chemotherapy arm).

^qCertainty was not rated down for indirectness or imprecision. Rated down 1 level for risk of bias. Due to the open-label nature of the study, there is substantial risk of bias for subjective outcomes. No empirically derived and validated MID was identified for the between-group difference in the incidence of any grade 3 or greater TEAE. The clinical experts consulted for this review suggested that a 10% between-group difference would be clinically meaningful, and this value was used as the threshold.

^rCertainty was not rated down for indirectness or imprecision. Rated down 1 level for risk of bias. Due to the open-label nature of the study there is substantial risk of bias for subjective outcomes. No empirically derived and validated MID was identified for the between-group difference in the incidence of treatment-emergent SAE. The clinical experts consulted for this review suggested that a 10% to 15% between-group difference would be clinically meaningful, and this range was used as the threshold.

^sCertainty was not rated down for indirectness. Rated down 1 level for risk of bias. Due to the open-label nature of the study there is substantial risk of bias for subjective outcomes. Rated down 2 levels for imprecision. No empirically derived and validated MID was identified for the between-group difference in the incidence of fatal TEAEs. The clinical experts consulted for this review suggested that a greater than 0% between-group difference would be clinically meaningful and this value was used as the threshold. The point estimate suggests clinically meaningful increases in fatal TEAEs, while the upper and lower bounds of the 95% CI cross the between-group difference threshold of 0% suggested by clinical experts. Given the small number of events, there is substantial uncertainty in the between-group difference.

Source: BLINCYTO Clinical Study Report.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Conclusions

The E1910 (adult-only population) and the AALL1731 (pediatric-only population) trials were phase III, open-label, multicentre, international studies aimed at evaluating the efficacy and safety of blinatumomab used in the consolidation phase of multiphase chemotherapy for the treatment of patients with Ph-negative B-cell precursor ALL.

A post hoc analysis in the E1910 trial aligned with the target patient population under review, which consists of patients with MRD-agnostic, Ph-negative, B-cell precursor ALL. The results of the post hoc analysis showed that blinatumomab plus chemotherapy demonstrated clinically meaningful improvements in OS and RFS compared to chemotherapy, with high to moderate certainty of evidence across different time points. The E1910 trial met its primary end point, with statistically significant improvements in OS favouring the blinatumomab plus chemotherapy group in MRD-negative patients. Secondary analyses for OS in MRD-positive patients and RFS in MRD-negative or MRD-positive patients were supportive of the benefit observed with blinatumomab plus chemotherapy over chemotherapy in the primary analyses, with high to moderate certainty of evidence across different time points. Post hoc analyses are at risk of data manipulation; however, results of the post hoc analyses were consistent with those for the primary (OS) and secondary (RFS) outcomes in patients with MRD-negative disease, mitigating concerns about data validity.

The primary analysis in the AALL1731 trial for the overall trial population aligned with the present target patient population and suggested clinically meaningful improvements in DFS with blinatumomab plus chemotherapy compared to chemotherapy. Post hoc analyses for OS suggested little to no difference between blinatumomab plus chemotherapy compared to chemotherapy in the target patient population. Post hoc analyses are at risk of data manipulation; however, results of the OS post hoc analyses were consistent with clinical expectations, based on input from the clinical experts consulted by CDA-AMC, mitigating concerns about data validity. DFS and OS results for populations with SR-average and SR-high risk category were overall consistent with the results observed in the overall trial population. GRADE assessment was not conducted for results of the AALL1731 trial, as only limited public data were available.

According to clinical experts consulted for this review, the harms profile of blinatumomab plus chemotherapy was consistent with their expectations, given the known AEs.

While blinatumomab is currently reimbursed for patients with Ph-negative CD19-positive B-cell precursor ALL with MRD-positive disease, the clinical experts consulted for this review anticipated similar efficacy for the indications currently funded and being reviewed. According to the clinical experts, both options provide unique advantages, and, therefore, the choice between these 2 options should be left to the treating physician and patient.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of blinatumomab, 28 mcg per day for adult patients weighing 45 kg or more and 15 mcg/m² per day for adult patients weighing less than 45 kg and pediatric patients, lyophilized powder for solution, IV infusion by infusion pump in the treatment of Ph-negative CD19-positive B-cell precursor ALL in the consolidation phase of multiphase chemotherapy in the frontline setting.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

ALL is a rare and aggressive hematologic malignancy of undifferentiated lymphoid precursors characterized by the proliferation of immature and abnormal lymphoid cells in the bone marrow and peripheral blood.¹ The proliferation of these immature and abnormal lymphoid cells in the bone marrow subsequently prevails over the production of normal bone marrow elements, ultimately resulting in decreased red blood cells, white blood cells, and platelet counts.²⁰ Common symptoms of ALL include fatigue, reduced energy, dry mouth, lack of appetite, and sweating, along with psychological symptoms such as irritability, nervousness, and sadness.⁹

In 2019 alone, 440 new cases of ALL were diagnosed in Canada (excluding Quebec), resulting in an age-standardized incidence rate of 1.5 per 100,000 Canadians.² Between 2015 to 2017, the 5-year net survival for patients in Canada aged 15 to 99 years was 47%,³ with improved survival rates among younger patients.²¹ While ALL is the least common type of leukemia in adults, it is the most prevalent cancer among children and young adults.⁴ In Canada, ALL accounts for 75% of all childhood cancers and over half of the new ALL cases in 2019 occurred in Canadians aged 19 years of age and under.³ The annual incidence rate of ALL among children under the age of 15 years is 3 to 4 new cases per 100,000 children.²²

WHO classifies ALL based on the type of lymphocytes affected and specific gene or chromosomal changes in the leukemia cells.²³ The 2 major subtypes of ALL based on lymphocytes are B-lymphoblastic (B-cell) and T-lymphoblastic leukemia.^24,25 B-cell phenotypes are the most common, accounting for approximately 85% of pediatric ALL cases and around 75% of adult ALL cases.^5,6 The leukemia cells in many patients with B-cell ALL have chromosomal abnormalities with 1 of the most prevalent abnormalities occurring in the Philadelphia chromosome (occurring in 1% to 3% of childhood ALL cases and 11% to 29% of adult ALL cases).⁷ According to the Surveillance, Epidemiology, and End Results (SEER) database in the US, the 5-year OS between 2010 and 2017 for adult and pediatric patients was 72% for ALL (overall) and 73% for patients with Ph-negative ALL; when focusing only on pediatric patients aged 0 to 14 years, the corresponding estimates were 93% in both cohorts, with an inverse relationship observed between age and survival age categories.²¹

While there is no standard staging system, ALL is commonly classified as untreated (newly diagnosed patients who have not been treated yet), remission (patients who are treated and are in remission), relapsed (leukemia has come back after treatment), or refractory (ALL did not respond to treatment).⁴ The Toronto Pediatric Cancer Stage Guidelines describe ALL using a 2-tier staging system, with Tier 1 categorizing patients based on central nervous system (CNS)–positive and CNS-negative status and Tier 2 categorizing patients based on no CNS involvement and no blasts in cerebrospinal fluid (CSF) (CNS-1), no CNS involvement and blasts in CSF (CNS-2), and CNS involvement and blasts in CSF (CNS-3).²⁶

Determining the ALL subtype and presence of chromosomal abnormalities is critical for understanding the disease status, risk factors, and treatment planning. According to the Canadian Cancer Society, the prognostic factors for ALL include age, white blood cell count, ALL classification, chromosome changes, and presence of leukemia cells in the CNS and early relapse.⁴ ALL diagnoses typically begin with a review of the patient’s health history, followed by a physical exam.²⁷ Alberta Health Services Guidelines recommend that leukemia diagnoses be based on the results of bone marrow studies incorporating morphological assessment, immunophenotyping, cytogenetic, fluorescent in situ hybridization (FISH), and molecular evaluation.⁸ MRD assessment provides information on the prognosis and chance of relapse, with higher MRD levels indicating greater chance of relapse.⁸

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

The treatment of Ph-negative B-cell precursor ALL typically includes 3 phases: induction, consolidation (sometimes called “intensification”), and maintenance.⁴ While treatment regimens differ in terms of specific drug selection, dosing, and duration, most regimens include vincristine, asparaginase, corticosteroids (dexamethasone is often preferred to prednisone, as it penetrates the blood-brain barrier and acts on resting leukemic blast cells), immune modulators (methotrexate), and anthracycline (daunorubicin, doxorubicin, idarubicin), with or without cyclophosphamide or cytarabine.²⁸ Details of specific regimens identified by clinical experts consulted for this review as commonly used in Canada for ALL are summarized in Table 3. Patients are stratified according to risk characteristics (i.e., age, white blood cell count at diagnosis, CNS and/or testicular disease, genetic abnormalities, and MRD after induction therapy) to ensure that the appropriate intensity of treatment is administered to patients with high risk of relapse, while avoiding unnecessary toxicity.^25,29,30 At diagnosis, pediatric patients with ALL are categorized into 3 risk groups:³¹

• SR, defined as children aged 1 to less than 10 years who have a white blood cell count less than 50,000/µL of blood at the time of diagnosis and absence of CNS or testicular disease

• high risk, defined as children aged 10 and older and/or children who have a white blood cell count of 50,000/µL of blood or more at the time of diagnosis

• very high risk, defined as children under 1 year of age, children identified by certain genetic changes in their leukemia, children who have a slow improvement from initial treatment, and children who have signs of leukemia after the first 4 weeks of treatment.

Throughout all phases, CNS prophylaxis is given to prevent ALL from spreading to the CNS.²⁵ The entire Ph-negative B-cell ALL treatment may take more than 2 years.

Induction Therapy

Induction is the first phase of treatment and is typically initiated in the hospital.²⁵ During this phase, a multidrug combination of chemotherapies and steroids are typically used with the goal of achieving a CR, defined as less than 5% of blasts remaining.⁴

At the completion of induction therapy, bone marrow aspirates and biopsies are used to determine whether CR has been achieved, and, if it has been achieved, MRD status is assessed.^13,25 MRD quantification is an essential component of patient evaluation over the course of sequential ALL therapy, as previous studies have demonstrated a strong correlation between the presence of MRD and the risk of relapse.³²

Consolidation Therapy

The objectives of consolidation treatment for ALL are to enhance and solidify the initial response achieved through induction chemotherapy while minimizing the risk of relapse.⁴ High doses of chemotherapy are the primary consolidation treatment, and many of the same drugs received during induction are given during consolidation.

Children with SR are assigned to 3 risk-of-relapse groups based on tumour genetics, CNS status, and MRD:

• SR-favourable includes those with favourable cytogenetics (ETV6: RUNX1 or double trisomies of chromosomes 4 and 10 [DT]), and end-of-induction bone marrow MRD less than 0.01%.

• SR-high includes those with unfavourable cytogenetics (iAMP21, KMT2A rearrangement, t(17;19), hypodiploidy), end-of-induction MRD of 0.01% or greater, or neutral cytogenetics with CNS-2 status.

• All others are classified as SR-average.

Children with SR-favourable and SR-average disease typically receive conventional consolidation treatment with some combination of vincristine, mercaptopurine, methotrexate, doxorubicin, dexamethasone, pegaspargase, cyclophosphamide, cytarabine, thioguanine, and intrathecal methotrexate. Children assigned to SR-high, high risk, and very high–risk groups receive consolidation treatment with the same drugs, albeit at a stronger dose and for a longer period of time.

In adult patients with MRD-positive disease, Alberta Health Services recommends consolidation treatment with immunotherapy using 1 to 2 cycles of blinatumomab.⁸ MRD-positive adult patients may be considered for allogeneic SCT.^8,13

Blinatumomab is currently Health Canada–approved and publicly funded for the treatment of patients with Ph-negative CD19-positive B-cell precursor ALL in first or second hematologic CR with MRD greater than or equal to 0.1%. Under the currently funded indication, adult and pediatric patients can receive treatment with up to 4 sequential cycles of blinatumomab if they have previously received at least 3 intensive chemotherapy blocks of treatment that are age-appropriate. The indication currently funded for blinatumomab partially overlaps with the indication currently under review. Differences between the indication currently funded versus that currently being reviewed for blinatumomab in patients who are MRD-positive include remission status (first and second remission versus first remission), MRD restrictions (great than or equal to 0.1% versus no MRD restriction), administration schedule (sequential cycles versus alternating with consolidation chemotherapy), and number of cycles of blinatumomab treatment for pediatric patients (maximum of 4 versus 2 cycles of blinatumomab).

Maintenance Therapy

Maintenance therapy is the final and usually the longest phase of treatment. The objective of this phase is to kill more cancer cells and stop any remaining leukemia cells from growing.⁴ Regimens are typically less intensive than prior chemotherapy and are given in an outpatient setting with the goal of reducing the risk of relapse.

Maintenance therapy for pediatric patients with ALL typically include vincristine, dexamethasone, mercaptopurine, and methotrexate.

Table 3: Chemotherapy Regimens Used in Canada for Ph-Negative B-Cell Precursor ALL Treatment

COG = Children’s Oncology Group; ALL = acute lymphoblastic leukemia; DFCI = Dana-Farber Cancer Institute; IT = intrathecal; Ph = Philadelphia chromosome.

Source: National Comprehensive Cancer Network (NCCN) guidelines, 2024.³³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Drug Under Review

Key characteristics of blinatumomab are summarized in Table 4 with other treatments available for the treatment of patients with Ph-negative CD19-positive B-cell precursor ALL.

Blinatumomab 28 mcg/day for patients weighing 45 kg or more and 15 mcg/m² per day (not to exceed 28 mcg/day) for patients weighing less than 45 kg as a continuous IV infusion delivered at a constant flow rate using an infusion pump received Health Canada authorization for the treatment of patients with Ph-negative CD19 positive B-cell precursor ALL in the consolidation phase of multiphase chemotherapy. A single cycle of treatment is 28 days (4 weeks) of continuous IV infusion followed by a 14-day (2-week) treatment-free interval. As per the blinatumomab product monograph, the safety and efficacy of blinatumomab have been established in pediatric patients (as young as 1 month to less than 18 years of age) with Ph-negative relapsed or refractory B-cell ALL. The safety and efficacy of blinatumomab have not been established in pediatric patients under 1 month of age.³⁴ A Notice of Compliance (NOC) was issued on December 27, 2024.

The Health Canada–approved indication is for blinatumomab as consolidation treatment for Ph-negative CD19 B-cell ALL, regardless of age (pediatric and adult patients), MRD status, or line of treatment. The sponsor’s reimbursement request is for the treatment of adult and pediatric patients with Ph-negative CD19-positive B-cell precursor ALL in the consolidation phase of multiphase chemotherapy in the frontline setting. The sponsor’s reimbursement request differs from the Health Canada indication in that it is limited to patients in the frontline setting, while remaining consistent with the Health Canada indication regarding age and MRD status. In Canada, blinatumomab is currently Health Canada–authorized for the treatment of:

• patients with Ph-negative CD19-positive B-cell precursor ALL in the consolidation phase of multiphase chemotherapy

• patients with Ph-negative CD19-positive B-cell precursor ALL in first or second hematologic CR with MRD greater than or equal to 0.1%; to be selected for treatment based on detection of MRD as determined by an accredited laboratory using validated assay methods

• adult patients with relapsed or refractory B-cell precursor ALL

• pediatric patients with Ph-negative relapsed or refractory B-cell precursor ALL.

Blinatumomab has been previously reviewed by CDA-AMC for the treatment of:

• patients with Ph-negative CD19-positive B-cell precursor ALL in first or second hematologic CR with MRD greater than or equal to 0.1% (final recommendation to reimburse for adult and pediatric patients with clinical criteria and/or conditions, issued on October 29, 2020)

• adult patients (i.e., 18 years of age or older) with Ph-positive B-cell precursor ALL, who have relapsed after or are refractory to at least 1 second-generation or later tyrosine kinase inhibitor, or are intolerant to second-generation or later tyrosine kinase inhibitors and intolerant or refractory to imatinib (final recommendation to reimburse with clinical criteria and/or conditions, issued on April 4, 2019)

• pediatric patients with Ph-negative relapsed or refractory B-cell precursor ALL (final recommendation to reimburse for those who are in second or later relapse, who relapsed after allogeneic hematopoietic SCT, or who have refractory disease with clinical criteria and/or conditions, issued on August 23, 2017)

• patients with Ph-negative relapsed or refractory B-cell precursor ALL (final recommendation to reimburse for adult patients with clinical criteria and/or conditions, issued on August 31, 2017)

• patients with Ph-negative relapsed or refractory B-cell precursor ALL (final recommendation to not reimburse for adults who have only had 1 prior systemic chemotherapy and to reimburse with clinical criteria and/or conditions for adults those who have had at least 2 prior lines of systemic therapy, issued on April 1, 2016).

Blinatumomab is a bispecific T-cell engager molecule that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor complex with CD19 on benign and malignant B-cells, including B-cell precursor ALL cells. The antitumour activity of blinatumomab immunotherapy is not dependent on T-cells bearing a specific T-cell receptor or on peptide antigens presented by cancer cells but is polyclonal in nature and independent of human leukocyte antigen molecules on target cells. Blinatumomab mediates the formation of a cytolytic synapse between the T-cell and the tumour cell, releasing proteolytic enzymes (such as perforin and granzymes) to kill both proliferating and resting target cells, which closely resembles a natural cytotoxic T-cell reaction. Blinatumomab is associated with transient upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, resulting in elimination of CD19-positive cells.

In B-cell ALL, CD19 is typically present on leukemic cells, making it a valuable target for immunotherapies like blinatumomab. Clinical trials for blinatumomab may not require patient selection based on CD19 status, as CD19 expression is generally assumed in B-cell ALL cases. Instances of CD19-negative B-cell ALL are extremely rare.³⁵

Testing Procedure Considerations

The current standard of care in Canada for adult and pediatric patients with Ph-negative CD19-positive B-cell precursor ALL in first or second hematologic CR is to determine eligibility for blinatumomab as a consolidation therapy based on MRD positivity.^8,49,50 MRD refers to the presence of subclinical disease detected after a patient with ALL has reached CR morphologically.^33,51 MRD positivity is defined by the sponsor as greater than or equal to 0.1% mononuclear cells.³⁴ If blinatumomab becomes funded regardless of the MRD status, as per the new indication under review, MRD testing would no longer be needed as a companion diagnostic. The sponsor mentioned that, although blinatumomab use regardless of the MRD status is anticipated to become the preferred approach (i.e., all patients who reach CR after induction should be offered blinatumomab), blinatumomab use based on MRD positivity, as per the previous indication, should still be an option, with the choice between treatment approaches up to the clinician and patient.⁵² In addition, the clinical experts consulted for this review noted that MRD testing should still be conducted before and during treatment with blinatumomab to risk stratify, to prognosticate outcomes, and to guide disease management, including as part of multifactorial decisions around discontinuing treatment to proceed with allogeneic stem cell transplant.^33,51,53-56

Table 4: Key Characteristics of Blinatumomab and Regimens Used in the Modified DFCI Protocol and COG Protocol

ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; b.i.d. = twice daily; CNS = central nervous system; COG = Children’s Oncology Group; DFCI = Dana-Farber Cancer Institute; GI = gastrointestinal; IM = intramuscular; MRD = minimal residual disease; Ph = Philadelphia; p.o. = per oral; RNA = ribonucleic acid; SR = standard risk.

^aHealth Canada–approved indication.

^bThe protocols for the modified DFCI were informed by Alberta Health Services for the adult population²⁵ and Vrooman et al. for the pediatric population.³⁶ The clinical experts consulted for this review confirmed both DFCI protocols matched those currently used in Canadian clinical practice. The Children’s Oncology Group protocol was informed by the clinical expert consulted for this review with experience treating children in all.

Source: Draft product monograph for blinatumomab (Blincyto)³⁴ and product monographs for vincristine,³⁷ cyclophosphamide,³⁸ cytarabine,³⁹ dexamethasone,⁴⁰ daunorubicin,⁴¹ doxorubicin,⁴² etoposide,⁴³ methotrexate,⁴⁴ 6-mercaptopurine (Purinethol),⁴⁵ pegaspargase (Oncaspar),⁴⁶ prednisone,⁴⁷ thioguanine.⁴⁸

According to the clinical experts consulted for this review, multiparameter flow cytometry is the only method currently available in Canada for MRD testing. Flow cytometry analyzes cells as they flow in a stream through a beam of light. Individual cell types can be identified by conjugating a fluorescent dye to a monoclonal antibody. Multiparameter flow cytometry uses multiple fluorescent dyes to detect a variety of markers that may be found on leukemic cells.⁵⁷ MRD testing by flow cytometry requires fresh cellular materials obtained through a bone marrow biopsy.⁵³ Samples need to be tested by the receiving laboratory within 24 to 48 hours of collection to ensure viability of the cells.⁵³ MRD testing using flow cytometry is not standardized in Canada, and, therefore, policies, procedures, and equipment sensitivity can differ among leukemia or cancer centres.⁵³ MRD testing by flow cytometry requires the expertise of a highly trained pathologist to correctly interpret the results.^53,58 Laboratories in Canada that perform flow cytometry for MRD testing can detect the presence of residual cancer cells with a sensitivity threshold of 10^–3 cells (i.e., 1 cancer cell among 1,000 bone marrow cells or 0.1%), although some laboratories are able to detect up to 10^–4 cells (i.e., 1 cancer cell among 10,000 bone marrow cells or 0.01%).⁵³ As well, the panel of antibodies used to detect leukemia cell markers may differ between laboratories.⁵³ The clinical experts, however, confirmed that the panels should be relatively equal in their ability to detect leukemia cells. Molecular methods used for testing the MRD status, such as real time quantitative polymerase chain reaction and next-generation sequencing, are not yet available in Canada, although they are in use and standardized in other countries.^{33,51,53,58-60} Molecular methods can detect MRD at higher sensitivities than flow cytometry can, but they are more expensive, have longer turnaround times, and require an index pretreatment analysis using the diagnostic biopsy sample.^58,59

CDA-AMC considered the potential impacts of MRD testing in adult and pediatric patients with Ph-negative CD19-positive B-cell precursor ALL if blinatumomab becomes funded in the consolidation phase of multiphase chemotherapy in the frontline setting, regardless of the MRD status, including impacts to health systems, patients (including families and caregivers), and costs. While MRD testing is widely available and routinely performed, it might not be consistently funded across jurisdictions in Canada. Key considerations and relevant information available from materials submitted by the sponsor, input from the clinical experts consulted by the review team, and sources from the literature were validated by the review team when possible and are summarized in Table 5.

Table 5: Considerations for MRD Testing in Adult and Pediatric Patients With Ph-Negative CD19-Positive B-Cell Precursor ALL in the Consolidation Phase of Multiphase Chemotherapy in the Frontline Setting

ALL = acute lymphoblastic leukemia; CR = complete remission; MRD = minimal residual disease; NGS = next-generation sequencing; PCR = polymerase chain reaction; Ph = Philadelphia chromosome.

^aCanada’s Drug Agency has not evaluated or critically appraised this evidence to determine its validity or reliability.

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

CDA-AMC received 2 inputs for this submission. The first input, provided by LLSC, included survey results of adult patients with ALL and their caregivers. The second input was a joint submission provided by LLSC, Ac2orn, OPACC, and Childhood Cancer Canada and was based on interviews with 3 caregivers of pediatric patients with B-cell ALL who received blinatumomab treatment. The patient group input for pediatric patients was supplemented with information on disease experience and experience with currently available treatments, gathered from previous patient group submissions to CDA-AMC for blinatumomab for pediatric patients with Ph-negative B-cell precursor ALL in the relapsed or refractory setting (pCODR 10099 Blinatumomab ALL for pediatrics in 2017 and PX0367 Blinatumomab for ALL for pediatrics in 2024).

LLSC is a national charitable organization dedicated to finding a cure for blood cancers and improve the quality of life of people affected by blood cancers and their families by funding research and providing educational resources, services, and support. Ac2orn is a national organization committed to advocating for translational research and effective treatments to realize the goal of curing cancers in children, adolescents, and young adults. OPACC advocates for families and organizations navigating the childhood cancer journey. Childhood Cancer Canada supports children diagnosed with cancer and their families.

Input received for adults with ALL is summarized first followed by patient input from caregivers of pediatric patients with ALL.

LLSC conducted a survey in October and November 2024. The respondents were patients with ALL (69%) and their caregivers (28%). Out of 103 respondents providing their age, 9% were aged 0 to 17 years and were disqualified from the survey. The survey respondents included 49% aged 18 to 39 years, 32% aged 40 to 64 years, 8% aged 65 to 74 years, and 3% aged 75 years or older. Among 82 adults providing responses, most were from Canada, 1 was from the US, and 1 was international. A negative to very negative impact on personal or home life due to ALL was reported by 82% of respondents. When considering their social life, 75% of respondents reported negative to very negative impacts due to ALL. Low energy, fear of infections, frequent hospital visits, depression and/or anxiety, ALL symptom burden, and inadequate nutrition were reported as factors contributing to negative impacts of ALL. Eighteen respondents had experience with blinatumomab. Among all other types of treatment, chemotherapy was the most commonly reported type of ALL treatment (98% of respondents) followed by SCT (48% of respondents), radiation therapy (45% of respondents), immunotherapy (27% of respondents), targeted therapy (7% of respondents), CAR T-cell therapy (5% of respondents), and other types (16% of respondents; included natural medicine, Chinese medicine, sound baths, meditation, transfusions steroids, and antiemetics). Fatigue and neutropenia were reported by the respondents as the most severe side effects of current treatments (excluding blinatumomab), followed by thrombocytopenia, infections, nausea, vomiting, diarrhea, anemia, fever, peripheral edema, headaches, infusion reactions, neurologic symptoms, and cytokine release syndrome. These side effects had substantial impacts on patients’ lives, including frequent hospitalizations and lower functionality. LLSC added that the most important outcomes for patients include gaining longer remission with consideration of side effects, quality of life, and financial costs.

According to LLSC, 18 respondents stated that they or the person they care or cared for were treated with blinatumomab for ALL. The methods of access were primarily through clinical trials (33%) and compassionate use programs (27%); the remainder of patients accessed blinatumomab through private insurance, Régie de l'assurance maladie du Québec (RAMQ) — Quebec socialized health care, government funding, or they did not know. Out of 15 respondents, 67%, 20%, and 13% of respondents believed that their ALL completely, partially, or did not respond to blinatumomab, respectively. Respondents were asked to rate the severity of the side effects of blinatumomab (from 1 — did not experience to 4 — severe). Among 15 respondents, the highest-rated side effects, as measured by weighted averages, were neutropenia (2.29), fatigue or weakness (2.27), and fever (2), followed by anemia (1.71), thrombocytopenia (1.71), infections (1.64), headaches (1.57), neurologic symptoms (i.e., confusion, seizures, difficulty speaking; 1.53), cytokine release syndrome (1.5), diarrhea (1.47), peripheral edema (1.47), nausea or vomiting (1.4), and infusion reactions (i.e., chills, rash, difficulty breathing; 1.27). In terms of comparing blinatumomab to other treatments, among 15 respondents, 40% felt it was as difficult to tolerate as other treatments, 27% felt it was less or much less difficult, and 7% felt it was more difficult to tolerate. Additionally, out of 15 respondents, 40% strongly agreed, 20% agreed, 33% felt neutral, and 7% disagreed that blinatumomab improved their quality of life compared to other treatments. Most patients indicated that they were likely to take blinatumomab again or recommend it to other patients.

The joint patient group input for pediatric patients gathered information through interviews with 3 caregivers of pediatric patients with B-cell ALL. According to this patient group submission, to avoid repetitive questioning and to minimize emotional strain and undue harm, the interviews were focused on experiences and quality of life associated with blinatumomab treatment. For all other information, this patient group input referred to previous LLSC-Ac2orn-OPACC- joint submissions to CDA-AMC for relapsed or refractory ALL in pediatric patients. First, the following section presents the disease experience and experience with currently available treatments gathered from previous patient input submissions. Second, it summarizes patients’ and caregivers’ experience with blinatumomab treatment and patients’ quality of life during blinatumomab treatment compared to their experience with prior treatments for pediatric ALL, based on the joint patient group submission for this current review.

Based on input gathered in previous patient input submissions to CDA-AMC for pediatric patients with relapsed or refractory ALL, children may experience a variety of symptoms, including severe fatigue, pain, high fever, bleeding, bruising, bone pain, and swollen lymph nodes. However, the impacts of pediatric cancer relapse on the child and their family extend beyond physical symptoms. It was highlighted in the patient group submissions that relapse and immunosuppression severely limit children’s ability to engage in normal activities, placing a significant emotional and physical burden on both the child and their family. Families experience intense stress, financial strain, and disrupted daily routines, with caregivers often facing severe impacts on their mental health. It was explained in the patient group submissions that the standard of care for treating relapsed or refractory pediatric ALL typically involves a combination of strategies, including drug therapy and radiation. For patients with refractory disease, these aggressive treatments often result in serious side effects, such as immunosuppression, severe pain, infections, anemia, and organ damage, which can significantly impact the child's quality of life. There is a significant unmet need for more effective, less toxic therapies that improve quality of life by reducing treatment burden and minimizing the need for frequent hospital visits. Outpatient treatment options that decrease hospital stays was also cited as crucial for maintaining normalcy and reducing stress for both patients and their families. In terms of improved outcomes, it was noted in the patient group submissions that patients and their families are looking for options that are not only effective but also gentle on their children. They seek innovative therapies that can provide significant benefits without causing undue harm or severe side effects. Additionally, having these treatments covered by drug plans is crucial, as coverage alleviates the financial burden on families.

In the 3 caregiver interviews conducted by the joint patient group submission for this present review, 2 of the caregivers had children who were 2 years old, and 1 had a child who was 10 years old at diagnosis. Two caregivers were residents of Ontario, and 1 resided in British Columbia. The input focused on patients' and caregivers' experiences with administering blinatumomab treatment at home, as well as on comparing their quality of life during blinatumomab treatment to their experiences with prior treatments for pediatric ALL. According to the joint submission, the current conventional therapy for pediatric patients with B-cell ALL living in Canada is chemotherapy infusions, which are often accompanied by serious side effects, negative impact on patients’ physical health, and long hospital stays. Based on the joint input, all 3 caregivers mentioned that they and the patients had overall positive experiences with blinatumomab, especially in comparison to chemotherapy infusion. Because blinatumomab is an outpatient treatment with “gentler” effects, the patients were able to live with family, play with peers, and stay out of the hospital. The 3 caregivers reported that they felt nervous, the child experienced fever, and the child experienced side effects at the start of blinatumomab treatment. According to the patient group input, cognitive testing was done routinely at every blinatumomab bag change to check for neurologic AEs; none of the caregivers reported neurologic AEs as a side effect in the children. Caregivers reported an extra burden because they had to receive a new medication bag of blinatumomab every 4 days and had to visit the medical centre for any glitches in the blinatumomab delivery system. Caregivers noted that, because blinatumomab is a relatively new treatment method, knowledge of blinatumomab’s delivery method was limited among health care professionals. Some caregivers emphasized the need for greater variety for the backpack delivery system for blinatumomab that would be able to accommodate pediatric patients of all ages. According to the joint submission, all 3 caregivers related that blinatumomab made a big difference to the quality of life for their patients, themselves, and the rest of their family compared to traditional chemotherapy infusion. Financial stress was experienced by caregivers due to the high cost and lack of public funding for blinatumomab. Finally, the joint submission made the following suggestions for improved outcomes with new therapies:

• Provide caregivers with tips and tools on what to expect with the blinatumomab delivery system, and some at-home solutions to help alleviate practical challenges such as driving to cancer centres at unexpected times.

• Train nurses at local hospitals to administer blinatumomab (to mitigate the requirement of driving to cancer centres).

• Improve blinatumomab knowledge and skills among the nurses at the cancer centres.

• Provide more choices in the delivery system backpacks based on body size and strength of the patient.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of Ph-negative B-cell precursor ALL. One of the clinical experts has specific expertise in the diagnosis and management of adults with Ph-negative B-cell precursor ALL, while the other has expertise in pediatrics with Ph-negative B-cell precursor ALL.

Unmet Needs

The clinical experts consulted for this review felt the overarching goal of Ph-negative B-cell precursor ALL treatment is to achieve CR, prevent relapses, and cure the disease (thus providing long-term survival), while minimizing acute and late toxicities. Current conventional therapy remains suboptimal, as not all patients respond to available treatments, relapse remains a substantial risk, and many patients experience toxicity-related AEs. The clinical experts consulted for this review noted that unplanned inpatient admissions due to complications associated with current conventional therapy are common. Further, as ALL is the most common childhood cancer, the clinical expert with experience treating pediatric patients with ALL highlighted that decreasing relapse rates in ALL would have a significant impact on childhood cancer mortality rates and obviate the need for additional expensive and/or toxic therapies.

Place in Therapy

The clinical experts consulted for this review felt that blinatumomab would add an alternative first-line treatment option for patients with Ph-negative B-cell precursor ALL. The experts recommended using 1 to 4 cycles of blinatumomab in sequence with conventional consolidation chemotherapy. Compared to current treatment options, clinical experts noted that blinatumomab’s unique mechanism of action blocking CD19 antigen expressed on the leukemic blasts, has the potential to improve overall response rate, RFS, and OS, while decreasing AEs associated with the frequent use of intensive chemotherapy, potentially improving quality of life for patients with Ph-negative B-cell precursor ALL. If blinatumomab reduces the use of allogeneic SCT by preventing relapse, clinical experts noted that the risk of treatment-related mortality may also decrease.

Patient Population

The clinical experts consulted for this review noted any adult or pediatric patient with Ph-negative B-cell precursor ALL who achieves a CR following induction therapy, regardless of risk (i.e., MRD and pediatric risk groups) and age, would be best suited for first-line consolidation treatment with blinatumomab.

The clinical expert with experience treating pediatric patients noted that the sole exception may be to exclude pediatric patients from receiving blinatumomab if their expected event-free survival on a particular chemotherapy backbone is expected to be greater than 95% (i.e., those with SR-favourable risk category). However, experts flagged that the molecular characterization of leukemia is rapidly evolving, and the identification of a new high-risk somatic change may alter how patients are currently classified.

The experts felt that adults with Ph-negative B-cell precursor ALL who have a poor PS (i.e., ECOG PS greater than 2) should not be eligible for blinatumomab, while no PS restriction should be made in children, as blinatumomab has been shown to be well tolerated and potentially life-saving. Similar to the pivotal trial exclusion criteria, clinical experts consulted for this review felt there were insufficient data to recommend blinatumomab treatment in patients with acute undifferentiated leukemia and those with Burkitt leukemia.

As BCR-ABL reverse transcriptase-polymerase chain reaction molecular testing to determine Ph status and assessment of CR following induction therapy are standard clinical practice in Canada, clinical experts noted that no additional testing would be required before initiating blinatumomab treatment.

Assessing the Response to Treatment

Outcome metrics for Ph-negative B-cell precursor ALL used in clinical practice are typically aligned with those used in clinical trials. The clinical experts consulted for this review noted that treatment response in clinical practice and in clinical trials is based on bone marrow evaluation (including morphological evaluation and MRD assessment) at the end of induction and consolidation treatment. In both clinical practice and in clinical trials, MRD negativity is defined as less than 0.1% (or 0.01% if flow-based MRD testing can reach 10^–4) in adults and less than 0.01% in children (except for pediatric patients with SR and DT, in whom it is defined as less than 0.1%). Clinical experts consulted for this review felt that definitions of relapse were well established and aligned across centres and clinicians and were similar between clinical practice and trials. RFS, DFS, OS, and other survival parameters, such as relapse incidence, are long-term parameters used to assess treatment response in both clinical trials and clinical practice. In both clinical practice and clinical trials, AEs are used to assess treatment benefit.

The clinical expert with experience treating adults with ALL noted that, following the completion of maintenance treatment, relapse is assessed every 3 months during the first year, every 6 months during the second year, and then annually between years 3 and 5.

The clinical expert with experience treating pediatric patients with ALL noted that, following the completion of maintenance treatment, relapse is assessed monthly for the first 3 months, every 3 months for the first year, every 4 months in the second year, every 6 months in the third year, and then annually for the rest of the patient’s life; however, follow-up practices vary by centre.

Discontinuing Treatment

The clinical trial, blinatumomab’s label, and the clinical experts consulted for this review noted that blinatumomab should be discontinued in the event of grade 4 cytokine release syndrome, grade 4 neurotoxicity and/or psychiatric events, and grade 4 thrombosis. Other grade 4 toxicities that are deemed clinically significant may require discontinuation of blinatumomab. Toxicities that require dose interruption of blinatumomab and that do not return to grade 1 or less by 14 days (or in the case of neurotoxicity, by 7 days) necessitate discontinuation of blinatumomab. Recurrent toxicities leading to dose interruption of blinatumomab also require permanent discontinuation of blinatumomab. One of the clinical experts consulted for this review also noted that patients who develop any debilitating conditions (such as ECOG PS of greater than 2) should discontinue blinatumomab treatment.

The clinical expert with experience treating adults noted that, while they were in agreement with these discontinuation criteria, the benefits of treatment, availability of alternative treatments, risks of discontinuation, and patients’ willingness to continue treatment must also be taken into account. The clinical expert with experience treating adults also noted that blinatumomab should be discontinued in the event of disease progression and relapse or upon the patient’s request.

Prescribing Considerations

Clinical experts indicated that treatment with blinatumomab should be initiated on an inpatient basis (3 days for the first infusion and 2 days for subsequent infusions); if it is well tolerated, subsequent infusions can be performed in an outpatient clinic.¹⁰ Given the pharmacy, nursing, and monitoring requirements for blinatumomab infusions, specialist care at an oncology centre is required. Both clinical experts consulted for this review felt that any conventional chemotherapy used for ALL treatment can be combined with blinatumomab. They also felt that clinicians should have the ability to adjust the dosage, number of cycles, and cycle length of blinatumomab based on toxicity and individual patient’s needs.

The clinical expert with experience treating adults noted that at least 2 cycles of blinatumomab should be given before SCT to deepen the patient’s remission. SCT would likely be required in patients in their second CR (regardless of MRD status) or in first CR with continuous MRD positivity and would be considered in patients in first CR with MRD-negative status after initially presenting with the highest risk disease for relapse.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Three clinician groups each submitted inputs to CDA-AMC: OH-CCO Hematology Cancer Drug Advisory Committee (with input from 6 clinicians); POGO (input from 11 clinicians); and CLSG-GCEL (input from 7 clinicians). One group provided input relevant to pediatric patients (POGO) and another for adults (CLSG-GCEL), while the third group did not specify an age group of patients represented.

The clinician groups were generally in agreement with the feedback received from the clinical experts consulted for this review. In terms of the goals of therapy, the clinical experts and clinician groups indicated that the main goals are cure of the disease while minimizing toxicity. Other goals include achieving CR, preventing relapse, and avoiding need for second-line therapies, such as allogenic SCT or CAR T-cell therapy. In pediatric patients, the POGO group stated that relapse therapies carry significant toxicity that leave young patients with a wide variety of potential lifelong late effects. In adults, the clinician groups noted the substantial risk of relapse, even in patients who are MRD-negative. Thus, additional treatments are needed to improve survival, CR and relapse rate, and to minimize or reduce toxicity of treatments (during consolidation and/or later therapies).

All clinician groups agreed that the patient population suitable to receive blinatumomab during consolidation include those newly diagnosed with Ph-negative CD19-positive B-cell precursor ALL, regardless of MRD status. Both the pediatric clinical expert consulted for this review and the POGO group indicated that patients who meet the SR-average or high-risk stratification criteria, have less favourable outcomes with chemotherapy alone and are expected to benefit from the addition of blinatumomab during consolidation therapy. Those who meet the SR-favourable stratification criteria have excellent response rates (event-free survival greater than 95%) with chemotherapy alone and may not require blinatumomab therapy. The POGO group noted an unmet need for augmentation therapies that have a tolerable adverse effect profile and may allow for “breaks” in therapy to facilitate recovery from cytotoxic-associated complications, such as fungal infections. According to input from POGO, patients with Ph-positive B-cell precursor ALL may also benefit from blinatumomab therapy. The clinician groups agree that standard response assessment for ALL would be relevant to monitoring the effects of blinatumomab, including MRD status, duration of response, relapse, and OS. The adult clinician groups noted the MRD threshold of 0.1% (≥ 10³) is obsolete, and the current standard is greater than or equal to 0.01% (≥ 10⁴).

The experts consulted and clinician groups agreed that blinatumomab would be discontinued if the patient experienced disease progression or significant toxicity, and that specialist care in an ALL treatment centre is warranted. The POGO group expressed that reimbursement strategies should account for all forms of drug wastage that may occur when pediatric doses are prepared.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by for this review are summarized in Table 6.

Table 6: Summary of Drug Plan Input and Clinical Expert Response

ALL = acute lymphoblastic leukemia; AUL = acute undifferentiated leukemia; COG = Children’s Oncology Group; ECOG = Eastern Cooperative Oncology Group; FISH = fluorescence in situ hybridization; MRD = minimal residual disease; PCR = polymerase chain reaction; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; Ph = Philadelphia chromosome; SR = standard risk.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of blinatumomab, 28 mcg/day for adult patients weighing 45 kg of more and 15 mcg/m² per day for adult patients weighing less than 45 kg and pediatric patients, lyophilized powder for solution, IV infusion by infusion pump in the treatment of Ph-negative B-cell precursor ALL in the consolidation phase of multiphase chemotherapy in the frontline setting. The focus will be placed on comparing blinatumomab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of blinatumomab is presented in this section, with the CDA-AMC critical appraisal of the evidence included at the end of the section. The systematic review section includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this section using the GRADE approach follows the critical appraisal of the evidence.

Included Studies

Clinical evidence from the following is included in the review and appraised in this document:

• 2 studies: 1 pivotal RCT in adult patients identified in the sponsor’s systematic review and a second RCT provided by the sponsor in a pediatric population of patients with Ph-negative B-cell precursor ALL.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 7.

Table 7: Details of Studies Included in the Systematic Review

ALL = acute lymphoblastic leukemia; BCR = B-cell receptor; B-LLy = B-lymphoblastic lymphoma, CNS = central nervous system; CR = complete remission; CRi = complete remission with incomplete peripheral blood count recovery; DFS = disease-free survival; DS = Down syndrome; ECOG = Eastern Cooperative Oncology Group; EOI = end of induction; MRD = minimal residual disease; OS = overall survival; PS = performance status; RFS = relapse-free survival; SCT = stem cell transplant; SR = standard risk; TRM = treatment-related mortality.

^aEnd-of-consolidation MRD assessed via flow cytometry.

Source: BLINCYTO E1910 Clinical Study Report, Gupta et al., and Clinicaltrials.gov.^19,62,67,68 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The E1910 trial was a randomized, open-label, controlled, phase III study aimed at evaluating the efficacy and safety of blinatumomab for the treatment of adult patients with Ph-negative B-cell precursor ALL. The E1910 trial was sponsored by the National Cancer Institute (NCI) and administered by the Eastern Cooperative Oncology Group–American College of Radiology Imagine Network (ECOG-ACRIN Cancer Research Group). Patients with Ph-negative B-cell precursor ALL were recruited from 77 centres in the US, Israel, and Canada. All patients initially received induction chemotherapy for up to 3 months (defined as Step 1, Arm A), and those who achieved CR or CRi continued on study and received intensification treatment (defined as Step 2, Arm B; Figure 1). MRD status was then determined and, initially, patients with both MRD-negative and MRD-positive status were then randomized (Step 3) to receive either blinatumomab plus chemotherapy (Arm C) or chemotherapy (Arm D). Randomization was stratified by MRD status, age (30 to 54 years versus 55 years or older), CD20 status (positive versus negative), rituximab use (yes versus no), and intention to receive allogeneic SCT (yes versus no). Following a protocol amendment related to the FDA accelerated approval of blinatumomab therapy for patients with MRD-positive status (March 2018), these patients were assigned (rather than randomized) to blinatumomab plus chemotherapy (Arm C). Before the protocol amendment, 44 patients with MRD-positive status were randomized (22 of 286 [7.7%] to each treatment arm) and, following the protocol amendment, 18 (6.3%) patients were assigned to the blinatumomab plus chemotherapy arm. Patients in both treatment groups received maintenance therapy for 2.5 years from the start of the intensification phase (Step 4, Arm E). The chemotherapy regimen in the E1910 trial builds upon the UKALLXII/E2993 chemotherapy regimen, with dosing modifications based on C10403 AYA trial.^69-71 Details of the regimen used in the E1910 trial are summarized in Table 9.

The primary objective of the E1910 trial was to compare the OS of patients treated with blinatumomab plus chemotherapy to chemotherapy in the FAS (i.e., patients with MRD-negative status following induction and intensification chemotherapy). Secondary objectives relevant to this review were to compare RFS of patients treated with blinatumomab plus chemotherapy to chemotherapy in the FAS, to compare OS and RFS of patients treated with blinatumomab plus chemotherapy to chemotherapy in the Step 3 MRD-positive analysis set, and to assess toxicities of blinatumomab and the chemotherapy regimen. Post hoc objectives were to compare OS and RFS of blinatumomab plus chemotherapy to chemotherapy in the Step 3 analysis set. The primary analysis of the E1910 trial results presented in this report are from the June 23, 2023, DCO date. The study design of the E1910 trial is depicted in Figure 1.

Similarly, the AALL1731 trial was a randomized, open-label, controlled, phase III study aimed at evaluating the efficacy and safety of blinatumomab for the treatment of pediatric patients with B-cell ALL. The AALL1731 trial was supported by grants from the NCI of the National Institutes of Health, St. Baldrick’s Foundation, and in part by Amgen. Pediatric patients with SR B-cell ALL were recruited from 228 centres in Australia, Canada, New Zealand, and the US. All patients initially received induction treatment before being stratified into 3 categories based on risk of relapse (SR-favourable, SR-average, and SR-high) and receiving consolidation treatment (Figure 2). Patients with average or high risk of relapse were randomized to either blinatumomab plus chemotherapy or chemotherapy arms. The 1:1 randomization was stratified according to risk groups (SR-average versus SR-high) and Down syndrome among those with SR-average (yes versus no). In both treatment groups of the AALL1731 trial, patients received 1 56-day cycle of interim maintenance II and then proceeded to receive 84-day cycles of maintenance therapy to continue for 2 years after the start of postconsolidation therapy. Patients classified as having high risk of relapse in the AALL1731 trial received an augmented Berlin-Frankfurt-Münster chemotherapy backbone, while those classified as having average risk of relapse received the standard therapy. Details of the regimen used in the AALL1731 trial are summarized in Figure 3 and Figure 4, Table 22, and Table 23.

In the AALL1731 trial, the primary end point was DFS and the primary objective was to determine whether the addition of blinatumomab (administered as nonsequential cycles) to conventional chemotherapy would improve DFS in all randomized patients with SR B-cell ALL (patients either had an average or high risk of relapse on the basis of clinical features). None of the secondary or exploratory objectives (Table 7) in the AALL1731 trial were relevant to this review. A post hoc objective was to determine whether the addition of blinatumomab to conventional chemotherapy would improve OS in all randomized patients.

The final analysis for DFS was planned when 194 DFS events were observed. Interim efficacy and futility monitoring were planned for when 20% (futility only), 40%, 60%, 80%, and 100% of the expected information (i.e., 194 DFS events) was observed, using the alpha-t² spending function for efficacy monitoring and the futility monitoring method described by Anderson and High. Results were reviewed by the Data Safety Monitoring Committee. Details of the study design of the AALL1731 trial can be found in Figure 2. The results from the AALL1731 trial are from an interim analysis with a DCO of June 30, 2024.

At the planned interim analysis (June 30, 2024, DCO), the Data Safety Monitoring Committee recommended that the blinatumomab randomization be permanently closed based on the 3-year DFS estimates of 96.0% (SE = 1.2%) for the blinatumomab plus chemotherapy arm versus 87.6% (SE = 2.1%) for the chemotherapy alone arm. The associated HR was 0.39 (95% CI, 0.24 to 0.64), which exceeded the prespecified interim efficacy stopping criteria. (Data for the AALL1731 trial were sourced from published data only, and the exact stopping criteria were not publicly reported.)

The clinical expert with experience treating pediatric patients indicated that, while the nomenclature for treatment phases used in the AALL1731 trial differ from the historical 3-phase terminology (i.e., remission or induction, consolidation, and maintenance), the treatment phases during which blinatumomab is prescribed (i.e., consolidation, interim maintenance, and delayed intensification) can be viewed as the historical consolidation phase.”

Induction Phase

In both the E1910 and AALL1731 trials, all patients initially received induction chemotherapy.

In the E1910 trial, patients initially received 2 cycles of combination induction chemotherapy, with the addition of pegaspargase for patients younger than 55 years of age and the addition of rituximab for patients with CD20-positive ALL (Figure 1). The induction phase in the E1910 trial was defined as Step 1 and took up to 3 months. In the AALL1731 trial, a common 3-drug dexamethasone-based induction treatment was used. Patients with CNS-2 disease also received twice weekly cytarabine in addition to their initial dose (except on days 8 and 29, when methotrexate is administered) until 3 consecutive cerebrospinal samples were clear of blasts. At the end of induction, all eligible patients were stratified into 3 risk groups: SR-favourable, SR-average, and SR-high (Table 8).

Those with SR-average risk category with undetectable MRD assessed by high-throughput screening (HTS) were nonrandomly assigned to receive the AALL1731 trial chemotherapy, and their results are not reported here. Patients who had Down syndrome and in whom ALL was classified as SR-high were nonrandomly assigned to receive blinatumomab with lower toxicity chemotherapy, and their results are not reported here.

Intensification Phase

After the E1910 trial induction, patients in hematologic CR or CRi continued on study and received 1 intensification cycle of high-dose methotrexate with pegaspargase for CNS prophylaxis (Figure 1). In the E1910 trial, the intensification phase was defined as Step 2. Remission status was assessed after intensification treatment. CR was defined as neutrophil count of 1.0 × 10⁹/ L or greater, platelet count of 100 × 10⁹/L or greater, no leukemic blasts present in the peripheral blood, adequate bone marrow cellularity with trilineage hematopoiesis, 5% or less blasts in the bone marrow, and no extramedullary leukemia (e.g., CNS or soft tissue involvement). The definition of CRi is the same as CR with the exception of incomplete platelet recovery (i.e., platelets greater than 75 × 10⁹/L and less than 100 × 10⁹/L) or incomplete neutrophil count recovery (i.e., greater than 0.75 × 10⁹/L and less than 1 × 10⁹/L). MRD status was determined centrally by 6-colour flow cytometry, with MRD negativity defined as ≤ 1 × 10^–4 (0.01%).

In the AALL1731 trial, patients proceeded directly to consolidation chemotherapy.

Table 8: Definitions of Cohorts in the AALL1731 Trial

CNS = central nervous system; DT = double trisomies 4 and 10; IF-EM = extramedullary disease induction failure; MRD = minimal residual disease; SR = standard risk.

^aNeutral cytogenetics is defined as the absence of favourable and unfavourable cytogenetics.

^bPresence of iAMP21, KMT2A-R (formerly MLL-R), hypodiploidy (modal chromosome number less than 44, DNA index < 0.81, or other clear evidence of a hypodiploid clone), or t(17;19).

^cNo steroid pretreatment within 1 month before diagnosis.

^dReceived steroid pretreatment within 1 month before diagnosis.

Source: Gupta et al.⁶⁸

Consolidation Phase

Patients enrolled in the E1910 trial with MRD-negative status proceeded to randomization of consolidation treatment. Those with MRD-positive status initially underwent randomization. However, after the approval of blinatumomab therapy for patients with MRD-positive status, a protocol amendment assigned all subsequent patients with MRD-positive status to the blinatumomab group.

Those randomized to chemotherapy in the E1910 trial received three 28-day cycles of chemotherapy and one 42-day cycle of chemotherapy (Figure 1). Those randomized or assigned to the blinatumomab plus chemotherapy arm initially received two 28-day cycles of blinatumomab with a 2-week treatment-free break between the cycles, followed by chemotherapy (three 28-day cycles of chemotherapy and one 42-day cycle of chemotherapy), with one 28-day cycle of blinatumomab before the final chemotherapy cycle, and then 1 final 28-day cycle of blinatumomab. In the E1910 trial, the consolidation phase was defined as Step 3.

All remaining patients in the AALL1731 trial with SR-average and SR-high received a 28-day cycle of consolidation chemotherapy with slightly different regimens for those with SR-average and SR-high. Patients with SR-high after induction therapy who had MRD of 0.1% or greater were reassessed for MRD at the end of 56-day consolidation phase, which is common practice according to the clinical expert with experience treating pediatric patients. Patients with end-of-consolidation MRD of less than 0.1% were randomized, those with MRD of 0.1% to less than 1.0% (N = 14) were nonrandomly assigned to receive blinatumomab plus chemotherapy (results are not available), and those with MRD greater than 1% (N = 7) were removed from the trial. The clinical expert treating children agreed to generalize the results of patients with SR-high and MRD of less than 0.1% at the end of consolidation phase to patients with MRD of 0.1% to less than 1.0%. The clinical expert treating children noted that the patient population with SR-high and end-of-consolidation MRD of 1% or greater (N = 7) was removed from the trial, as these patients reflect a rare and very high–risk subgroup that is considered refractory and would be managed differently. Following consolidation treatment, all remaining patients were randomized to received two 28-day cycles of nonsequential blinatumomab in combination with chemotherapy or chemotherapy alone. Those assigned to the blinatumomab plus chemotherapy arm proceeded to receive 1 28-day cycle of blinatumomab followed by a 56-day interim maintenance cycle, another 28-day blinatumomab cycle, and then a 56-day (if SR-average) or 63-day (if SR-high) delayed intensification cycle. Those assigned to the chemotherapy arm proceeded directly to the first 56-day interim maintenance cycle, followed directly by the 56-day (if SR-average) or 63-day (if SR-high) delayed intensification cycle.

Maintenance Phase

In both studies, all patients received maintenance therapy regardless of the treatment group assignment.

In the E1910 trial, maintenance therapy continued for 2.5 years from the start of the intensification phase (Figure 1). In the E1910 trial, the maintenance phase was defined as Step 4.

In both treatment groups of the AALL1731 trial, patients received one 56-day cycle of interim maintenance II treatment and then proceeded to receive 84-day cycles of maintenance therapy to continue for 2 years after the start of postconsolidation therapy (defined as either the second cycle of blinatumomab or delayed intensification) (Figure 2).

Figure 1: Schematic of the E1910 Trial’s Study Design

Note: In the E1910 trial, the induction phase was called Step 1, the intensification phase was called Step 2, the consolidation phase was called Step 3, and the maintenance phase was called Step 4.

Source: BLINCYTO Clinical Study Report.¹⁹

Figure 2: Schematic of the AALL1731 Trial’s Study Design

ALL = acute lymphoblastic leukemia; CMTX = Capizzi methotrexate; DS = Down syndrome; DT = double trisomy of chromosomes 4 and 10; EOC = end of consolidation; EOI = end of induction; EscMTX = escalating-dose methotrexate; Exp = experimental; HDMTX = high-dose methotrexate; HTS = high-throughput screening; MRD = minimal residual disease; NCI = National Cancer Institute; Ph = Philadelphia chromosome; SR-Avg = standard-risk average; SR-Fav = standard-risk favourable; SR-high = standard-risk high.

¹NCI SR with steroid pretreatment, CNS-3, or testicular leukemia transfer to AALL1732 at beginning of induction.

²Four week, 3 drug induction.

³Patients with Ph-positive ALL go off-study before day 15 of induction and, if eligible, enrol on AALL1631.

⁴Patients with DS SR B-cell ALL lacking high-risk features and with EOI MRD < 0.01% receive treatment on the SR-Fav or SR-Avg B-cell ALL arm.

⁵Unfavourable cytogenetics include KMT2A-R, iAMP21, hypodiploidy, t(17;19).

⁶Neutral cytogenetics: lacking favourable and unfavourable cytogenetic features.

⁷Refer to the definition of extramedullary disease induction failure (IF-EM) in Section 3.3.5 of the AALL1731 protocol.

⁸SR-favourable: NCI SR (non-Down syndrome and Down syndrome) B-cell ALL, CNS-1 or CNS-2, with favourable cytogenetics (ETV6-RUNX1 fusion or DT), day 8 PB MRD < 1%, and end-of-induction bone marrow MRD < 0.01%.

⁹Meet features for therapy on the SR chemotherapy backbone.

¹⁰Meet features for therapy on the high-risk chemotherapy backbone.

¹¹End-of-consolidation bone marrow MRD evaluation is required for patients with SR-high risk category with end-of-induction bone marrow MRD ≥ 0.1% and is recommended but not required for patients with SR-high risk category with end-of-induction bone marrow MRD 0.01% to 0.099%. Patients with treatment failure during the consolidation phase received off-protocol therapy.

¹²Timed from the start of the phase following consolidation phase for a total of 2 years for both females and males.

Source: From New Engl J Med, Gupta S et al., Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. Copyright © (2025) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Populations

Inclusion and Exclusion Criteria

Detailed inclusion and exclusion criteria are provided in Table 7.

Briefly, in the E1910 trial, patients between the ages of 30 and 70 years with newly diagnosed Ph-negative B-cell precursor ALL and an ECOG PS of 0 to 3 were eligible for the induction phase (Step 1). New diagnoses of B-cell precursor ALL were based upon bone marrow or peripheral blood immunophenotyping and Ph-negativity was established by conventional cytogenetics, FISH, and/or polymerase chain reaction. Patients with Ph-positive ALL, Burkitt leukemia or lymphoma, mature B-cell leukemia, T-cell ALL, T-cell lymphoblastic lymphoma, or B-cell lymphoblastic lymphoma were ineligible. Patients were excluded if they had an antecedent hematologic disorder, history of recent myocardial infarction, or uncontrolled heart failure. Patients could not have a concurrent active malignancy for which they were receiving treatment, and those with pre-existing significant CNS pathology or uncontrollable seizure disorders were excluded. Following induction therapy, only those with an ECOG PS of 0 to 2, who achieved a CR or CRi and were CNS-negative for leukemia were eligible for postinduction intensification (Step 2). Patients eligible for consolidation treatment (Step 3) randomization or assignment to the blinatumomab plus chemotherapy or chemotherapy arm must have had an ECOG PS of 0 to 2, have maintained peripheral blood evidence of a remission, and have a CR or CRi.

In the AALL1731 trial, patients who were older than 1 year and younger than 10 years of age with newly diagnosed SR B-cell ALL and who were enrolled on Project: Every Child (APEC14B1) were eligible for enrolment. Newly diagnosed B-cell ALL was based on bone marrow samples or peripheral blood immunophenotyping. Those with acute undifferentiated leukemia, CNS-3 leukemia, or testicular leukemia were ineligible for enrolment. Treatment was discontinued in the event of Ph-positive identification. Data for patients who were enrolled in the AALL1731 trial and deemed eligible but did not undergo randomization (including those with Down syndrome and a high risk of relapse, or those with localized B-cell lymphoblastic lymphoma) are not reported here.

Interventions

In both the E1910 and AALL1731 trials, the main study intervention was blinatumomab administered as a continuous IV infusion over 28-day cycles.

In the E1910 trial, a fixed dose of 28 mcg/day of blinatumomab was administered after the completion of induction and intensification therapy for 4 cycles (2 cycles immediately following induction and intensification therapy, 1 cycle during the consolidation phase, and 1 cycle immediately following chemotherapy consolidation treatment; Table 9). Patients weighing less than 45 kg were given 15 mcg/m² per day of blinatumomab at the same interval. In both treatment arms, patients received consolidation chemotherapy followed by maintenance therapy (Table 21). The chemotherapy regimen in the E1910 trial builds upon the UKALLXII/E2993 chemotherapy regimen with dosing modifications based on C10403 AYA trial.

In the AALL1731 trial, 15 mcg/m² per day up to a maximum of 28 mcg/day of blinatumomab was administered after the completion of consolidation treatment for 2 cycles (1 cycle immediately following consolidation therapy and 1 cycle following interim maintenance I) (Figure 2). Each cycle was followed by 7 days of rest. In both treatment arms, patients received standard of care chemotherapy interim maintenance, delayed intensification, interim maintenance II, and maintenance therapy (Table 22 and Table 23).

In both studies, it was recommended that patients be hospitalized for at least the first 2 to 3 days of the first cycle of blinatumomab and the first 1 to 2 days of each subsequent cycle. However, the decision to hospitalize was at the discretion of the investigator. In the outpatient setting, either the patient returned to the study site for all changes of infusion bags or an ambulatory or home care service performed infusion bag changes in the patient’s home. Treatment continued until disease progression, relapse, treatment discontinuation, unacceptable toxicity, withdrawal of consent, or end of study treatment. In the E1910 trial, treatments were delayed if the absolute neutrophil count was less than 0.75 × 10⁹/L and the platelet count was 75 × 10⁹/L or less. Blinatumomab dose modifications were allowed in both studies in the event of AEs deemed to be possibly, probably, or definitely related to treatment. Generally, in the event of a grade 3 AE, treatment was stopped immediately and withheld until the AE resolved to grade 1 or lower. Treatment was discontinued in the event of grade 4 AEs.

In lieu of consolidation and maintenance treatment in the E1910 trial, patients could proceed to allogeneic SCT at the discretion of the treating physician (immediately following intensification treatment in the chemotherapy arm and immediately following the initial 2 cycles of blinatumomab for those in the blinatumomab plus chemotherapy arm).

In the E1910 trial, reasons for early removal from protocol treatment were categorized as:

• treatment completed per protocol criteria

• disease progression relapse during active treatment

• AEs, side effects, or complications

• death on study

• patient withdrawal or refusal after beginning protocol therapy

• alternative therapy

• patient off treatment for other complicating disease

• other.

In the AALL1731 trial, reasons for removal from protocol treatment included:

• progressive disease at the end of Induction (B-lymphoblastic lymphoma [B-LLy] only)

• consolidation failure (B-cell ALL only)

• failure to achieve CR at the end of consolidation treatment (B-LLy only)

• definitive relapse

• identified as Ph-positive (BCR-ABL1)

• incomplete induction phase data for risk stratification (B-cell ALL only)

• patient found at any point after enrolment to be unevaluable (e.g., major deviations from protocol therapy, found to have MYC translocation associated with mature [Burkitt] B-cell ALL or B-LLy)

• AE requiring removal from protocol therapy

• refusal of further protocol therapy by patient, parent, or guardian

• completion of planned therapy

• physician determination that removal is in the patient’s best interest

• development of a second malignancy

• receiving radiation therapy other than protocol-defined cranial and testicular radiation for patients with Down syndrome.

Table 9: Regimens Used in the Consolidation Phase of the E1910 Trial

IM = intramuscular; IT = intrathecal; SC = subcutaneous.

Source: BLINCYTO Clinical Study Report.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Figure 3: Regimens Used in the AALL1731 Trial in Patients With SR-Average

IT = intrathecal; max = maximum; PEG = pegaspargase; PO = orally; SR-avg = standard risk with average risk of relapse; SR-high = standard risk with high risk of relapse; SQ = subcutaneous.

Source: From New Engl J Med, Gupta S et al., Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. Copyright © (2025) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 4: Regimens Used in the AALL1731 Trial in Patients With SR-High

IT = intrathecal; max = maximum; PEG = pegaspargase; PO = orally; SR-avg = standard risk with average risk of relapse; SR-high = standard risk with high risk of relapse; SQ = subcutaneous.

Source: From New Engl J Med, Gupta S et al., Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. Copyright © (2025) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 10, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical experts consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, we selected end points that were considered to be most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. Selected efficacy end points and notable harms outcomes considered important for informing expert committee deliberations were assessed using GRADE. The results of the pediatric trial were not appraised using GRADE, as only limited published results were provided. Additionally, the pediatric data became available closer to the end of the clinical review process, which precluded an evaluation using the GRADE framework. In summary, OS and RFS from the E1910 trial for the Step 3 analysis set and stratified by MRD status (i.e., FAS and Step 3 MRD-positive analysis set) and grade 3 and greater TEAEs, treatment-emergent SAEs, and fatal TEAEs from the E1910 trial’s Step 3 analysis set were assessed using GRADE.

Table 10: Outcomes Summarized From the Studies Included in the Systematic Review

DCO = data cut-off; DFS = disease-free survival; MRD = minimal residual disease; NR = not reported; OS = overall survival; RFS = relapse-free survival; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Note: Statistical testing was not performed on any of the end points in the E1910 trial to adjust for multiple comparisons.

^aPrimary analysis DCO in E1910 was on June 23, 2023, and in AALL1731 was on June 30, 2024.

Source: BLINCYTO Clinical Study Report.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

In the E1910 trial, treatment response was assessed before the start of each cycle of treatment (i.e., induction, intensification, consolidation, SCT), during the postintensification period, and after treatment every 3 months for the first 2 years from study entry, then every 6 months between 2 to 5 years from study entry, and once annually during 6 to 10 years following study entry. The frequency at which treatment response was assessed in the AALL1731 trial was not reported in documentation received by the CDA-AMC review team.

For survival outcomes in the E1910 trial, the reference date for analyses was defined as the randomization date for analyses of OS and RFS among patients who were MRD-negative and was either the randomization date (for those who were randomized before the protocol amendment) or registration date (for patients who were assigned to the blinatumomab plus chemotherapy arm following the protocol amendment) for patients who were MRD-positive. In the AALL1731 trial, the reference date was the end of the consolidation phase (i.e., when patients were randomized).

Overall Survival

In the E1910 trial, OS was defined as time from the reference date to death due to any cause. In the AALL1731 trial, OS was defined as the time from randomization to death or censoring at the date of last contact.

Clinical experts consulted for this review advised that an OS between-group difference of 5% in adults with Ph-negative B-cell precursor ALL and greater than 0% in the pediatric patients with Ph-negative B-cell precursor ALL is considered clinically meaningful. As a result, in the E1910 trial, a 5% between-group difference in OS in the Step 3 analysis set, the FAS, and the Step 3 MRD-positive analysis set would be considered clinically meaningful differences. In the AALL1731 trial, a between-group difference of greater than 0% in OS in the overall cohort and subgroups stratified by risk of relapse (i.e., SR-average and SR-high) would be considered clinically meaningful.

Relapse-Free Survival

In the E1910 trial, RFS was defined as time from randomization to relapse or death due to any cause. Relapse was defined as the reappearance or persistence of blasts in the blood, presence of greater than 5% blasts (not attributable to another cause), or, in the case of isolated CNS relapse, the study chair was consulted and a bone marrow biopsy was performed to confirm the presence or lack of medullary relapse. Specimens were assessed centrally. RFS was not estimated in the AALL1731 trial.

Clinical experts consulted for this review advised an RFS between-group difference of 5% to 7% in the overall adult population with Ph-negative B-cell precursor ALL and 5% to 10% in the populations stratified by MRD status is considered clinically meaningful. In the E1910 trial, a 5% to 7% between-group difference in OS in the Step 3 analysis set and a 5% to 10% between-group difference in OS in the FAS and the Step 3 MRD-positive analysis set would be considered clinically meaningful differences.

Disease-Free Survival

In the AALL1731 trial, DFS was defined as the time from randomization to the date of relapse, a second malignant neoplasm, or death, whichever occurred first. Relapse included bone marrow relapse, CNS relapse, testicular relapse, or other extramedullary relapse. Specimens were assessed centrally. DFS was not estimated in the E1910 trial.

Clinical experts consulted for this review advised a DFS between-group difference of 3% to 5% in both the overall population and risk-of-relapse stratified populations is considered clinically meaningful. In the AALL1731 trial, a 3% to 5% between-group difference in DFS in the overall cohort and subgroups stratified by risk of relapse (i.e., SR-average and SR-high) would be considered clinically meaningful.

Harms End Points

To assess the toxicities of blinatumomab plus chemotherapy compared to chemotherapy, TEAEs, treatment-emergent SAEs, grade 3 and higher TEAE, fatal TEAE, and TEAEs of special interest were collected in the E1910 trial for all patients who received at least 1 dose of protocol-specified therapies.

SAEs were defined as an SAE requiring expedited reporting via the Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP AERS).

AEs of special interest identified in the product monograph and highlighted as important by clinical experts consulted for this review included:

• cytokine release syndrome

• tumour lysis syndrome (TLS)

• neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome

• serious infections, including sepsis, pneumonia, Fusarium infection, fungal pneumonia, septic shock, Aspergillus infection, bronchopneumonia, Candida infection, enterococcal bacteremia, Escherichia sepsis, and lung infection

• pancreatitis.

In the AALL1731 trial, AEs were assessed with the use of the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The occurrence of selected AEs of grade 3 or higher were summarized. No further details of how AEs were analyzed in the AALL1731 trial were available.

The estimated threshold at which clinical experts consulted for this review deemed fatal TEAEs to be clinically meaningful in both adults and pediatric patients with Ph-negative B-cell precursor ALL was greater than 0%. Thus, a between-group difference of greater than 0% fatal TEAEs in the Step 3 analysis set, the FAS, and the Step 3 MRD-positive analysis set of the E1910 trial and in the overall cohort, the SR-average cohort, and the SR-high cohort of the AALL1731 trial would be considered clinically meaningful. For any grade 3 or greater TEAE, the estimated clinically significant threshold suggested by clinical experts consulted for this review was 10% and greater and, for treatment-emergent SAEs, it was 10% to 15%. A between-group difference of greater than 10% for grade 3 or greater TEAE and 10% to 15% in treatment-emergent SAEs in the Step 3 analysis set, the FAS, and the Step 3 MRD-positive analysis set of the E1910 trial and in the overall cohort and subgroups stratified by risk of relapse (i.e., SR-average and SR-high) of the AALL1731 trial would be considered clinically meaningful.

Considerations that informed the selection of efficacy outcomes to be summarized and assessed using GRADE include the following.

Survival outcomes identified by the patient and clinician group input and specified by the clinical experts consulted for this review were OS and RFS. OS was a key input for the pharmacoeconomic model and was deemed relevant by the clinical experts consulted for this review. For OS, the clinical experts noted that assessing survival at 3 years would allow enough events to have occurred while still showing any early benefit. Clinical experts noted that relapse events would be expected to occur before survival events. For both OS and RFS, a later time point with enough patients at risk are necessary to assess any sustained benefit. As such OS at year 3 and 5 and RFS at year 1, 3, and 5 in the E1910 trial were selected for GRADE. OS and RFS outcomes were assessed in the Step 3 analysis set (i.e., the MRD-agnostic population) to align with the unrestricted reimbursement request under review. OS and RFS in the FAS and the Step 3 MRD-positive analysis set were also assessed in GRADE to align with the primary and secondary outcomes of the E1910 trial and allow for any differences across populations to be highlighted.

Safety and toxicity outcomes were identified as important outcomes by patient and clinical group input. Any grade 3 or greater TEAEs, treatment-emergent SAEs, and fatal TEAEs were identified as the most important safety outcomes by the clinical experts consulted for this review. Safety and toxicity outcomes were only assessed in the Step 3 analysis set of the E1910 trial for GRADE, as this is the population that aligns with the reimbursement request under review, and clinical experts consulted for this review advised to prioritize this population.

Statistical Analysis

The statistical analyses for all study end points included in this review are presented in Table 11.

Table 11: Statistical Analysis of Efficacy End Points From Studies Included in the Systematic Review

ALL = acute lymphoblastic leukemia; CI = confidence interval; COG = Children’s Oncology Group; DCO = data cut-off; DFS = disease-free survival; FAS = full analysis set; HR = hazard ratio; KM = Kaplan-Meier; NA = not applicable; OS = overall survival; PPAS = per-protocol analysis set; RFS = relapse-free survival; RMST = restricted mean survival time; SCT = stem cell transplant; SR-average = standard risk with average risk of relapse; SR-high = standard risk with high risk of relapse.

Source: BLINCYTO Clinical Study Report,¹⁹ BLINCYTO Statistical Analysis Plan v3.0,⁷² and Gupta et al. (2024).⁶⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Sample Size and Power Calculation

The E1910 trial planned to enter a total of 488 patients with Ph-negative B-cell precursor ALL aged 30 to 70 years. It was assumed that a total of 190 (39% of the 488) patients would be MRD-negative and be randomized to receive either blinatumomab plus chemotherapy or chemotherapy alone. It was assumed the survival function of this patient population with ALL could be described by a cure rate model. For patients who were MRD-negative, a 35% long-term cure rate and 13-month median OS in the noncured group in the control arm were assumed. After adjustment for sequential monitoring with 190 patients who were MRD-negative, the study would have 80% power to detect a 45% reduction in hazard rate in the blinatumomab plus chemotherapy arm relative to the chemotherapy arm, using 1-sided log-rank test at the significance level of 0.025 (assuming 2 years of follow-up, which is equivalent to detecting an improvement in the 3-year OS rate from 45% to 64%). The number of events needed was 94.

In the AALL1731 trial, a 5-year baseline DFS rate of 90.1% was assumed (excluding patients with undetectable MRD by HTS). As a result, the AALL1731 trial planned to enrol between 6,420 and 6,720 patients to randomize approximately 2,245 patients and consequently to have about 81% power (2-sided alpha 5%, minimum follow-up of 3 years) to detect (via group sequential log-rank tests) an improvement in 5-year postconsolidation DFS from 90.1% to 93.4% (HR = 0.655; total expected events = 194). Interim DFS analyses were planned when 20% (for nonbinding futility only), 40%, 60%, and 80% of the anticipated 194 DFS events had occurred, with the use of alpha-t² spending functions. A 1-sided P value of 0.025 was used for the interim analyses of DFS; all other analyses used 2-sided P values.

Statistical Test or Model

The preplanned comparison of OS between the E1910 trial treatment arms in the ITT population was conducted using the 1-sided stratified log-rank test with age (30 to 54 versus 55 or older years of age), CD20 status (positive versus negative), rituximab use (yes versus no), and whether patients intend to receive allogeneic SCT or not. Postrelapse systemic anticancer therapies were allowed at the discretion of the treating physician to reflect real-world clinical practice, with no restriction or control over their use and no adjustment in the OS analysis for their potential differential distribution between arms. Critical values for the primary OS comparison were determined using a truncated version of the Lan-DeMets error spending rate function, corresponding to the O’Brien-Fleming boundary, taking into account the errors spent at the interim efficacy analyses such that the overall 1-sided type I error is maintained at 0.025.

Time to events for OS and RFS in the E1910 trial were summarized with HRs using stratified Cox regression models adjusted for sequential monitoring and age (30 to 54 versus 55 or older years of age), CD20 status (positive versus negative), rituximab use (yes versus no), and whether patients intend to receive allogeneic SCT or not.

Additionally, in the E1910 trial, OS and RFS KM plots were presented by treatment arm. Summaries of the proportion alive and/or relapse-free at select time points, KM quartiles (when estimable), the number of patients with events, and the number of patients censored were presented.

While the primary analyses in the AALL1731 trial were stratified log-rank tests (stratified by SR-average with and without Down syndrome, SR-average with Down syndrome, and SR-high), descriptive DFS and OS rates were estimated using the KM method and SE and CIs estimated by the method of Peto. All survival time analyses assume a Weibull distribution with shape parameter of 0.6 (based on historical data) unless otherwise noted.

Multiple Testing Procedure

No multiple testing procedures were used in the E1910 or AALL1731 trials.

Data Imputation Methods

In the E1910 trial, missing or incomplete data for AEs (onset date for late AEs) and death were imputed. Date of AEs was imputed if at least the year of the event was known. The date of death was imputed if at least the year of death is known and if the known date of death is earlier than or the same as the date last known to be alive. If the date of death was fully missing, or if the last known date alive was later than the date of death, the patient’s survival time was censored.

Based on results of similar previous Children’s Oncology Group ALL trials, the AALL1731 trial did not anticipate or plan for substantial or informative missingness.

Post Hoc Analyses

In the E1910 trials, a post hoc analysis was performed comparing the OS and RFS of blinatumomab plus chemotherapy to chemotherapy alone in the Step 3 analysis set.

In the AALL1731 trial, post hoc analyses included evaluating the duration of OS, relapse (overall and according to site of relapse), and DFS in subgroups defined according to patient-related and disease-related factors (described in the Subgroup Analyses section).

Subgroup Analyses

The following prespecified subgroup analyses were performed in the E1910 trial:

• gender (female or male)

• race (groupings from original study) (American Indian or Alaska Native, Asian, Black, or African American, Native Hawaiian or Other Pacific Islander, or white)

• ethnicity (Hispanic or Latino or not Hispanic or Latino)

• age (≥ 18 years to < 35 years [in practicality, the lower bound of this bracket aligns with the enrolment criteria of ≥ 30 years], ≥ 35 years to < 55 years, ≥ 55 years to < 65 years, or ≥ 65 years).

In the AALL1731 trial, the DFS analysis was repeated among those with SR-average and SR-high risk category. Additionally, the following post hoc subgroup analyses of DFS were performed, but were not formally powered:

• sex (female or male)

• race or ethnic group (Hispanic, non-Hispanic Asian, non-Hispanic Black, non-Hispanic white, or other or unknown)

• CNS status (CNS-1 [defined by no leukemic blasts as assessed by cytologic evaluation] or CNS-2 [defined by < 5 white cells per microlitre and the presence of blasts or traumatic lumbar puncture with the presence of blasts as assessed by cytologic evaluation but the absence of blasts as calculated by means of the Steinherz-Bleyer algorithm])

• cytogenetic risk group (favourable, neutral, or unfavourable)

• MRD in bone marrow on day 29, as assessed by multiparameter flow cytometry (less than 0.01% or greater than and equal to 0.01%)

• MRD in bone marrow on day 29, as assessed by HTS (detectable less than 1 × 10^–5 or detectable greater than and equal to 1 × 10^–5).

Subgroup analyses in both the E1910 and AALL1731 trials are reported as supportive evidence.

Sensitivity Analyses

In the E1910 trial, sensitivity analyses on primary efficacy analyses (OS and RFS) in the population that was MRD-negative were repeated:

• using the per-protocol analysis set (includes subjects in FAS excluding the following protocol deviations: noncompliant treatment administration at Step 3 and subjects randomized but ineligible for Step 3 treatment)

• where OS or RFS is censored at the time of allogeneic SCT, using the FAS

• where OS or RFS is censored at the time of allogeneic SCT or start of nonprotocol systemic anticancer therapy, whichever is earlier, using the FAS

• RMST by Step 3 arm and difference in RMST with 95% CI will be presented using the FAS.

In the AALL1731 trial, a post hoc per-protocol sensitivity analysis that included only randomly assigned patients who started postconsolidation therapy was performed. In the event of strong evidence of nonproportionality of the DFS KM survival curves, a RMST sensitivity analysis was used with follow-up truncated at the time of the last follow-up visit. No other information on sensitivity analysis was available.

Analysis Populations

The analysis populations are defined in Table 12.

Table 12: Analysis Populations of the E1910 and AALL1731 Trials

ALL = acute lymphoblastic leukemia; FAS = full analysis set; ITT = intention-to-treat; MRD = minimal residual disease; PPAS = per-protocol analysis set; SR-average = standard risk with average risk of relapse; SR-high = standard risk with high risk of relapse.

Source: BLINCYTO E1910 Clinical Study Report and Gupta et al. (2024).^19,68 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Throughout the Results section, a summary of the E1910 trial is initially presented followed by a summary of the AALL1731 trial.

Unless otherwise specified, patient disposition results from the E1910 trial are presented among those included in the Step 3 analysis set; efficacy data are presented among those included in the Step 3 analysis set, the FAS, and the Step 3 MRD-positive analysis set; and harm results are presented among the Step 3 safety analysis set.

In the AALL1731 trial, patient disposition is presented among those with SR-average and SR-high risk categories, efficacy data are presented among the overall cohort, and those with SR-average and SR-high risk categories, and harm results are presented among those with SR-average and SR-high risk categories who started postconsolidation protocol therapy.

Patient Disposition

Of 488 patients enrolled in the E1910 trial for induction therapy, 147 discontinued treatment primarily due to other reasons (n = 41) and disease progression relapse (n = 21), and 8 patients did not initiate treatment (Table 24). While 333 patients registered for intensification treatment, 2 patients did not initiate treatment and 45 discontinued treatment primarily due to disease progression relapse during active treatment (n = 12). As a result, 286 eligible patients were randomized or assigned to a treatment arm and included in the Step 3 analysis set (152 patients in the blinatumomab plus chemotherapy arm and 134 patients in the chemotherapy arm; Table 13). A higher percentage of patients in the blinatumomab plus chemotherapy arm completed Step 3 (consolidation) treatment (94 of 152 [61.8%]) compared to those in the chemotherapy arm (70 of 134 [52.2%]). The primary reason for discontinuation of consolidation treatment was due to AEs or complications in the blinatumomab plus chemotherapy arm (9.2%) and in the chemotherapy arm it was primarily due to disease progression or relapse during active treatment (15.7%). In both arms, the primary reason for discontinuing the study was due to death (19.7% in the blinatumomab plus chemotherapy arm and 39.6% in the chemotherapy arm).

In the AALL1731 trial, 4,264 patients with SR B-cell ALL were screened for enrolment and 246 patients were excluded before risk stratification at the end of induction (Table 24). An additional 2,578 patients were ineligible or excluded from randomization, ultimately resulting in 1,440 patients randomized to either blinatumomab plus chemotherapy (n = 718) or chemotherapy (n = 722). Among those randomized, 835 had SR-average risk category (n = 417 in the blinatumomab plus chemotherapy arm and n = 418 in the chemotherapy arm) and 605 had SR-high risk category (n = 301 in the blinatumomab plus chemotherapy arm and n = 304 in the chemotherapy arm). No data were provided on the percentage of patients completing or discontinuing the intervention treatment in the AALL1731 trial.

Table 13: Summary of Patient Disposition Postrandomization From Studies Included in the Systematic Review

DCO = data cut-off; FAS = full analysis set; MRD = minimal residual disease; NA = not applicable; NR = not reported; SR-average = standard risk with average risk of relapse; SR-high = standard risk with high risk of relapse.

Source: BLINCYTO E1910 Clinical Study Report and Gupta et al. (2024).^19,68 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics for the Step 3 analysis set are outlined in Table 14 and are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. Additional baseline characteristics from the E1910 trial that were deemed to be less clinically relevant by the clinical experts consulted for this review are presented in Table 25 for completeness.

The baseline demographics and characteristics in the E1910 trial were generally well balanced between the 2 treatment arms. For the blinatumomab plus chemotherapy arm (N = 152) and chemotherapy arm (N = 134), 45.4% and 52.2% of patients, respectively, were male (versus 54.6% and 47.8% were female, respectively), and the median age at enrolment was 51 years (range, 30 to 69 years) and 50.5 years (range, 30 to 70 years), respectively. The majority of patients were younger than 55 years (60.5% in the blinatumomab plus chemotherapy arm and 56.7% in the chemotherapy arm). Fewer patients in the blinatumomab plus chemotherapy arm were aged 65 years or older (7.9%) than in the chemotherapy arm (14.9%). The majority of patients were white (77.0% in the blinatumomab plus chemotherapy arm and 82.1% in the chemotherapy arm) and were not of Hispanic or Latino ethnicity (82.2% in the blinatumomab plus chemotherapy arm and 82.8% in the chemotherapy arm). Most patients had an ECOG PS of 0 (37.5% and 36.6%, respectively) or 1 (57.2% and 60.4%, respectively), and the primary country of residence was the US (92.1% and 89.6%, respectively), with relatively few patients coming from Canada (6.6% and 5.2%, respectively). Baseline characteristics stratified by MRD status were generally similar between treatment arms for patients who were MRD-negative but not for those who were MRD-positive (Table 26).

In both those with SR-average and SR-high risk categories, the baseline demographics and characteristics in the AALL1731 trial were generally well balanced between the 2 treatment arms. Slightly fewer patients were female (range from 45.1% [137 of 304] in the SR-high chemotherapy arm to 49.6% [207 of 417] in the SR-average blinatumomab plus chemotherapy arm) than male, and median age ranged from 4.0 years (range, 1.0 to 9.9 years) in the SR-average blinatumomab plus chemotherapy arm to 4.6 years (range, 1.0 to 10.0 years) in the SR-high blinatumomab plus chemotherapy arm. The majority of patients were non-Hispanic white (range from 46.1% [140 of 304] in the SR-high chemotherapy arm to 51.8% [156 of 301] in the SR-high blinatumomab plus chemotherapy arm). Just 3.8% (32 of 835) of the SR-average cohort had Down syndrome, while patients with SR-high risk category who had Down syndrome were not included in the randomized population. Patients were primarily from the US (87.4% [730 of 835] in the SR-average cohort and 87.4% [529 of 605] in the SR-high cohort), with just 5.6% and 6.8% of patients in the SR-average and SR-high cohorts, respectively, coming from Canada.

Table 14: Summary of Baseline Characteristics From Studies Included in the Systematic Review

CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; IQR = interquartile range; HTS = high-throughput sequencing; MPFC = multiparameter flow cytometry; MRD = minimal residual disease; NA = not applicable; NR = not reported; PS = performance status; SD = standard deviation; SR-average = standard risk with average risk of relapse; SR-high = standard risk with high risk of relapse.

Notes: Step 3 analysis set includes all Step 3 randomized or registered patients.

MRD-positive before Step 3: MRD value ≥ 0.01%; MRD-negative before Step 3: MRD value ≤ 0.01%.

Baseline is the last assessment taken on or before the date of first protocol-specified therapy administration for Step 3. If no protocol-specified therapy is administered for Step 3, then baseline is the last assessment taken on or before the date of randomization or Step 3 registration. For baseline, body surface area and weight consider the latest nonmissing assessment taken before postrandomization or Step 3 registration.

DCO date: June 23, 2023.

^aCNS-1 was defined by no leukemic blasts, as assessed by cytologic evaluation. CNS-2 was defined by fewer than 5 white cells per microlitre and the presence of blasts or traumatic lumbar puncture with the presence of blasts as assessed by cytologic evaluation but the absence of blasts as calculated by means of the Steinherz-Bleyer algorithm.

^bPatients with DT and MRD of 0.01% to less than 0.1% in the bone marrow at the end of induction therapy as assessed by multiparameter flow cytometry were categorized as having SR B-cell ALL with an average risk of relapse but did not undergo MRD testing by HTS.

Source: BLINCYTO E1910 Clinical Study Report and Gupta et al. (2024).^19,68 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

No data on exposure to treatment in the AALL1731 trial were provided.

Exposure to Protocol Treatments

Of the 147 patients in the Step 3 safety analysis set of the E1910 trial who received blinatumomab plus chemotherapy, 37 patients (25.2%) received on-protocol allogeneic SCT compared to 28 of 128 (21.9%) in the chemotherapy arm (Table 15). All patients in the chemotherapy arm had observed data for exposure to consolidation chemotherapy compared to just 92 patients in the blinatumomab plus chemotherapy arm. A similar number of patients in both treatment arms had observed data for exposure to maintenance chemotherapy (n = 78 and n = 71, respectively). The relative dose intensity of consolidation and maintenance chemotherapy was similar in both treatment arms.

In the E1910 trial, all 147 patients in the blinatumomab plus chemotherapy arm received at least 1 dose of blinatumomab. The median relative dose intensity of 0.84 (IQR 0.73 to 0.99) indicates that more than three-quarters of patients received lower doses of blinatumomab than planned.

Table 15: Summary of Patient Exposure to Treatments From Studies Included in the Systematic Review

IQR = interquartile range; NA = not applicable; RDI = relative dose intensity; SCT = stem cell transplant; SD = standard deviation.

Note: DCO date: June 23, 2023.

^aRegimen-specific relative dose intensity is calculated as (actual dose intensity/planned dose intensity).

^bRelative dose intensity is reported for all chemotherapy regimens used during the phase of treatment.

Source: BLINCYTO Clinical Study Report.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Nonprotocol Treatments

By the June 23, 2023, DCO of the E1910 trial, a similar percentage of patients in both arms of the E1910 trial received nonprotocol therapy for ALL before a protocol-defined relapse (4 of 152 [2.6%] in the blinatumomab plus chemotherapy and 6 of 134 [4.5%] in the chemotherapy arm), with the most common type being nonprotocol chemotherapy in both arms (1.3% and 2.2%, respectively; Table 16).

Table 16: Summary of Exposure to Nonprotocol Therapy for ALL From Studies Included in the Systematic Review

ALL = acute lymphoblastic leukemia.

Source: BLINCYTO Clinical Study Report.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Use of Subsequent Therapies

Following a protocol-defined relapse in the E1910 trial, a higher percentage of patients in the chemotherapy arm received off-protocol allogeneic SCT (12 of 134 [12.7%] versus 12 of 152 [7.9%] in the blinatumomab plus chemotherapy arm) and off-protocol blinatumomab (25.4% versus 0.0% in the blinatumomab plus chemotherapy arm; Table 17). Receipt of CAR T-cell therapy was █████████████ in the blinatumomab plus chemotherapy arm (████) than in the chemotherapy arm (████).

Table 17: Summary of Exposure to Off-Protocol Therapy for ALL From Studies Included in the Systematic Review

ALL = acute lymphoblastic leukemia; CAR = chimeric antigen receptor; SCT = stem cell transplantation.

^aSponsor clarified off-protocol therapies were those given following a protocol-defined relapse.

^bCAR T-cell therapy information was collected from sites in the first quarter of 2024 in response to an FDA query.

Source: BLINCYTO Clinical Study Report.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

Efficacy Results From the E1910 Trial

OS in the Step 3 Analysis Set

OS results for the Step 3 analysis set of the E1910 trial at the June 23, 2023, DCO are summarized in Table 18. The median follow-up time for OS was 4.5 years for both treatment arms, and the median OS was NE in either arm. The OS stratified HR was 0.47 (95% CI, 0.30 to 0.74, P < 0.001) favouring the blinatumomab plus chemotherapy arm. The difference in survival probabilities for blinatumomab plus chemotherapy versus chemotherapy was 16.9% in year 1 and 20.8% in year 5. The KM plot for OS in the Step 3 analysis set is presented in Figure 5.

Figure 5: Kaplan-Meier Analysis for OS — E1910 Trial Step 3 Analysis Set

CI = confidence interval; NE = not evaluable; OS = overall survival; SOC = standard of care.

Notes: Censor indicated by vertical bar I. Step 3 randomization or registration date is the reference date for analysis of the descriptive OS analyses.

DCO date: June 23, 2023.

Source: BLINCYTO Clinical Study Report.¹⁹

OS in the FAS

OS results for the FAS of the E1910 trial at the June 23, 2023, DCO are summarized in Table 19. The median follow-up time for OS was 4.5 years for both treatment arms, and a higher percentage of deaths occurred in the chemotherapy arm (40 of 112 [35.7%]) compared to the blinatumomab plus chemotherapy arm (19 of 112 [17.0%]). The median OS was NE in both arms. The difference in survival probabilities for blinatumomab plus chemotherapy versus chemotherapy was 15.6% in year 1 and 19.9% in year 5. The KM plot for OS in the FAS is presented in Figure 6.

Subgroup and sensitivity analyses were generally consistent with those of the main analysis (Table 27, Table 30, Table 31, and Table 32).

Figure 6: Kaplan-Meier Analysis for OS — E1910 Trial FAS

CI = confidence interval; FAS = full analysis set; NE = not evaluable; OS = overall survival; SOC = standard of care.

Notes: Censor indicated by vertical bar I. Step 3 randomization date is the reference date for analysis of the primary OS end point.

DCO date: June 23, 2023.

Source: BLINCYTO Clinical Study Report.¹⁹

OS in the Step 3 MRD-Positive Analysis Set

OS results for the Step 3 MRD-positive analysis set of the E1910 trial at the June 23, 2023, DCO are summarized in Table 19. The median follow-up time for OS was 4.6 years for the blinatumomab plus chemotherapy arm and 5.0 years for the chemotherapy arm. A higher percentage of deaths occurred in the chemotherapy arm (13 of 22 [59.1%]) compared to the blinatumomab plus chemotherapy arm (11 of 40 [27.5%]). Median OS was NE in the blinatumomab plus chemotherapy arm and was 1.9 (95% CI, 0.6 to NE) years in the chemotherapy arm. The difference in survival probabilities for blinatumomab plus chemotherapy versus chemotherapy was 31.3% in year 1 and 32.3% in year 5. The KM plot for OS in the Step 3 analysis set is presented in Figure 7.

Figure 7: Kaplan-Meier Analysis for OS — E1910 Trial Step 3 MRD-Positive Analysis Set

CI = confidence interval; MRD = minimal residual disease; NE = not evaluable; OS = overall survival; SOC = standard of care.

Notes: Censor indicated by vertical bar I. Step 3 randomization or registration date is the reference date for descriptive OS analyses using MRD-positive patients at Step 3.

DCO date: June 23, 2023.

Source: BLINCYTO Clinical Study Report.¹⁹

RFS in the Step 3 Analysis Set

The RFS results for those in the Step 3 analysis set of the E1910 trial are reported in Table 18. The median follow-up time for RFS was 4.5 years for both treatment arms, and median time to a relapse event was NE in both arms. The difference in the probability of remaining relapse-free for blinatumomab plus chemotherapy versus chemotherapy was 12.2% in year 1, 17.3% in year 3, and 18.4% in year 5. The KM plot for RFS in the Step 3 analysis set is presented in Figure 8.

Figure 8: Kaplan-Meier Analysis for RFS — E1910 Trial Step 3 Analysis Set

CI = confidence interval; HR = hazard ratio; KM = Kaplan-Meier; NE = not evaluable; RFS = relapse-free survival; SOC = standard of care.

Notes: Censor indicated by vertical bar I. Step 3 randomization or registration date is the reference date for analysis of the descriptive RFS analyses.

DCO date: June 23, 2023.

Source: BLINCYTO Clinical Study Report.¹⁹

RFS in the FAS

The RFS results for those in the FAS of the E1910 trial are reported in Table 19. The median follow-up time for RFS was 4.5 years for both treatment arms. Median time to a relapse event was NE in both arms. The difference in the probability of remaining relapse-free for blinatumomab plus chemotherapy versus chemotherapy was 8.2% in year 1, 15.4% in year 3, and 16.5% in year 5. The KM plot for OS in the Step 3 analysis set is presented in Figure 9.

Subgroup analyses were generally consistent with those of the main analysis (Table 27).

Figure 9: Kaplan-Meier Analysis for RFS — E1910 Trial FAS

CI = confidence interval; FAS = full analysis set; NE = not evaluable; RFS = relapse-free survival; SOC = standard of care.

Notes: Censor indicated by vertical bar I. Step 3 randomization date is the reference date for the RFS analysis of the secondary end point examining RFS in MRD-negative patients at Step 3.

DCO date: June 23, 2023.

Source: BLINCYTO Clinical Study Report.¹⁹

RFS in the Step 3 MRD-Positive Analysis Set

The RFS results for those in the Step 3 MRD-positive analysis set of the E1910 trial are reported in Table 19. The median follow-up time for RFS was 4.6 years in the blinatumomab plus chemotherapy arm and 5.0 years in the chemotherapy arm. Median time to a relapse event was NE (95% CI, NE to NE) in the blinatumomab plus chemotherapy arm and 0.6 (95% CI, 0.2 to NE) years in the chemotherapy arm. The difference in the probability of remaining relapse-free for blinatumomab plus chemotherapy versus chemotherapy was 38.0% in year 1 and 32.4% in years 3 and 5. The KM plot for OS in the Step 3 analysis set is presented in Figure 10.

Figure 10: Kaplan-Meier Analysis for RFS — E1910 Trial Step 3 MRD-Positive Analysis Set

CI = confidence interval; MRD = minimal residual disease; NE = not evaluable; RFS = relapse-free survival; SOC = standard of care.

Notes: Censor indicated by vertical bar I. Step 3 randomization or registration date is the reference date for descriptive RFS analyses using MRD-positive patients at Step 3.

DCO date: June 23, 2023.

Source: BLINCYTO Clinical Study Report.¹⁹

Efficacy Results From the AALL1731 Trial

Overall Survival

OS results in the overall cohort of the AALL1731 trial at the June 30, 2024, DCO are summarized in Table 18. The median duration of follow-up was 2.5 years (IQR, 1.6 to 3.2 years). The probability of survival from randomization to 3 years was 98.4% (SE = 0.9%) for those in the blinatumomab plus chemotherapy arm and was 97.1% (SE = 1.1) for those in the chemotherapy arm. The KM plot is presented in Figure 11.

Subgroup analyses stratified by patients with SR-average and SR-high risk categories were consistent with those of the main analysis (Figure 11 and Table 28).

Figure 11: Kaplan-Meier Analysis for OS — AALL1731 Trial

ALL = acute lymphoblastic leukemia; ITT = intention-to-treat; OS = overall survival; SR-average = standard risk with average risk of relapse; SR-high = standard risk with high risk of relapse.

Notes: OS was not a protocol-specified formal end point.

DCO date: June 30, 2024.

Source: From New Engl J Med, Gupta S et al., Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. Copyright © (2025) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Disease-Free Survival

DFS results in the overall cohort of the AALL1731 trial at the June 30, 2024, DCO are summarized in Table 18. The median duration of follow-up was 2.5 years (IQR, 1.6 to 3.2 years). The probability of survival from randomization to 3 years was 96.0% (SE = 1.2%) for those in the blinatumomab plus chemotherapy arm and was 87.9% (SE = 2.1%) for those in the chemotherapy arm. The DFS stratified HR was 0.39 (95% CI, 0.24 to 0.64), favouring the blinatumomab plus chemotherapy arm. The KM plot for DFS in the overall cohort is presented in Figure 12.

Subgroup analyses stratified by patients with SR-average and SR-high risk categories were consistent with those of the main analysis (Figure 12 and Table 28). Post hoc subgroup analyses were generally consistent with those of the main analysis (Figure 13). Of note, when stratifying results of the overall cohort only by MRD status by multiparameter flow cytometry at day 29 (i.e., at the end of induction), results were similar to the overall cohort in those with a MRD less than 0.01% (i.e., MRD-negative) and 0.01% and greater (i.e., MRD-positive).

Sensitivity analyses using RMST indicated that the addition of blinatumomab to chemotherapy improved DFS, as measured by the difference in RMST by 72 days (95% CI, 36 to 108 days; P < 0.001 by stratified log-rank test; Table 33). Sensitivity analyses using RMST among patients with SR-average and SR-high were consistent with those of the main analysis (Table 33).

Figure 12: Kaplan-Meier Analysis for DFS — AALL1731 Trial

ALL = acute lymphoblastic leukemia; DFS = disease-free survival; KM = Kaplan-Meier; SR-average = standard risk with average risk of relapse; SR-high = standard risk with high risk of relapse.

Note: DCO date: June 30, 2024.

Source: From New Engl J Med, Gupta S et al., Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children. Copyright © (2025) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Table 18: E1910 and AALL1731 Trials — Summary of Key Efficacy Results in the Overall Trial Populations

CI = confidence interval; DFS = disease-free survival; HR = hazard ratio; IQR = interquartile range; KM = Kaplan-Meier; NE = not evaluable; NR = not reported; OS = overall survival; RFS = relapse-free survival; SE = standard error.

Notes: OS analyses in E1910 and AALL1731, RFS analysis in the Step 3 analysis set of E1910, and DFS analysis in the overall cohort of AALL1731 were performed post hoc.

DCO dates: E1910 = June 23, 2023; AALL1731 = June 30, 2024.

^aThe HR estimates are obtained from a stratified Cox regression model. An HR < 1.0 indicates a lower average death rate and a longer survival for patients in the blinatumomab plus chemotherapy arm relative to patients in the chemotherapy-only arm.

^bOne-sided stratified log-rank test P value is provided.

^cYears are calculated as days from randomization or registration date to event or censor date, divided by 365.25.

^dDefined as median KM time to censoring in the E1910 trial.

^eTime to censoring measures follow-up time by reversing the status indicator for censored events.

^fP values are presented from interim analyses; however, thresholds for efficacy or futility were not reported in the trial’s statistical analysis plan. As a result, these P values should not be interpreted as evidence of statistical significance.

Source: BLINCYTO E1910 Clinical Study Report and Gupta et al. (2024).^19,68 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 19: E1910 Trial — Summary of Key Efficacy Results Stratified by MRD status, FAS and Step 3 MRD-Positive Analysis Set

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; MRD = minimal residual disease; NE = not evaluable; OS = overall survival; RFS = relapse-free survival.

Note: DCO date: June 23, 2023.

^aThe HR estimates are obtained from a stratified Cox regression model. A HR < 1.0 indicates a lower average death rate and a longer survival for patients in the blinatumomab plus chemotherapy arm relative to patients in the chemotherapy-only arm.

^bOne-sided stratified log-rank test P value is provided.

^cYears are calculated as days from randomization or registration date to event or censor date, divided by 365.25.

^dDefined as median KM time to censoring in the E1910 trial.

^eTime to censoring measures follow-up time by reversing the status indicator for censored events.

Note: OS analyses in the MRD-negative cohort (FAS) was the primary end point of E1910; OS in the MRD-positive cohort (Step 3 MRD-positive analysis set) and RFS in the MRD-negative and MRD-positive cohorts were secondary end points in E1910.

Source: BLINCYTO Clinical Study Report.¹⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

Refer to Table 20 for harms data.

Treatment-Emergent AEs

By June 23, 2023, a similar percentage of patients in both treatment arms of the Step 3 safety analysis set in the E1910 trial experienced a TEAE (145 of 147 [98.6%] in the blinatumomab plus chemotherapy arm and 125 of 128 [97.7%] in the chemotherapy arm). The 3 most common TEAEs in the blinatumomab plus chemotherapy arm were investigations (e.g., blood cell counts; 91.8%), blood and lymphatic system disorders (e.g., anemia; 62.6%), and nervous system disorders (e.g., headache; 57.8%). In the chemotherapy arm, the 3 most common TEAEs were investigations (96.9%), blood and lymphatic system disorders (70.3%), and gastrointestinal disorders (e.g., diarrhea; 44.5%).

TEAEs of any grade in the AALL1731 trial were not provided in the materials received by the CDA-AMC review team.

Grade 3 or Higher TEAEs

A similar percentage of patients in both treatment arms of the Step 3 safety analysis set in the E1910 trial experienced a grade 3 or greater TEAE (141 of 147 [95.9%] in the blinatumomab plus chemotherapy and 125 of 128 [97.7%] in the chemotherapy arm). In the blinatumomab plus chemotherapy arm, the 3 most common grade 3 or higher TEAEs were the same as the 3 most common TEAEs of any grade (i.e., investigations [89.8%], blood and lymphatic system disorders [39.5%], and nervous system disorders [22.4%]). In the chemotherapy arm, the 3 most common grade 3 or higher TEAEs were investigations (96.1%), blood and lymphatic system disorders (57.0%), and infection and infestation (e.g., sepsis; 24.2%).

The reporting of TEAEs in the AALL1731 trial were restricted to selected grade 3 or higher ones stratified by patients with SR-average or SR-high. Generally, it was reported that the percentage of select grade 3 of higher TEAEs were well balanced across treatment arms in the AALL1731 trial. Notable differences included a higher percentage of patients in the blinatumomab plus chemotherapy arms of both the SR-average (47.0% [165 of 351]) and SR-high (57.1% [156 of 273]) risk categories who experienced febrile neutropenia than in the chemotherapy arm alone (39.6% [149 of 376] and 50.5% [140 of 277], respectively), and in the SR-average risk category, a higher percentage of patients in the blinatumomab plus chemotherapy arm who experienced sepsis or catheter-related infection (14.8%) and other infections (32.8%) than in the chemotherapy arm alone (5.1% and 26.3%, respectively). In both SR-average and SR-high risk categories, the 3 most common grade 3 or higher TEAEs in the blinatumomab plus chemotherapy arms were febrile neutropenia (47.0% and 57.1%, respectively), other infection (32.8% and 35.2%, respectively), and sepsis or catheter-related infection (14.8% and 20.9%, respectively). In both SR-average and SR-high risk categories, the 3 most common grade 3 or higher TEAEs in the chemotherapy arms were febrile neutropenia (39.6% and 50.5%, respectively), other infections (26.3% and 37.9%, respectively), and mucositis (15.4% and 17.7%, respectively).

In both SR-average and SR-high subgroups, 1 patient in the blinatumomab plus chemotherapy group and no patient in the chemotherapy group experienced cytokine release syndrome of grade 3 or higher. In the SR-average subgroup, 3 (0.9%) and 4 (1.1%) patients experienced pancreatis of grade 3 or higher in the blinatumomab plus chemotherapy and chemotherapy groups, respectively. Patients in this subgroup experienced neurotoxic events of grade 3 or higher (seizure: 4 [1.1%] and 7 [1.9%]; all other CNS events: 2 [0.6%] and 3 [0.8%]; and peripheral neuropathy: 2 [0.6%] and 9 [2.4%] in the blinatumomab plus chemotherapy and chemotherapy groups, respectively). In the SR-high subgroup, 11 (4.0%) and 8 (2.9%) of patients experienced pancreatis of grade 3 or higher in the blinatumomab plus chemotherapy and chemotherapy groups, respectively. Patients in this subgroup experienced neurotoxic events of grade 3 or higher (seizure: 10 [3.7%] and 7 [2.5%]; all other CNS events: 3 [1.1%] and 4 [1.4%]; peripheral neuropathy: 6 [2.2%] and 2 [0.7%] in the blinatumomab plus chemotherapy and chemotherapy groups, respectively).

Withdrawals Due to AEs

Withdrawals due to AEs were not reported among the Step 3 safety analysis set of the E1910 trial; however, they were available for the Step 3 analysis set. Among patients included in the Step 3 analysis set, 14 of 152 patients (9.2%) in the blinatumomab plus chemotherapy arm discontinued treatment due to AEs, side effects, or complications compared to 5 of 134 patients (3.7%) discontinuing due to AEs, side effects, or complications in the chemotherapy arm.

Withdrawals due to AEs in the AALL1731 trial were not provided in the materials received by the CDA-AMC review team.

Treatment-Emergent SAEs

A higher percentage of patients in the blinatumomab plus chemotherapy arm of the Step 3 safety analysis set in the E1910 trial experienced treatment-emergent SAEs (82 of 147 [55.8%]) than in the chemotherapy arm (36 of 128 [28.1%]). The 3 most common treatment-emergent SAEs in the blinatumomab plus chemotherapy arm were infections and infestations (22.4%), investigations (15.6%), and nervous system disorders (15.0%). In the chemotherapy arm, the 3 most common treatment-emergent SAEs were infections and infestations (14.8%), blood and lymphatic system disorders (11.7%), and investigations (4.7%).

Treatment-emergent SAEs in the AALL1731 trial were not provided in the materials received by the CDA-AMC review team.

Fatal TEAEs

A similar percentage of patients in both treatment arms of the Step 3 safety analysis set in the E1910 trial had a fatal TEAE (3 of 147 [2.0%] in the blinatumomab plus chemotherapy arm and 2 of 128 [1.6%] in the chemotherapy arm). In the blinatumomab plus chemotherapy arm, 2 of the fatal TEAEs were due to sepsis (1.4%) and 1 was due to intracranial hemorrhage (0.7%). In the chemotherapy arm, 1 of the fatal TEAEs was due to sepsis (0.8%) and 1 was due to cardiac arrest (0.8%).

In AALL1731, 5 patients had a fatal TEAE while in remission, all of whom were classified as having high risk of relapse. Two of the patients were in the chemotherapy arm (both deaths were sepsis-related) and 3 patients were in the blinatumomab plus chemotherapy arm (1 death was due to sepsis, 1 was due to multiorgan failure, and 1 was due to hypoxic ischemic encephalopathy). None of the deaths occurred during blinatumomab cycles.

Notable Harms

Among TEAEs of special interest identified in the product monograph and highlighted as important by clinical experts consulted for this review, TLS was not reported for the Step 3 safety analysis set in the E1910 trial. Cytokine release syndrome occurred in a higher percentage of patients in the blinatumomab plus chemotherapy arm (23 of 147 [15.6%]) than in the chemotherapy arm (0 of 128 [0.0%]). While infections were not stratified by those deemed serious, any infections and infestations occurred in a higher percentage of patients in the blinatumomab plus chemotherapy arm (34.7%) than in the chemotherapy arm (27.3%). However, most subcategories of infections of special interest, including Fusarium infection, fungal pneumonia, septic shock, Aspergillus infection, bronchopneumonia, Candida infection, enterococcal bacteremia, Escherichia sepsis, and lung infection, were not reported. Finally, relatively few patients in both treatment arms experienced neurotoxicity (2.4% in the blinatumomab plus chemotherapy arm versus 0.0% in the chemotherapy arm) or pancreatitis (0.0% and 0.8%, respectively).

Some of the TEAEs of special interest identified in the product monograph and highlighted as important by clinical experts consulted for this review are covered in the reporting of grade 3 or greater TEAEs. However, data on notable harms of any grade were not available.

Notable harms in the AALL1731 trial were not provided in the materials received by the CDA-AMC review team.

Table 20: E1910 and AALL1731 Trials — Summary of Harms Results