Reimbursement Review

Blinatumomab

Requester: Public drug programs

Therapeutic area: Philadelphia chromosome–positive acute lymphoblastic leukemia

What Is Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia?

• Philadelphia (Ph) chromosome–positive acute lymphoblastic leukemia (ALL), characterized by the t(9;22)(q34;q11.2) or BCR‑ABL1 rearrangement, occurs in about 3% of pediatric cases of ALL, 5% to 25% of adolescent and young adult cases, and 25% of adult cases, with prevalence increasing with age. Patients with ALL can present with fatigue, dyspnea, infections, and easy or spontaneous bruising or bleeding. In children, pain in the extremities or joints may be the only presenting symptom.

• Data on the prevalence and incidence of Ph-positive ALL in Canada were not available at the time of the clinical review. However, according to estimates, 440 people in Canada were newly diagnosed with ALL (incidence rate of 1.5 per 100,000 people) in 2019.

What Are the Treatment Goals and Current Treatment Options for Ph-Positive ALL?

• Adult patients with ALL and their caregivers identified treatment options that offer prolonged disease remission while minimizing toxicity and helping patients to maintain quality of life as treatment goals. Goals of first-line treatment for patients with Ph‑positive ALL identified by clinicians include achieving and maintaining deep molecular remission, reducing the risk of relapse, prolonging survival, minimizing the need for second- or later-line therapies, and limiting acute and long‑term toxicities.

• Chemotherapy plus a tyrosine kinase inhibitor (TKI) was considered a relevant treatment to compare with blinatumomab plus a TKI.

What Is Blinatumomab and Why Did Canada’s Drug Agency Conduct This Review?

• Blinatumomab is a drug that is administered by IV infusion.

• At the request of the participating public drug programs, Canada’s Drug Agency (CDA‑AMC) reviewed blinatumomab to inform a recommendation on whether it should be reimbursed in combination with a TKI as a first-line treatment for adult and pediatric patients with Ph‑positive ALL.

How Did CDA-AMC Evaluate Blinatumomab?

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects of blinatumomab and compared the costs of blinatumomab in combination with a TKI versus other first-line treatments used in Canada for Ph‑positive ALL in adult and pediatric patients. Chemotherapy plus a TKI was considered a relevant treatment to compare with blinatumomab plus a TKI.

• The clinical evidence was identified through systematic searches for available studies.

• The review was also informed by 1 patient group submission and 3 clinician group submissions (in response to our call for input) and by input from the participating public drug programs with respect to issues that may affect their ability to implement a recommendation.

• Two hematologists, 1 from Atlantic Canada and 1 from Ontario, were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• CDA-AMC reviewed the following clinical evidence:

  • 1 single-arm, phase II trial (the GIMEMA LAL2116 D-ALBA study) of blinatumomab plus dasatinib in 63 patients aged 18 years or older with newly diagnosed, Ph-positive ALL

  • 1 single-arm, phase II trial (the SWOG-S1318 study) of blinatumomab plus dasatinib in a cohort of 24 patients aged 65 years or older with newly diagnosed, Ph-positive ALL who were previously untreated

  • 1 single-arm, phase II trial (the MD Anderson Cancer Center study) of blinatumomab plus ponatinib in a subgroup of 53 patients aged 18 years or older with newly diagnosed, Ph-positive ALL.

• Based on evidence without a comparison for blinatumomab plus dasatinib:

  • The results for molecular response rate after consolidation or postremission therapy in adult and older patients with Ph‑positive ALL and for the minimal residual disease negativity rate at day 28 in older patients with Ph‑positive ALL were favourable, according to the clinical experts consulted; this can likely be attributed to blinatumomab plus dasatinib, despite the single-arm design, because responses do not typically occur spontaneously. The interpretation of these results was limited by risk of bias (due to open-label design and missing outcome data) and by the fact that the uncertainty around the estimates was not quantified (i.e., no confidence intervals were reported).

  • Single-arm designs cannot support causal conclusions for time-to-event end points, and interpretation is limited to clinical opinion. The clinical experts consulted by the review team conveyed that the 3‑year and 4‑year overall survival (OS) rates and 3‑year and 4‑year disease-free survival rates in adult and older patients with Ph‑positive ALL were favourable compared to the rates observed in current clinical practice. There was potential for risk of bias in the measurement of disease-free survival, and there was limited clarity about potential missing data.

  • Results for relapse-free survival were not available in the SWOG‑S1318 study, despite the existence of a planned end point.

  • The evidence was insufficient to determine the effects of blinatumomab plus dasatinib on the occurrence of relapse. There was limited reporting about potential missing data. The differing lengths of follow-ups across patients and competing risks (i.e., death) were not considered.

• Based on evidence without a comparison for blinatumomab plus ponatinib:

  • The results for complete molecular response rate at the end of cycle 1 and overall were favourable, according to the clinical experts consulted; despite the single-arm design, this can likely be attributed to blinatumomab plus ponatinib because responses do not typically occur spontaneously. The interpretation of these results was limited by risk of bias (i.e., due to the open-label design and reliance on a post hoc population) and by the fact that the uncertainty around the estimates was not quantified (i.e., no confidence intervals were reported).

  • Single-arm designs cannot support causal conclusions for time-to-event end points, and interpretation is limited to clinical opinion. The clinical experts consulted by the review team conveyed that the 1‑year OS rate and 3‑year event-free survival rate in adults with Ph‑positive ALL were favourable compared to the rates observed in current clinical practice. There was potential for risk of bias in the measurement of event-free survival, and there was limited follow-up for OS.

• There was no evidence to inform how blinatumomab plus a TKI affects patients’ health-related quality of life.

• There was no evidence to inform the beneficial and harmful effects and costs of blinatumomab plus a TKI as first‑line treatment for Ph‑positive ALL in pediatric patients.

• There was no evidence to inform how blinatumomab plus a TKI compares with chemotherapy plus a TKI as first‑line treatment for Ph‑positive ALL in adult or pediatric patients.

• There was a high rate of serious adverse events. However, the clinical experts consulted believed that the reported harms were as expected. The trials were not adequate in size to capture less common adverse events.

Economic Evidence

Reimbursing blinatumomab for the first-line treatment of Ph-positive ALL in adult and pediatric patients is expected to increase costs to the public drug programs.

Background

Introduction

The objective of the clinical review is to review and critically appraise the evidence on the beneficial and harmful effects of blinatumomab in combination with a tyrosine kinase inhibitor (TKI) for the first-line treatment of Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) in adult and pediatric patients. The focus is on comparing blinatumomab plus a TKI to relevant comparators in clinical practice in Canada and identifying gaps in the current evidence. The economic review consists of a cost comparison for blinatumomab plus a TKI versus relevant comparators for the same population. The comparators that were considered relevant to the reviews were chemotherapy plus a TKI.

Table 1: Information on the Drug Under Review and on the CDA-AMC Review

ALL = acute lymphoblastic leukemia; CDA-AMC = Canada’s Drug Agency; Ph = Philadelphia chromosome; TKI = tyrosine kinase inhibitor.

Context for the Review

Submission History for the Drug Under Review

Canada’s Drug Agency (CDA-AMC) has previously reviewed blinatumomab for the treatment of:

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

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

• adult patients with Ph-positive BCP ALL who have relapsed after or are refractory to at least 1 second-generation or later TKI, or who are intolerant to second-generation or later TKIs and intolerant or refractory to imatinib (a final recommendation to reimburse with clinical criteria and/or conditions was issued on April 4, 2019)

• adult and pediatric patients with Ph-negative, CD19-positive, BCP ALL who are in their first or second hematologic complete remission and are minimal residual disease (MRD)-positive (a final recommendation to reimburse in adult and pediatric patients with clinical criteria and/or conditions was issued on October 29, 2020)

• pediatric patients with Ph-negative, relapsed or refractory B-cell ALL who are in their first relapse (a final recommendation to reimburse in pediatric patients with clinical criteria and/or conditions was issued on February 4, 2025)

• adult and pediatric patients with Ph-negative, CD19-positive B-cell ALL who are in the consolidation phase of multiphase chemotherapy (a final recommendation to reimburse with clinical criteria and/or conditions was issued on May 1, 2025, for adult and pediatric patients whose Ph-negative, CD19-positive B-cell ALL is in remission, regardless of whether patients still have detectable traces of cancer).

Through the Oncology Working Group, the public drug programs have requested a review of blinatumomab in combination with a TKI for the first-line treatment of Ph-positive ALL in adult and pediatric patients (refer to Table 1).

Sources of Information

The contents of this Clinical Review are informed by studies identified through systematic literature searches, input received from interested parties (a patient group, 3 clinician groups, and drug programs), and input from clinical experts consulted for this review.

Calls for patient group, clinician group, and industry input are issued for each nonsponsored reimbursement review. The following submissions were received for the initial project scope on blinatumomab in combination with dasatinib: 1 patient group submission from the Leukemia & Lymphoma Society of Canada (LLSC); and clinician group submissions from the Canadian Leukemia Study Group – Groupe Canadienne d’Étude sur la Leucémie (CLSG-GCEL), the Pediatric Oncology Group of Ontario (POGO), and the Ontario Health (Cancer Care Ontario) (OH [CCO]) Hematology Cancer Drug Advisory Committee (DAC). LLSC provided input from a survey of 94 adult patients with ALL (or caregivers) that had been previously submitted for a reimbursement review for the treatment of adult and pediatric patients with Ph-negative, CD19-positive BCP ALL during the consolidation phase of multiphase chemotherapy in the frontline setting;¹ the submission was supplemented by contextualizing prior input as relevant for the current reimbursement review. CLSG-GCEL provided input from 9 clinicians and information from publicly sourced documents, congress abstracts, and published literature. POGO provided input from 13 clinicians specializing in pediatric oncology from its Technology and Therapeutic Advisory Committee in collaboration with pediatric leukemia experts across Ontario. Input from the OH (CCO) Hematology DAC was submitted by 1 clinician on behalf of the committee (the number of clinicians who provided information through email was not specified). The full submissions received are available on the project landing page in the consolidated input document.

Input from patient and clinician groups is considered throughout the review, including in the selection of outcomes to include in the clinical review and in the interpretation of the clinical evidence. Relevant patient and clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections of the review.

The drug programs provide input on each drug being reviewed through the reimbursement review process by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted for this review are summarized and provided to the expert committee in a separate document.

Each review team includes at least 1 clinical expert 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. Two hematologists with expertise in the diagnosis and management of ALL participated as part of the review team, with representation from Atlantic Canada and Ontario.

Disease Background

ALL is a heterogeneous hematologic disease characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs.² Both the International Consensus Classification of myeloid neoplasms and acute leukemias and the fifth edition of the WHO classification of hematolymphoid tumours categorize ALL according to lymphoid lineage, cytogenetic findings, and molecular features.³ The diagnosis of ALL generally requires demonstration of at least 20% bone marrow lymphoblasts, based on hematopathology review of bone marrow aspirate and biopsy materials from peripheral blood or other involved tissue (e.g., lymph node material); this includes comprehensive immunophenotyping through flow cytometry.² ALL is broadly divided into leukemias of B-cell and T-cell lineage.³ More than two-thirds of ALL cases worldwide are B-cell phenotype, with 75% of cases occurring in children younger than 6 years and a second peak incidence in adults older than 60 years.⁴ The risk factors for developing ALL may include age older than 70 years, exposure to chemotherapy or radiation, infections, and genetic disorders, such as Down syndrome.^2,4 The factors used to define disease risk — and those associated with poor prognosis in adult and childhood ALL — include patient age, white blood cell (WBC) count, cytogenetic and molecular features, the presence of central nervous system (CNS) disease, and response to induction or consolidation therapy.^2,4,5

Ph-positive ALL is characterized by the t(9;22)(q34;q11.2) or BCR-ABL1 rearrangement.³ Ph positivity occurs in about 3% of pediatric ALL cases, 5% to 25% of adolescent and young adult ALL cases, and 25% of adult ALL cases, with prevalence increasing with age.^2,6 In adults with Ph-positive ALL, approximately half of cases express the p210 BCR-ABL1 isoform, with the remainder expressing the p190 fusion protein.³ In children with Ph-positive ALL, the leukemic clone almost always expresses the p190 isoform.³ In addition to the Ph, many cases of ALL have additional cytogenetic abnormalities. For example, splicing abnormalities of IKZF1 (a protein required for normal lymphoid development) may be associated with resistance to TKIs.³

Clinical presentation of patients with ALL is typically nonspecific and may include fatigue or lethargy, dyspnea, infections, fever, night sweats, unintentional weight loss, and easy or spontaneous bruising or bleeding.^2,4 In children, pain in the extremities or joints may be the only presenting symptom.² The presence of lymphadenopathy, splenomegaly, and/or hepatomegaly may be found in approximately 20% of patients with ALL.^2,4

While the 5-year overall survival (OS) has been estimated at 89% for pediatric patients and 61% for adolescents and young adults, survival estimates are approximately 20% to 40% for adults with ALL.² For adults with Ph-positive ALL, the estimated 5-year OS is 25%.²

Data on the prevalence and incidence of Ph-positive ALL in Canada were not available at the time of the clinical review. However, according to estimates, 440 people in Canada were newly diagnosed with ALL (incidence rate of 1.5 per 100,000 people) in 2019.⁷

According to the patient group input, ALL negatively affects patients’ personal and home lives (e.g., by leading to changes in living arrangements, disruption of daily routines, and caregiving burdens), their mental health (e.g., by causing emotional distress), and their relationships (e.g., because of isolation due to immunosuppression, reduced social engagements due to fatigue and physical limitations, loss of friendships and social connections, and emotional withdrawal due to changes in appearance or self-confidence).

Current Management

Treatment Goals

According to the patient group input, adult patients with ALL and their caregivers seek new treatments that offer prolonged disease remission while allowing them to maintain quality of life. Although minimizing toxicity was also an important treatment goal, many patients expressed a willingness to face potential or unknown adverse events (AEs) to achieve longer remission from ALL.

With respect to clinician input, the clinical experts and clinician groups agreed that patients with Ph-positive ALL need first-line treatments that prolong survival and reduce both the risk of relapse and the need for second- or later-line therapies, including allo-SCT whether used in later lines of therapy or for consolidation. The clinical experts also emphasized the importance of achieving and maintaining deep molecular remission (i.e., MRD negativity); CLSG-GCEL noted that BCR-ABL transcript levels measured through MRD assessment are good predictors of both relapse risk and OS. Finally, the clinical experts expressed that patients with Ph-positive ALL would benefit from treatments associated with minimal acute and long-term toxicities.

Current Treatment Options

Patients with Ph-positive ALL are treated according to a contemporary published protocol, according to the clinical experts. Although the selection of drugs, dose schedules, and treatment durations can vary across therapy regimens, the treatment approach broadly includes phases of induction, consolidation, and maintenance.² Commonly used treatment regimens for ALL include pediatric or pediatric-inspired multidrug therapy adapted from groups such as Berlin-Frankfurt-Münster, the Children’s Oncology Group (COG), the Dana Farber Cancer Institute (DFCI), the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia, and the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen developed by the MD Anderson Cancer Center (MDACC).²

The backbone of induction regimens for ALL typically includes a combination of vincristine, anthracyclines (e.g., doxorubicin), and corticosteroids (e.g., dexamethasone or prednisone) with or without L-asparaginase and/or cyclophosphamide.² For patients younger than 65 years (including adolescents and young adults) with Ph-positive ALL and without substantial comorbidities, the recommended first-line treatment is a TKI in combination with multidrug therapy, blinatumomab, blinatumomab and corticosteroids, or hyper-CVAD.² The choice of a TKI plus a glucocorticoid or a TKI plus chemotherapy may be influenced by individual centres and patient preference. The selection of a TKI (e.g., dasatinib, imatinib, or ponatinib) may be guided by efficacy (e.g., ponatinib has been associated with improved outcomes compared with first- or second-generation TKIs^8,9), patient comorbidities, and the drug’s toxicity profile.¹⁰ The intent of induction therapy is to reduce tumour burden by clearing as many leukemic cells as possible from the bone marrow,² with the goal of achieving initial complete hematologic remission (CHR) and reduced disease symptoms.¹⁰ The role of allogeneic hematopoietic cell transplant (allo-HCT), historically considered as standard of care, has become less clear with the advent of TKIs that target BCR-ABL.²

Although CNS involvement at the time of diagnosis is uncommon (occurring in 3% to 7% of cases), more than 50% of patients will eventually develop CNS leukemia in the absence of CNS-directed therapy (e.g., cranial irradiation or intrathecal [IT] therapy).² Therefore, all patients with Ph-positive ALL receive CNS prophylaxis to clear leukemic cells within sites that cannot be readily accessed by systemic chemotherapy due to the blood-brain barrier, with the goal of preventing CNS disease or relapse.² CNS prophylaxis can include systemic therapy (e.g., methotrexate or cytarabine) and/or IT therapy (e.g., IT methotrexate, IT cytarabine, or triple-IT therapy with methotrexate, cytarabine, and corticosteroid).²

The intensity of a treatment regimen (i.e., low, moderate, or high) is based on the presence of myelosuppressive cytotoxic drugs and the relative dose intensity of included drugs.² Low-intensity induction therapy can include a TKI in combination with either blinatumomab, a corticosteroid, or vincristine and dexamethasone.² Moderate-intensity induction includes most multidrug or anthracycline-containing regimens (e.g., a variant of hyper-CVAD with reduced doses of chemotherapy and no anthracycline, referred to as mini–hyperfractionated cyclophosphamide, vincristine, and dexamethasone).² High-intensity induction therapy is suitable for medically fit patients, given that it may be associated with substantial treatment-related morbidity and mortality (e.g., a TKI combined with a hyper-CVAD–based regimen consisting of 8 cycles of alternating courses of cyclophosphamide, vincristine, doxorubicin, and dexamethasone with high-dose methotrexate, cytarabine, and leucovorin rescue).¹⁰ For adults aged 65 years or older, dose reductions of pegylated asparaginase, anthracycline, and/or other myelosuppressive drugs may be warranted.²

More than 90% of adults with Ph-positive ALL will achieve CHR with TKI-based induction therapy. However, nearly all patients’ disease will relapse without postremission management.¹¹ Postremission management of Ph-positive ALL is informed by general medical fitness and burden of residual disease as assessed by MRD.¹¹ It can include consolidation therapy (also called the intensification phase) soon after achieving complete remission (CR) and maintenance therapy.¹⁰ Consolidation therapy can include blinatumomab combined with a TKI, continued multidrug therapy, a corticosteroid combined with a TKI, or a TKI alone, in rare circumstances. For patients who achieve MRD negativity following consolidation therapy, subsequent treatment can include maintenance TKI or allo-HCT followed by post-HCT with TKI alone.² Although the optimal duration of maintenance treatment with a TKI is unknown,² it is generally continued indefinitely for patients who do not undergo a transplant.¹² For patients receiving a maintenance TKI, the treatment regimen may also include methotrexate, 6-mercaptopurine, steroids, and vincristine or vinblastine.² The goal of postremission management is to eliminate leukemic cells that remain after achievement of CR, achieve and sustain MRD negativity, enable long-term disease control, prolong survival, and potentially achieve cure.¹⁰

Unmet Needs and Existing Challenges

Patient group input: LLSC conducted an online survey from October 2024 to November 2024 of 94 adults aged 18 to 75 years or older with ALL and their caregivers across Canada, including 2 respondents who resided outside of Canada. Acknowledging that the input had been submitted previously for a reimbursement review of blinatumomab without specifying the ALL subtype, line of treatment, or treatment phase, the patient group indicated that the disease and treatment experiences are highly relevant to the current reimbursement review.

Of 82 respondents, 82% reported that ALL had a negative or very negative impact on their personal or home lives, causing emotional distress, changes in living arrangements, disruption of daily routines, and caregiving burdens. Most patients (75%; 61 of 81 individuals) also expressed that ALL had a negative or very negative impact on their social lives, causing isolation due to immunosuppression, loss of friendships and social connections, reduced social engagements due to fatigue and physical limitations, and emotional withdrawal due to changes in appearance or self-confidence. Factors identified by 80 respondents as contributing to the negative impact of ALL included low energy (85%), fear of infections (75%), frequent hospital visits (71%), depression or anxiety (64%), symptoms (58%), and inadequate nutrition (28%).

Patients with ALL (n = 82) received a broad range of treatments, including chemotherapy (98%), stem cell transplant (48%), radiation therapy (45%), immunotherapy (27%), targeted therapy (7%), chimeric antigen receptor (CAR) T-cell therapy (5%), and others (16%) (e.g., natural or Chinese medicine, sound baths, meditation, transfusions, steroids, and anti-emetics). Twenty-two percent of respondents were patients who had been treated with blinatumomab for ALL or caregivers of such patients. No patient had experience with blinatumomab plus dasatinib. The 15 respondents who had been treated with blinatumomab reported that their disease had responded completely (67%), partially (20%), or not at all (13%). No AEs of treatment with blinatumomab were reported as severe. Patients treated with induction chemotherapy (n = 63) versus blinatumomab (n = 15) reported the following AEs (using a weighted average of ratings on a severity scale of 1 to 4, with higher scores indicating worse severity): fatigue or weakness (3.56 versus 2.27), neutropenia (3.26 versus 2.29), fever (2.49 versus 2), thrombocytopenia (2.97 versus 1.71), infections (2.87 versus 1.64), nausea or vomiting (2.87 versus 1.4), diarrhea (2.82 versus 1.47), anemia (2.73 versus 1.71), peripheral edema (2.42 versus 1.47), headaches (2.41 versus 1.57), infusion reactions (2.08 versus 1.27), neurologic symptoms (1.92 versus 1.53), and cytokine release syndrome (CRS) (1.15 versus 1.5). Compared to other treatments, treatment with blinatumomab was considered less difficult to undergo by about 53% of patients and was associated with better quality of life by about 60% of patients. Of 14 patients treated with blinatumomab who responded to the question, nearly 79% would be willing to receive blinatumomab again or would recommend it to other patients.

Factors that were important to patients when considering new treatment options (n = 70) were quality of life during treatment (73%), number or severity of AEs (70%), duration of remission (44%), and financial costs (44%). The patient group emphasized the advantages of a chemotherapy-sparing treatment combination to potentially reduce the physical and emotional burden of treatment for older adults, maintain quality of life, and minimize the frequency of hospital visits, thereby offering greater equity and convenience in care access and reducing the financial burden of treatment.

Clinician input: The clinical experts indicated that current treatments impose burdens in accessing and undergoing care (e.g., frequent hospital visits and prolonged admissions during induction therapy), total duration of therapy (conventional approaches can mean > 2 years of treatment), and toxicity (e.g., substantial toxicities are associated with multidrug chemotherapy or steroid-containing regimens, especially for older patients or those with comorbidities). The experts reported that, despite available chemotherapy treatments and advances in TKIs, not all patients with Ph-positive ALL are able to achieve durable and deep disease remission (i.e., MRD negativity); relapses can occur despite early response to treatment. For individuals who do not exhibit adequate response to conventional chemotherapy and a TKI, allo-SCT is a subsequent option; however, it is associated with substantial morbidity, mortality, and reduced quality of life, according to the experts. The experts added that patients, particularly younger adults, may be concerned about long-term toxicity and survivorship issues (e.g., cardiotoxicity, secondary malignancies, and/or infertility).

CLSG-GCEL agreed with the experts on the substantial burden of AEs from chemotherapy regimens and their impacts on patients’ quality of life. They added that relapses due to mutations that render leukemic cells less sensitive to a TKI may require a change to a different TKI (e.g., a change from imatinib to dasatinib or ponatinib). They also expressed that the high frequencies and lengthy durations of treatment have negative impacts on patients’ quality of life. The clinician groups agreed with the experts that subsequent treatments (e.g., allo-SCT or CAR T-cell therapy) are associated with substantial morbidity (e.g., long-term, late AEs) and reduced survival (e.g., early and late mortality); CLSG-GCEL noted that subsequent treatments are intensive and usually not appropriate for older patients.

Considerations for Using the Drug Under Review

The contents within this section have been informed by input from the clinical experts consulted for the purpose of this review and from clinician groups. The following has been summarized by the review team.

Place in Therapy

Patients with Ph-positive ALL are currently treated with chemotherapy-based regimens in combination with a TKI as standard of care. Blinatumomab combined with a TKI may be less intensive and better tolerated than standard of care chemotherapy combined with a TKI for adults, particularly older patients or those with comorbidities, according to the clinical experts consulted. While TKIs inhibit the BCR-ABL oncoprotein, blinatumomab is a bispecific T-cell engager that targets CD19-positive leukemia cells by engaging cytotoxic T-cells (i.e., CD3). The clinical experts reported that the combination of blinatumomab and a TKI as first-line treatment for adults with Ph-positive ALL has been associated with superior efficacy (e.g., high rates of MRD negativity indicative of deep molecular remissions and reduced rates of allo-SCT), reduced toxicity, and reduced reliance on transplant when compared with standard chemotherapy. According to the clinical experts, long-term follow-up from studies such as the GIMEMA LAL2116 D-ALBA trial and from patient cohorts reported by MDACC show that only a minority of patients required allo-HCT during their first remission, with transplant generally reserved for patients with poor molecular response; transplant-related mortality remained relatively low in those who required it. Therefore, the experts expressed that this combination treatment may improve quality of life, reduce exposure to toxic chemotherapy and steroids, shorten overall treatment duration, and spare patients from transplant when deep molecular remission is achieved. The experts added that blinatumomab plus a TKI in the first-line setting does not preclude the use of other therapies, such as transplant, for patients with Ph-positive ALL.

CLSG-GCEL agreed with the clinical experts that blinatumomab in combination with a TKI as first-line treatment for patients with Ph-positive ALL would spare patients from toxic drugs. POGO expressed that this treatment has the potential to prolong OS by reducing relapses and treatment-related mortality. CLSG-GCEL indicated that blinatumomab plus a TKI as first-line treatment for patients with Ph-positive ALL would represent a major shift in the current treatment paradigm and offer a simplified alternative to complicated regimens. The OH (CCO) Hematology DAC indicated that blinatumomab plus dasatinib would provide an important additional option in first-line treatment. The committee added that dasatinib may be preferred over other TKIs as first-line therapy for pediatric Ph-positive ALL because of its improved CNS penetration and its endorsement by the international Ph-positive ALL task force and investigators from the COG and the European intergroup study of postinduction treatment of Ph-positive ALL consortia. The committee added that this combination treatment may incur increased costs upfront, but that these may be offset by cost savings downstream (e.g., due to lower rates of relapse and reduced need for salvage treatment, such as allo-SCT or CAR T-cell therapy).

Patient Population

The clinical experts agreed that blinatumomab plus a TKI would be appropriate for nearly all patients with confirmed, Ph-positive ALL who are untreated. This combination treatment may not be suitable for individuals who are unable to undergo continuous IV infusion and monitoring (e.g., due to logistical or resource constraints or to geographical location). According to the clinical experts, eligible patients would be identified through a standard diagnostic work-up for ALL that is available (e.g., morphology or flow cytometry, BCR-ABL testing by reverse transcriptase polymerase chain reaction [RT-PCR], or cytogenetics). The experts also indicated that CD19 testing is a routine part of diagnostic flow cytometry and that CD19 negativity at the time of diagnosis of B-cell ALL is rare. CD19 expression is not required for treatment with a TKI.

The clinician groups echoed the clinical experts regarding diagnosis of ALL that includes standard immunophenotyping (e.g., CD19 marker) and molecular testing (e.g., ABL-class fusions, including BCR-ABL1), such that there is low likelihood of misdiagnosis or underdiagnosis when identifying patients with Ph-positive ALL who may be eligible for treatment with blinatumomab plus a TKI. The OH (CCO) Hematology DAC reported that patients of all ages who can tolerate treatment with blinatumomab should be considered for eligibility. POGO strongly advocated for pediatric patients with Ph-positive ALL to have equitable access to blinatumomab plus dasatinib, given blinatumomab’s mechanism of action, consensus among clinicians in Canada regarding its anticipated benefit for this patient population, and the recent CDA-AMC recommendation for reimbursement in adult and pediatric patients with Ph-negative, CD19-positive B-cell ALL.

Assessing the Response to Treatment

The clinical experts reported that in clinical practice, response to treatment for patients with Ph-positive ALL is assessed through blood counts and bone marrow evaluations, including MRD testing; repeat cerebrospinal fluid testing is also indicated. In line with outcomes used in clinical trials, treatment response is defined by the achievement of CHR and MRD negativity (determined through BCR-ABL–based MRD monitoring). Assessment of response to treatment should be conducted after induction and every 3 months thereafter, according to the clinical experts. The experts added that while a threshold for MRD may be prespecified (e.g., log reduction of ≥ 3.5 to 4.0), any detectable MRD is considered clinically significant, such that the most sensitive assay available should be used to determine complete MRD clearance after induction and subsequent therapy. The experts agreed that a clinically meaningful response would be sustained hematologic remission with a deep molecular response (i.e., persistent MRD negativity), which is associated with reduced risk of relapse and improved survival, with achievement of cure in some patients. The experts also expressed that, ideally, polymerase chain reaction (PCR)-based testing for BCR-ABL1 should be complemented by a testing method that confers greater sensitivity (e.g., immunoglobulin [Ig] gene rearrangement–based testing) because discordance between the 2 assay methods has been detected in approximately 20% of cases.

The clinician groups agreed with the experts on the use of MRD monitoring to assess treatment response. POGO indicated that failure to achieve MRD negativity at the end of consolidation treatment or following treatment with blinatumomab may require the escalation of treatment intensity, such as hematopoietic cell transplant in first CR. The OH (CCO) Hematology DAC noted that MRD testing may not be available at all laboratories. CLSG-GCEL added that relapse-free survival (RFS) can be estimated with long-term follow-up of patients.

Discontinuing Treatment

According to the clinical experts, discontinuation of treatment with blinatumomab plus a TKI should be considered in the event of lack of response (e.g., refractory disease), disease progression (i.e., hematologic relapse), or unacceptable or intolerable AEs (e.g., severe AEs or persistent or progressive neurologic symptoms). The experts added that treatment may also be temporarily discontinued to manage AEs, such as CRS or neurologic toxicities. If a patient experiences unacceptable toxicity due to treatment with a TKI, a switch to an alternative TKI may be indicated, according to the experts. The experts stated that TKIs differ in their ability to penetrate the CNS (e.g., dasatinib has demonstrated superior CNS penetration compared to imatinib or ponatinib) and that blinatumomab is ineffective for leukemia involving the CNS. They added that if alternative therapies are indicated (e.g., allo-SCT or CAR T-cell therapy), then blinatumomab should be discontinued, and a TKI would likely be restarted later.

CLSG-GCEL and POGO agreed with the experts that blinatumomab may be discontinued due to relapsed or refractory disease or treatment intolerance. POGO added that relapsed or refractory disease may warrant treatment intensification, but does not necessarily preclude ongoing combination therapy. CLSG-GCEL specified that morphological relapse identified through MRD assessment may indicate the need to switch TKIs (due to mutations) or use salvage treatment (e.g., allo-SCT or CAR T-cell therapy). As an example, POGO indicated that a newer TKI may be warranted and guided by BCR-ABL1 mutational analysis if disease recurrence was deemed secondary to resistance to dasatinib. However, if the recurrence was noted to be CD19-negative, then blinatumomab would not be continued. According to CLSG-GCEL, intolerance to blinatumomab due to AEs can often be managed successfully, either with corticosteroids and/or temporary treatment withdrawal. POGO reported that dasatinib or other TKIs would be administered indefinitely during the maintenance phase until significant intolerance or relapsed disease.

Prescribing Considerations

The clinical experts expressed that treatment with blinatumomab plus a TKI should be initiated and managed primarily by a hematologist with expertise in the management of ALL in a hematology clinic, specialized centre, or hospital. Additionally, ongoing patient care may be managed in nonspecialized centres through a collaborative, shared-care approach.

The clinician groups generally agreed with the experts that treatment with blinatumomab plus a TKI should be administered in leukemia centres that have expertise in managing ALL and experience with blinatumomab (e.g., administration through infusion pumps, monitoring and management of AEs). CLSG-GCEL and POGO echoed the experts that after initiating inpatient treatment, it would be appropriate to administer remaining treatments and manage patients in an outpatient specialty cancer clinic, community hospital, or community clinic.

Clinical Review

Methods

The review team conducted a systematic review to identify evidence for blinatumomab in combination with a TKI for the first-line treatment of Ph-positive ALL in adult and pediatric patients. Studies were selected according to the eligibility criteria in Table 2. Additional evidence considered relevant to the systematic review included long-term extension studies of included randomized controlled trials, indirect treatment comparisons (ITCs) that adhered to the eligibility criteria (except for study design), and studies addressing important gaps that did not meet the eligibility criteria. Because direct evidence was lacking versus relevant comparators, a search for ITCs was also conducted.

Relevant comparators included treatments used in clinical practice in Canada in the patient population under review. Clinical expert input and patient and clinician group input were considered when selecting outcomes (and follow-up times) for review. The selected outcomes are those considered relevant to the expert committee deliberations. Detailed methods for the literature searches, study selection, data extraction, and risk of bias appraisal are in the Supplemental Material document (available on the project landing page) in Appendix 2.

Table 2: Systematic Review Eligibility Criteria

AE = adverse event; AESI = adverse event of special interest; ALL = acute lymphoblastic leukemia; HRQoL = health-related quality of life; Ph = Philadelphia chromosome; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TKI = tyrosine kinase inhibitor.

Clinical Evidence

An information specialist conducted a literature search of key bibliographic databases, trial registries, and grey literature sources using a peer-reviewed search strategy. The initial search was completed on September 25, 2025. From the search for primary studies, the review team identified 156 unique records, of which 132 were excluded by title and abstract. The review team screened 24 records by full text. No potentially relevant records were identified through other sources. In total, 6 reports of 3 studies were included in the systematic review: 2 reports^13,14 of the GIMEMA LAL2116 D-ALBA study, 1 report¹⁵ of the SWOG-S1318 study, and 3 reports^16-18 of the MDACC study. The review team relied on the latest data cut for each study, with information from publications that reported earlier data cuts used to supplement information that was not included in later publications. No reports of long-term extensions of the included studies were included.

From the search for ITCs, the review team identified 35 unique records by searching databases and registers; of these, 34 were excluded by title and abstract. The review team screened 1 record by full text. No potentially relevant records were identified through other sources. In total, no ITCs were included.

A list of excluded studies, including reasons for exclusion, is in the Supplemental Material document in Appendix 2.

Systematic Review

Description of Studies

Study Characteristics

Characteristics of the included studies are summarized in Table 3. Details regarding the study assessments and relevant outcome measures are in the Supplemental Material document in Appendix 2. No studies or subgroups of pediatric patients were identified in the included studies.

Blinatumomab Plus Dasatinib

The GIMEMA LAL2116 D-ALBA study^13,14 (NCT02744768¹⁹) and the SWOG-S1318 study¹⁵ (NCT02143414²⁰) were multicentre, phase II, open-label, single-arm trials that enrolled adult patients with Ph-positive ALL. Sources of funding for the GIMEMA LAL2116 D-ALBA and the SWOG-S1318 trials included the manufacturers of blinatumomab (Amgen) and dasatinib (Bristol-Myers Squibb). There were key differences between the studies’ eligibility criteria, interventions, and outcomes. The GIMEMA LAL2116 D-ALBA study evaluated the efficacy and safety of blinatumomab plus dasatinib as first-line treatment in adults aged 18 years or older with newly diagnosed Ph-positive ALL. The SWOG-S1318 study evaluated the efficacy and safety of blinatumomab plus dasatinib in adults aged 65 years or older with Ph-positive or Ph-like ALL; patients could have newly diagnosed or relapsed or refractory disease (however, despite the inclusion criteria, all enrolled patients were newly diagnosed with Ph-positive ALL). The GIMEMA LAL2116 D-ALBA study enrolled patients from sites in Italy, whereas the SWOG-S1318 study enrolled patients from sites in the US.

Blinatumomab Plus Ponatinib

The MDACC study^16-18 (NCT03263572²¹) was a single-centre (US), phase II, open-label, single-arm trial that evaluated the efficacy and safety of ponatinib plus blinatumomab in adults aged 18 years or older with Ph-positive ALL or with lymphoid-accelerated or blast-phase chronic myeloid leukemia; patients with the latter indication were evaluated separately. Sources of funding for the MDACC study included the manufacturers for blinatumomab (Amgen) and ponatinib (Takeda Oncology). Among patients with newly diagnosed Ph-positive ALL, those with prior treatment (i.e., who had received 1 or 2 courses of chemotherapy, with or without a TKI) were included; some of these patients were in CR at enrolment. Patients aged 18 years or older with relapsed or refractory, Ph-positive ALL or with previously treated lymphoid-accelerated or blast-phase chronic myeloid leukemia were also eligible for enrolment in the MDACC study. This report presents available data on the subgroup of patients with newly diagnosed, Ph-positive ALL who were previously untreated (referred to in the study as having active disease).

Treatment Regimens

Details of the treatment regimens are summarized in Table 3, with some key differences between the studies. The use of blinatumomab (dose, timing, and duration or number of cycles) differed across the studies. In the GIMEMA LAL2116 D-ALBA study, the choice of postconsolidation treatment (e.g., allo-SCT or a TKI) was at the discretion of the investigator. The duration of maintenance treatment with a TKI differed between the studies. Whereas patients continued to receive treatment with dasatinib indefinitely in the GIMEMA LAL2116 D-ALBA and SWOG-S1318 studies, patients were treated with ponatinib for up to 5 years in the MDACC study.

Table 3: Characteristics of Studies Included in the Systematic Review

ALL = acute lymphoblastic leukemia; CAR = chimeric antigen receptor; CIR = cumulative incidence of relapse; CML = chronic myeloid leukemia; CMR = complete molecular response; CNS = central nervous system; CR = complete remission; CRi = complete remission with incomplete platelet recovery; CSF = cerebrospinal fluid; DFS = disease-free survival; ECOG = Eastern Cooperative Oncology Group; EFS = event-free survival; GI = gastrointestinal; IQR = interquartile range; IT = intrathecal; IULN = institutional upper limits of normal; MRD = minimal residual disease; OS = overall survival; Ph = Philadelphia chromosome; RT-PCR = reverse transcriptase polymerase chain reaction; TKI = tyrosine kinase inhibitor; vs. = versus.

^aMolecular response was defined as 5% bone marrow blasts or less, the absence of blasts in the peripheral blood, no extramedullary involvement, and a full recovery of the peripheral blood count (i.e., neutrophil count of > 1,500 cells/mm³ and a platelet count of > 100,000/mm³).

Sources: Foa et al. (2020), Foa et al. (2024), Advani et al. (2023), Jabbour et al. (2023), Kantarjian et al. (2024), and Short et al. (2025).^13-18

Statistical Testing and Analysis Populations

In the GIMEMA LAL2116 D-ALBA study, to achieve 90% power at a 0.05 alpha level, sample-size calculations assumed an improvement in the complete molecular remission (CMR) rate from 40% after induction to 60% after 2 cycles (maximum of 5 cycles) of blinatumomab, informed by preliminary analysis,²² with 10% dropout over a total study duration of 12 months. A sample size of 60 patients was considered sufficient to achieve the desired power. There was no adjustment for multiple comparisons. All patients enrolled in the study were included in the intention-to-treat analysis for efficacy end points. Patients who received at least 1 dose of study treatment were included in the safety analysis, and all data were analyzed according to the treatment received. An interim futility analysis was planned after the first stage (29 patients), with a long-term follow-up period of 5 years following the study end date (the data cut-off date was not reported). In the second stage, if the total number of responses was 28 or more, the association would be deemed worthy of further investigation.

In the SWOG-S1318 study, sample size was not determined by statistical parameters; rather, it was set according to the number of eligible patients receiving postremission therapy who were considered evaluable for dose-limiting toxicities, in negotiation with the National Cancer Institute. The study initially accrued 9 patients; the enrolment of additional patients depended on the number who experienced dose-limiting toxicities. Based on 20 patients receiving postremission therapy, the response rate, OS, and disease-free survival (DFS) at each time point can be estimated to a maximum of 23% (95% confidence interval [CI]). With 20 patients, the probability of any particular toxicity can be estimated to within a maximum of 23% (95% CI). Any toxicity occurring at a rate of 15% or more is likely to be observed in at least 1 patient. The primary efficacy analyses were conducted at the data cut-off date of July 18, 2022, with a planned follow-up of 10 years after study registration. Analysis populations were not reported in the study.

In the MDACC study, sample-size calculations for patients aged 60 years or older (later expanded to ≥ 18 years or older) with Ph-positive ALL assumed a 35% CMR rate over 3 cycles with acceptable toxicity (i.e., ≤ 30% rate of drug-related AEs of grade ≥ 3), corresponding to a targeted posterior 95% credible interval of 0.25 to 0.44. A sample size of 90 patients was considered sufficient to achieve the desired power. All patients enrolled were assessed in the intention-to-treat analysis for efficacy. Among those with prior treatment, patients who achieved CR at study entry were assessed for event-free survival (EFS) and OS, and patients who did not achieve CR were assessed for CR, EFS, and OS. Patients were followed up approximately every 6 months for survival after the end of the study or treatment discontinuation.

Patient Disposition

In the GIMEMA LAL2116 D-ALBA study, the number of individuals who were screened for study eligibility was not reported. Of the 63 patients enrolled, 2 patients withdrew from the study (1 due to an AE and 1 because they experienced CHR after receiving dasatinib for 12 days). A total of 61 patients completed induction therapy with dasatinib. Between induction and the first cycle of blinatumomab, 2 patients withdrew due to AEs and 1 patient had early relapse; according to the authors, this was due to a protocol violation (delayed administration of blinatumomab). Between the first and second cycles of blinatumomab, 2 patients withdrew (1 due to a medical decision and 1 due to relapse). Between the second and third cycles of blinatumomab, 9 patients completed treatment. Between the third and fourth cycles of blinatumomab, 7 patients completed treatment. Between the fourth and fifth cycles of blinatumomab, 7 patients completed treatment. Overall, 58, 56, 45, 37, and 29 patients received 1, 2, 3, 4, and 5 cycles of blinatumomab, respectively. Of 29 patients who underwent postconsolidation treatment with a TKI only, 1 patient died of complications. Of 24 patients who received allo-SCT during their first CHR, 3 patients died of complications. Of 6 patients who received allo-SCT in their second CHR, 3 patients died (1 due to complications from infection and 2 due to progression).

In the SWOG-S1318 study, the number of individuals who were screened for study eligibility was not reported. Of the 24 patients enrolled, 2 patients died during treatment and 3 patients discontinued treatment (2 due to AEs and 1 due to refusing continuation), resulting in 19 patients who completed induction treatment. Eighteen patients started postremission treatment; 1 did not, due to insurance issues. A total of 16 patients completed postremission treatment after 2 patients withdrew due to AEs. During maintenance treatment, 9 patients discontinued treatment (6 due to AEs, 2 due to relapse, and 1 due to refusing continuation); 1 patient died. Six patients remained on maintenance treatment at the end of the study.

In the MDACC study, the disposition of the subgroup of patients with newly diagnosed, Ph-positive ALL without prior treatment at enrolment was not reported.

Protocol Deviations

Protocol deviations were not reported in the GIMEMA LAL2116 D-ALBA study. Revisions to the protocol were reported for only 1 version of the protocol in the SWOG-S1318 study.

There were several protocol amendments in the MDACC study.¹⁶ Notably, in August 2019, the eligible population of newly diagnosed, Ph-positive ALL was revised from patients aged 60 years or older to patients aged 18 years or older, based on early positive results in the study and results of other studies in Europe. The study sample size was increased to 90 patients from 60 patients in October 2021, then to 120 patients in March 2023, based on positive results for CMR. Protocol revisions included an evolution of the treatment regimen over time for patients who were at high risk of CNS relapse.

Baseline Characteristics

Patients’ baseline characteristics from the included studies of blinatumomab plus dasatinib are summarized in Table 4. The key differences in the baseline characteristics of patients between the GIMEMA LAL2116 D-ALBA and SWOG-S1318 studies were age (median of 54 years versus 73 years, respectively) and WBC count (median of 13,000 per mm³ versus 7,500 per mm³, respectively).

The baseline characteristics of patients in the MDACC study of blinatumomab plus ponatinib were not reported for the subgroup of patients without prior treatment at study enrolment (n = 53). Patients with newly diagnosed, Ph-positive ALL, with and without prior treatment (N = 76), had a median age of 50 years (range, 18 to 83), with a median WBC at diagnosis of 15.4 × 10⁹/L (range, 0.6 × 10⁹/L to 322.1 × 10⁹/L). Four percent of patients had known CNS involvement before enrolment. Of 75 patients with BCR-ABL1 transcript information, 80% had the p190 fusion protein and 20% had the p210 fusion protein.

Table 4: Summary of Baseline Characteristics From Studies of Blinatumomab Plus Dasatinib

Sources: Foa et al. (2020), Foa et al. (2023), and Advani et al. (2023).^13-15

Treatment Exposure, Concomitant Medications, and Subsequent Treatments

In the GIMEMA LAL2116 D-ALBA study, the median durations of induction or consolidation treatment were not reported. The median time from the end of induction therapy to the start of blinatumomab was 10 days (range, 7 to 41 days). Between the second and third cycles of blinatumomab, 9 patients completed treatment. Between the third and fourth cycles of blinatumomab, 7 patients completed treatment. Between the fourth and fifth cycles of blinatumomab, 7 patients completed treatment. Overall, 58, 56, 45, 37, and 29 patients received 1, 2, 3, 4, and 5 cycles of blinatumomab, respectively.

In the SWOG-S1318 study, duration of treatment exposure was not reported.

Concomitant medications were not reported in the GIMEMA LAL2116 D-ALBA study or the SWOG-S1318 study.

The GIMEMA LAL2116 D-ALBA study reported that 29 of 63 patients (46%) received neither chemotherapy nor transplant and remained on a TKI after consolidation treatment. Of patients receiving maintenance treatment with a TKI and without disease relapse, 28 patients remained on dasatinib and 1 patient was treated with ponatinib. Of 19 patients who remained on dasatinib and 4 patients who subsequently switched to imatinib (2 due to intolerance to dasatinib and 2 because of pleural effusion), all were alive in CHR. Of 5 patients who switched from dasatinib to ponatinib during maintenance treatment (4 due to molecular persistence and 1 due to molecular increase), 1 subsequently switched from ponatinib to imatinib for grade 3 heart failure, 1 died in CHR, and 4 were in CHR. The patient who received maintenance treatment with ponatinib was in CHR. Relapses occurred in 2 patients during blinatumomab treatment and in 4 patients during TKI maintenance. All 6 patients who had disease relapse received allo-SCT in their second CHR. Of the 4 patients who received ponatinib and chemotherapy before allo-SCT, 2 patients were alive in their second CHR and 2 patients died. The patient who received inotuzumab before allo-SCT died. The patient who received chemotherapy before allo-SCT was in their second CHR. Twenty-four patients (38%) received allo-SCT in their first CHR. Eighteen patients (29%) did not receive additional treatment before allo-SCT; of these, 3 died in CHR, 1 relapsed, and 14 remained alive in CHR. Five patients received ponatinib before allo-SCT; all remained alive in CHR. One patient received another unspecified treatment before allo-SCT and remained alive in CHR.

The SWOG-S1318 study reported that 1 patient proceeded to allo-SCT.

In the MDACC study, exposure and concomitant and subsequent treatments were not reported exclusively for the subgroup of patients with Ph-positive ALL who were untreated.

Critical Appraisal

Internal Validity

All the included studies were phase II, single-arm trials. The purpose of phase II trials is typically to provide preliminary information on efficacy and characterize safety. Due to the single-arm nature of the included studies, it is challenging to differentiate the potential effects of treatment from other causes or the natural history of the disease. In general, causal interpretations cannot be made. However, because it is unlikely that patients will achieve disease remission without treatment, it may be appropriate to attribute response to the combination of blinatumomab and a TKI. Nevertheless, time-to-event end points (e.g., OS and DFS) are considered to have poor interpretability in a single-arm study because patients’ disease histories can have substantial variability before the administration of study treatment, and this can be strongly prognostic of the specific outcome.²³ Due to the lack of control group, it is not possible to separate these factors from the effect of the experimental treatment regimen.

As is typical in phase II trials, the SWOG-S1318 study was designed to assess feasibility with a primary focus on safety; therefore, it is unclear if the sample-size calculations are appropriate for making conclusive statements regarding efficacy. Despite being the study with the largest number of enrolled patients, the GIMEMA LAL2116 D-ALBA study was very small. Relative to that study, the sample size was substantially smaller in the SWOG-S1318 study to increase the potential for variability and overestimation of effect estimates. Despite the phase II design, the statistical analysis plan for the GIMEMA LAL2116 D-ALBA study indicated a confirmatory intent for the primary end point of CMR. Although hierarchical testing was prespecified for CMR after 2 to 5 blinatumomab cycles, the results of such analyses were not reported (e.g., CIs and P values are absent); as a result, it is unclear if the testing strategy was applied or whether there is any rationale for not undertaking the planned hypothesis tests. Across the 3 studies, the presented findings were descriptive. Response- and remission-related results are reported without CIs. The lack of quantification of the uncertainty around these results limits credible interpretation, particularly in the context of the small trials, in which results are sensitive to random variation (reflected as imprecision). Findings for the MDACC study that were relevant to the population of interest (i.e., first-line treatment of patients with Ph‑positive ALL) were based on a post hoc analysis comparing disease status at enrolment (i.e., previously treated and in CR versus previously untreated with active disease) for CMR and survival. Post hoc analyses are common in phase II studies, but are at increased risk of bias in selection of the reported result because these are conducted after reviewing the available data. Results of such analyses are typically considered as exploratory. Additionally, the rationale for certain outcomes among this population being selected for reporting at various follow-up times was not justified by the study authors and may represent a selective reporting bias.

Scant information on baseline demographics and disease characteristics was available for enrolled patients in the trials, including Eastern Cooperative Oncology Group (ECOG) Performance Status (0 or 1 for the GIMEMA LAL2116 D-ALBA study; 0 to 2 for the SWOG-S1318 study) and comorbidities (especially for the SWOG-S1318 study, which enrolled an exclusively older population). Given that older patients are more likely to have comorbidities that affect disease prognosis or response to treatment (e.g., lack of response, AEs), the direction or magnitude of such potential effects are unclear in the absence of information. The MDACC study reported baseline characteristics for all study participants. As a result, the review team was unable to ascertain information for the subgroup of patients who were previously untreated (with active disease) or to determine how similar they are to patients enrolled in the other trials. Across all 3 studies, information about dose reductions of blinatumomab, TKI, or concomitant medications was not reported; therefore, it is unclear how these may have affected patients’ responses and what impacts these may have had on treatment effects.

End points that included a response and/or relapse component and AEs were based on investigator assessments without central independent review in the GIMEMA LAL2116 D-ALBA study (DFS and EFS), the SWOG-S1318 study (DFS), and the MDACC study (EFS). Despite the use of standardized criteria for response (including remission and relapse), there was a risk of subjectivity in the ascertainment of residual disease due to the range in thresholds for the percentage of bone marrow blasts detected. Additionally, there was wide variation in the timing of assessments (e.g., every 3 to 6 months in the MDACC study); this variation has the potential to affect the accuracy of results. AEs were ascertained without adjudication by a data monitoring committee in the GIMEMA LAL2116 D-ALBA study; the use of a data monitoring committee was not reported in the SWOG‑S1318 or MDACC studies. There is potential for bias in the measurement of the outcomes for response, DFS, EFS, and subjective harms due to the open-label design; however, the direction of any bias is unclear.

In the GIMEMA LAL2116 D-ALBA study, 6 patients required a switch of TKI due to AEs. No attempt was made to account for switching of TKIs (e.g., sensitivity analyses to evaluate results for patients who remained on dasatinib versus those who switched); therefore, it is unclear how this may have influenced treatment effects. Nearly half of patients underwent subsequent treatment with allo-SCT; of these treatments, 38% occurred during patients’ first CHR and 10% occurred during their second CHR. The authors attempted to explore the impact of allo-SCT on DFS and OS results in post hoc analyses; however, these analyses were subject to various sources of bias (e.g., informative censoring and selection bias), leaving the potential impact of this subsequent treatment on effect estimates unclear. In the SWOG-S1318 study, allogeneic transplant occurred in a single patient; this was reported in the discussion of the publication. Across all the included studies, a clear description of subsequent treatments was not provided. The potential impact of any subsequent treatments on estimates of OS is unknown.

For time-to-event end points, the number of events and number of patients censored were not reported in the GIMEMA LAL2116 D-ALBA study (for OS, DFS, and EFS), the SWOG-S1318 study (for OS and DFS), or the MDACC study (for OS and EFS). Importantly, the number of patients who were censored (and the reasons for censoring) would help inform the occurrence and extent of potential bias due to informative censoring. While this information may be inferred from patients who were lost to follow-up, such data were incomplete, limiting their relevance to the interpretation of survival results. In the most recent publications of both the GIMEMA LAL2116 D-ALBA and SWOG-S1318 studies, relapse was calculated using a crude analysis that did not consider differing lengths of follow-up, competing risk of death, or censoring; therefore, the calculations may misrepresent the true risk of relapse at any particular time point. EFS in the GIMEMA LAL2116 D-ALBA study was an end point that was neither prespecified nor defined. In the MDACC study, RFS was an additional protocol-specified end point; no information on this outcome was reported, and the reason for omitting this end point in the trial publications is unclear. Finally, censoring rules for OS, EFS, and RFS were not described in the MDACC study.

In the GIMEMA LAL2116 D-ALBA study, the proportion of patients with molecular response at specified time points from the last blinatumomab cycle appeared to be based on a complete case analysis. This type of analysis assumes that the data are missing completely at random (i.e., that there is no relationship with the observed data or the outcome); however, this assumption is not realistic and provides results that are at high risk of bias, given that patients who remained on treatment or study are likely to differ systematically from those who did not. Furthermore, only 46% of patients had completed 5 cycles of blinatumomab at the 18-month follow-up and were evaluable for molecular response; in addition, the study authors reported that molecular response was often lacking for patients who received allo-SCT. Because molecular response rate was a prespecified primary efficacy end point, it should have accounted for all patients by using an intention-to-treat analysis with suitable imputation methods for missing data. Data on losses at the long-term follow-up (53 months) were not reported; therefore, the magnitude of bias in treatment effect estimates due to missing data is unclear. In the SWOG-S1318 study, the data for patients who achieved CR during induction, were tested for peripheral blood or bone marrow BCR-ABL1, or achieved CMR or major molecular remission (MMR) any time after treatment appeared to be missing for some, and were likely analyzed according to observed cases only. Likewise, MRD status was assessed only in patients for whom data were available — a nonconservative analysis method that may overestimate the number of patients who are MRD-negative. Finally, 42% of patients discontinued treatment due to AEs. These discontinuations occurred in 8% of patients during both induction therapy and postremission therapy with blinatumomab and dasatinib and in 25% patients during maintenance treatment with prednisone and a TKI. Due to limited reporting in the publication, it is not fully clear how many patients were lost to follow-up. The efficacy analyses should have accounted for patients with missing data (e.g., discontinuations due to AEs and losses to follow-up) through imputation (e.g., by treating patients with missing response data as nonresponders); the lack of data imputation suggests that the study results may be overstated.

External Validity

According to the clinical experts consulted, the inclusion criteria of the trials were appropriate, overall, for enrolling patients with Ph-positive ALL who would be eligible for treatment with blinatumomab plus a TKI. The experts expressed that, unlike clinical trial settings that adopt formal, well-defined criteria, the criteria used in clinical practice to determine patients’ eligibility for treatment require greater flexibility in order to provide access to treatment to as many patients as possible. For example, individuals with an ECOG Performance Score of 0 or 1 in the GIMEMA LAL2116 D-ALBA study and 2 or lower in the MDACC study were eligible. The clinical experts noted that, in practice, patients with an ECOG Performance Status of 3 at presentation could be considered for treatment with blinatumomab plus a TKI, based on clinical judgment. While the trials included adults with Ph-positive ALL aged 18 years or older, the experts stated that an age-agnostic approach should be applied to broaden the population that may benefit from treatment with blinatumomab and a TKI (e.g., pediatric populations and older adults). However, no relevant studies of pediatric patients were located to inform generalizability to that population. Although overt CNS leukemia was an exclusion criterion in the trials because of concerns about blinatumomab-related neurotoxicity, the experts noted that in practice, patients who were CNS-positive would undergo diagnostic lumbar puncture and receive IT therapy to clear disease, after which treatment with blinatumomab plus a TKI would still proceed. The experts noted that patients who achieve CNS clearance can safely receive blinatumomab plus a TKI, with ongoing monitoring for neurologic AEs.

Despite limited information about the demographics and disease characteristics of enrolled patients at baseline, the clinical experts had no concerns about the generalizability of enrolled patients across the trials, noting that nearly all patients with Ph‑positive ALL, regardless of age or comorbidities, should be eligible for treatment with blinatumomab and a TKI.

The MDACC study was initially designed to enrol adults aged 60 years or older with newly diagnosed, Ph-positive ALL. The population was amended to include individuals aged 18 years or older based on early positive efficacy results. The resultant enrolled patients can be considered a post hoc population. Given that the study employed a chemotherapy backbone of reduced intensity with the rationale of targeting patients with Ph-positive ALL aged 60 years or older and those unfit for intensive chemotherapy, it is unknown if the treatment regimen may have suboptimal efficacy for younger patients or those who may be able to tolerate a standard dose-intensive protocol.

The clinical experts reported that treatment in adult ALL has evolved from adult-like protocols (i.e., the original hyper-CVAD treatment protocol) to pediatric and pediatric-inspired protocols. Although pediatric protocols have been adopted by several centres in Canada for use in patients of all ages, with some modifications, the experts acknowledged that there is no established upper age cut-off (e.g., patients aged 55 years or older). Therefore, many older patients are treated according to pediatric protocols. The experts noted that, while there is variability across centres in Canada on the specific treatment protocol used for patients with Ph-positive ALL, there is some agreement that the general approach of the GIMEMA LAL2116 D-ALBA study (i.e., with sequential administration of steroid, then TKI, followed by blinatumomab) is the preferred treatment backbone.

According to the clinical experts, dose modifications and concomitant medications permitted in the trials were generally considered as standard of care in clinical practice, including prophylaxis for infections and anticonvulsants. They indicated that the use of antibiotics or antivirals likely depends on the clinician or on institution-specific guidelines. The MDACC study protocol recommended that patients be treated with Aspirin 75 mg to 100 mg daily and a statin. The experts noted that in modern practice, patients would not be initiated on either Aspirin or a statin during treatment with blinatumomab and a TKI, adding that those who are already receiving a statin at study entry would be advised to cease its use.

Several patients in the GIMEMA LAL2116 D-ALBA study switched from protocolized dasatinib to other TKIs. The experts reported that the most common reasons for switching a patient to a different TKI would be lack of response (e.g., inability to achieve a deep molecular response), refractory disease (e.g., spontaneous mutation in the tyrosine kinase domain that results in loss of response), or intolerance (e.g., pleural effusion with dasatinib) with the current TKI; these reasons were aligned with the switching of TKIs in the study. The experts noted that such switches reflect real-world practice and underscore the importance of individualized TKI selection and monitoring of molecular response.

The GIMEMA LAL2116 D-ALBA study included allo-SCT as a subsequent treatment. According to the experts, before the TKI era, Ph-positive ALL was associated with poor prognosis for patients who did not undergo transplant. The experts indicated that the relatively high proportion of patients who received allo-SCT in the GIMEMA LAL2116 D-ALBA study (i.e., 48%; 30 of 63 patients) reflects standards of care during the study periods and/or risk-stratification of patients based on data before TKIs. Acknowledging that clinical practice has been slow to transition away from the transplant-dominant (pre-TKI and early-TKI) era, with variable transplant rates across centres and countries, the experts agreed that fewer patients with Ph-positive ALL are undergoing allo-SCT in modern care. The experts emphasized that first-line therapy with blinatumomab plus a TKI can be transplant-sparing for many patients, particularly those achieving early and sustained MRD negativity and, as a result, reductions in the morbidity and mortality associated with allo-HCT. In the MDACC study of ponatinib plus blinatumomab, only 2 patients underwent allo-HCT.

According to the clinical experts, the current standard testing method for assessment of MRD across most centres in Canada is RT-PCR, with increasing adoption of testing methods with greater sensitivity. The specific testing method used has implications on outcome definitions and the interpretation of results. CR, also termed CHR, conventionally refers to fewer than 5% bone marrow blasts. MRD negativity, also referred to as CMR, reflects the absence of detectable leukemia using sensitive techniques. The experts emphasized that any detectable MRD confers an increased risk of relapse; the goal of therapy is sustained MRD clearance. RT-PCR for BCR-ABL1 remains the standard method; however, next-generation sequencing (NGS) for Ig gene rearrangement-based assays provides greater sensitivity, detecting low-level disease that may be missed by PCR. Discordance between BCR-ABL1 PCR and Ig gene rearrangement-based NGS methods has been observed in more than 20% of cases. In some instances, BCR-ABL1 positivity by PCR may not reflect true residual disease when NGS or Ig gene rearrangement-based assays are negative. Therefore, these complementary methods are important both to identify low-level MRD that PCR testing may miss and to avoid overestimating disease in cases of apparent PCR positivity, guiding more accurate treatment decisions.

The available evidence did not provide information on how treatment with blinatumomab plus a TKI compares to chemotherapy plus a TKI. Furthermore, no information was available from the included studies to inform health-related quality of life (HRQoL).

Results

Efficacy

Details of OS, DFS, and EFS can be found in Appendix 3 in the Supplemental Material document. Kaplan-Meier plots of survival in each included study are in the following publications: Foa et al. (2024) (GIMEMA LAL2116 D-ALBA study), Advani et al. (2023) (SWOG-S1318 study), Jabbour et al. (2023) (MDACC study), and Kantarjian et al. (2024) (MDACC study).

Blinatumomab Plus Dasatinib

Key results at median follow-ups of 53 months (range not reported) in the GIMEMA LAL2116 D-ALBA study and 32.4 months (range not reported) in the SWOG-S1318 study (Table 5) are discussed in this section.

Survival:

• In the GIMEMA LAL2116 D-ALBA study, the 4-year OS probability was estimated at 80.7% (95% CI, 71% to 91.8%). In the SWOG-S1318 study, the 3-year OS probability was estimated at 87% (95% CI, 64% to 96%).

• In the GIMEMA LAL2116 D-ALBA study, the 4-year DFS probability was estimated at 75.8% (95% CI, 65.4% to 87.8%). In the SWOG-S1318 study, the 3-year DFS probability was estimated at 77% (95% CI, 54% to 90%).

• In the GIMEMA LAL2116 D-ALBA study, the 4-year EFS probability was estimated at 74.6% (95% CI not reported).

• The number of events were not reported in the GIMEMA LAL2116 D-ALBA study (for OS, DFS, and EFS) or the SWOG‑S1318 study (for OS and DFS).

Response:

• In the GIMEMA LAL2116 D-ALBA study, 98% of patients (62 of 63 patients) had a CHR, and 29% of patients (17 of 59 patients) had a CMR at the end of the induction phase with dasatinib (day 85). Fifty-two percent of patients (33 of 63 patients in the intention-to-treat population) had a CMR at the end of 2 cycles of blinatumomab. The proportions of patients with CMR were 75%, 77%, 70%, 85%, 90%, and 93% at 2, 4, 6, 8, 10, and 12 months, respectively, from the last blinatumomab cycle (denominators for the calculated proportions were not reported).

• In the SWOG-S1318 study, 92% of patients (22 of 24 patients) achieved CR during induction therapy with dasatinib. Based on the protocolized timing of measurement, few patients had data available to assess response to postremission therapy with blinatumomab plus dasatinib. Of 7 patients with a detectable transcript at the end of induction treatment, 5 patients (71%) achieved CMR after postremission therapy with blinatumomab plus dasatinib.

MRD status:

• In the SWOG-S1318 study, MRD data were available for 16 patients (67%) who achieved CR. Six patients (38%) were MRD‑negative and 9 patients (56%) were MRD-positive, as measured by flow cytometry, at day 28.

Occurrence of relapse:

• In the GIMEMA LAL2116 D-ALBA study, of the 14% of patients (9 of 63 patients) with relapse, 67% of patients (6 of 9 patients) died. The cumulative incidence of relapse was not reported at the long-term follow-up.

• In the SWOG-S1318 study, 29% of patients (7 of 24 patients) relapsed.

Blinatumomab Plus Ponatinib

Key results in patients with active disease (untreated) were not reported at the longest follow-up (median of 29 months [range, 5 to 75 months]) in the MDACC study. Available data (Table 5) include the following:

• At a median follow-up of 16 months (range, 11 to 24 months), the 1-year OS probability in patients who were untreated (n = 28) was estimated at 92% (95% CI, 72% to 98%). Results at longer follow-up were not reported. At a median follow-up of 24 months (range, 9 to 67 months), the 3-year EFS probability in patients who were untreated (n = 39) was estimated at 73% (95% CI, 52% to 86%). The number of events and number of patients censored were not reported.

• At a median follow-up of 16 months (range, 11 to 24 months), the proportion of patients who were untreated (n = 28) with CMR, MMR, no MMR, and no CR were 68%, 18%, 11%, and 4%, respectively, at the end of cycle 1. The proportions of patients with CMR, MMR, and no CR were 86%, 11%, and 4%, respectively, overall.

• Information on relapse was not available exclusively for patients who were untreated.

CR and MRD status were not assessed in the GIMEMA LAL2116 D-ALBA study or in the subgroup of patients who were untreated in the MDACC study. EFS was not assessed in the SWOG-S1318 study. DFS was not assessed in the MDACC study. RFS was prespecified in the MDACC study; however, results for this outcome were not available in the publication or trial registry. Although HRQoL was considered important to this review, it was not assessed in the included studies.

Table 5: Summary of Key Efficacy Results

CMR = complete molecular response; CR = complete remission; MMR = major molecular remission; MRD = minimal residual disease.

^aThe 95% confidence intervals were not reported for the proportion of patients with response outcomes in the SWOG-S1318 study.

^bMRD data were available for patients who achieved CR in the SWOG-S1318 study. MRD status was assessed using flow cytometry.

Sources: Foa et al. (2020), Foa et al. (2024), Advani et al. (2023), and Jabbour et al. (2023).^13-17

Harms

Detailed harms data are available in Appendix 3 of the Supplemental Material. Although CRS, serious infections, tumour lysis syndrome, neurologic toxicities, and pancreatitis were considered important to this review, these were not prespecified AEs of special interest in the included studies.

Key results are discussed in this section.

Blinatumomab Plus Dasatinib

• After a median follow-up of 53 months (range not reported) in the GIMEMA LAL2116 D-ALBA study:

  • The number of patients with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and AEs of grade 3 or higher were not reported.

  • SAEs and AEs of grade 3 or higher occurred in 42.9% of patients (27 of 63 patients). Commonly occurring SAEs or AEs of grade 3 or higher included pleural effusion (3 patients), and cytomegalovirus infection, pulmonary hypertension, cardiac failure, and diarrhea (2 patients each).

  • Withdrawals due to AEs at the long-term follow-up were not reported. At a median follow-up of 18 months, 3 patients (4.8%) had discontinued the study due to AEs. Reasons for the study discontinuations were not reported.

  • Five deaths occurred in the first CHR. Reasons for deaths were after stem cell transplant (3 patients), pneumonia during induction (1 patient), and endocarditis in a mechanical aortic valve carrier (1 patient).

• After a median follow-up of 32.4 months (range not reported) in patients with Ph-positive ALL in the SWOG-S1318 study:

  • The number of patients with TEAEs was not reported. Nonserious AEs occurred in 100% of patients during induction (n = 24) and postremission (n = 18) and in 93.8% of patients (15 of 16 patients) during maintenance. The nonserious AEs that occurred in at least 50% of patients during induction were decreased platelet count (66.7%), decreased neutrophil count (58.3%), fatigue (54.2%), anemia (54.2%), hypoalbuminemia (54.2%), decreased WBC (50.0%), and dyspnea (50.0%). Nonserious AEs occurring in at least 50% of patients during postremission treatment were anemia (66.7%), edema in the limbs (66.7%), fatigue (66.7%), fever (61.1%), anorexia (55.6%), hyperglycemia (50.0%), decreased neutrophil count (50.0%), decreased WBC count (50.0%), dyspnea (50.0%), and diarrhea (50%). Nonserious AEs occurring in at least 50% of patients during maintenance were diarrhea (68.8%), anemia (56.3%), nausea (56.3%), edema in the limbs (56.3%), fatigue (56.3%), and dyspnea (56.3%).

  • SAEs occurred in 58% of patients (14 of 24 patients) during induction, 56% of patients (10 of 18 patients) during postremission therapy, and 75% of patients (12 of 16 patients) during maintenance. The SAEs that occurred in at least 10% of patients during induction (n = 24) were infections (12.5%), diarrhea (12.5%), and fever (12.5%). SAEs occurring in at least 10% of patients during postremission therapy (n = 18) were decreased neutrophil count (11.1%), infections (11.1%), and confusion (11.1%). SAEs occurring in at least 10% of patients during maintenance therapy (n = 16) were lung infection (12.5%), dyspnea (12.5%), pleural effusion (12.5%), pericardial effusion (12.5%), hypertension (12.5%), diarrhea (12.5%), and dehydration (12.5%).

  • AEs of grade 3 or higher were not reported.

  • Treatment discontinuations due to AEs occurred in 41.7% of patients (10 of 24 patients). Reasons for treatment discontinuations were pleural effusion (in 4 patients) and pulmonary hypertension, rash, pericardial effusion, cytomegalovirus pneumonitis, hypoxia and edema, and edema (in 1 patient each). Study discontinuations due to AEs were not reported.

  • Three deaths (12.5%) occurred in the study. Two of 24 patients (8.3%) died during induction; 0 of 18 patients (0.0%) died during postremission treatment; and 1 of 16 patients (6.3%) died during maintenance.

Blinatumomab Plus Ponatinib

• AEs exclusively in the subgroup of patients without prior treatment were not available in the publications or trial registry of the MDACC study. After a median follow-up of 24 months (range, 9 to 67 months) in patients with newly diagnosed, Ph-positive ALL, with and without prior treatment (N = 60):

  • The number of patients with TEAEs was not reported. Instead, treatment-related AEs were reported, but the number of patients experiencing these was not provided. Treatment-related AEs that occurred in at least 15% of patients were fever or febrile neutropenia (35%), increased alanine transaminase or aspartate transaminase (30%), headache (23%), nausea or vomiting (15%), rash or skin disorder (15%), constipation (15%), and increased lipase or amylase (15%).

  • Treatment-related AEs of grade 3 to 4 included increased lipase or amylase in 6 patients (10%), elevated liver enzymes in 6 patients (10%), hypertension in 2 patients (3%), thrombosis in 1 patient (2%), cerebrovascular ischemia in 1 patient (2%), and coronary artery stenosis in 1 patient (2%). No treatment-related AEs of grade 5 occurred.

  • The number of patients with treatment discontinuations due to AEs was not reported. Treatment discontinuation due to AEs with blinatumomab occurred in 3 patients (5%), while treatment discontinuation due to AEs with ponatinib occurred in 9 patients (15%).

  • CRS (all grade 1 to 2) occurred in 7 patients (12%); all cases were in patients who were untreated (n = 39). Neurologic toxicities included tremors (grade 1 to 2) in 6 patients (10%), peripheral neuropathy or paresthesia in 8 patients (13%), and grade 1 dizziness in 1 patient (2%).

  • Three deaths (5%) occurred in the study. Of 39 patients who were untreated, 1 patient (3%) died on day 18 of the induction phase secondary to CNS bleeding. Of 59 patients who completed at least 1 course of blinatumomab plus ponatinib, 2 patients (3%) died in CR.

Discussion

Efficacy

Patients with ALL seek treatments that will prolong disease remission and help them to maintain HRQoL while being tolerable. Clinicians advocate for patients with Ph-positive ALL to have first-line treatment options that prolong survival, reduce the risk of relapse, and reduce the need for subsequent or salvage therapies. Available evidence for blinatumomab plus a TKI as first-line treatment in patients with Ph-positive ALL was identified in 3 small, phase II, single-arm trials. Single-arm trials are commonly used in settings where there is no available therapy.²⁴ However, current treatments are available for patients with previously untreated, Ph-positive ALL, including TKI-based multidrug regimens. Although Ph-positive ALL is a common genetic subgroup of ALL, a phase III study has yet to be completed, possibly due to feasibility issues. Because the primary objective of the included trials was to evaluate molecular response (in the GIMEMA LAL2116 D-ALBA study and the MDACC study) and safety (in the SWOG-S1318 study), results from larger trials with a relevant comparator may help inform important outcomes for patients.

Given the lack of a relevant comparator group in any study, it is not possible to isolate the treatment effect attributable to blinatumomab plus a TKI; the extent of its potential benefit over existing treatments cannot be directly quantified. In the absence of such evidence, the potential for benefit can be contextualized only based on clinical expert opinion about how the findings might compare to expectations for patients exposed to standard of care in current clinical practice. Within this interpretation, it can be considered that the patients in the trials may not be fully reflective of patients who might be treated in clinical practice in Canada. The experts and clinician groups indicated that the postinduction MRD time point is important because MRD status at that time predicts relapse and informs treatment decisions (e.g., to change the drug dose or switch TKIs); therefore, achievement of MRD negativity at 3 months is a key goal. According to the experts, historical observations based on need for transplant have signalled 3 to 4 months (or 12 to 16 weeks) as an indicator of optimal response; these time frames align with approximately 2 cycles of blinatumomab treatment. Altogether, the studies estimated that 70% to 80% of patients achieved CMR or MRD-negative status. According to the experts, these results demonstrate that most patients experienced excellent outcomes that were sustained or improved over the course of treatment; few patients were unable to achieve deep remission; and there was low likelihood of transplant (or there were few patients requiring transplant). Nevertheless, results for response and remission were challenging to interpret because the sample sizes were small, case analyses were completed without imputing missing data, and uncertainty was not quantified in estimates (i.e., CIs were not reported). The experts emphasized that the interpretation of MRD status should consider the assay used. They indicated that, while RT-PCR remains standard, more sensitive methods — such as NGS-based or Ig gene rearrangement assays — can detect low-level disease that may be missed by PCR, and that PCR positivity in the setting of negative NGS or Ig gene rearrangement results may not reflect true residual disease. Therefore, complementary testing is recommended by the experts to accurately define MRD status, inform relapse risk, and guide subsequent treatment decisions. There was variability in the assays used across the 3 studies, including RT-PCR by the GIMEMA LAL2116 D-ALBA study (to assess response and MRD), PCR by the MDACC study (to assess response), flow cytometry by the SWOG-S1318 study (to assess response and MRD) and the MDACC study (to assess MRD), and NGS in the MDACC study (also to assess MRD). It is unclear how these differences contribute to the interpretation of findings across the studies.

Time-to-event end points were estimated at different time points across the studies. OS (12 months in the MDACC study, 36 months in the SWOG-S1318 study, and 48 months in the GIMEMA LAL2116 D-ALBA study) showed consistent trends, ranging from 81% to 92%. DFS estimates were similar in the SWOG-S1318 study, at 36 months, and in the GIMEMA LAL2116 D-ALBA study, at 48 months. EFS estimates were similar in the MDACC study, at 36 months, and in the GIMEMA LAL2116 D-ALBA study, at 48 months. The clinical experts considered the estimates of OS, DFS, and EFS to be substantially improved compared to outcomes they have observed in current standard of care or expectations based on clinical practice. Ph-positive ALL was once associated with poor prognosis; survival estimates of approximately 80% to 90% at 12 to 48 months of follow-up are now considered clinically meaningful compared with current standard of care, according to the clinical experts. The experts emphasized the importance of measurable residual disease as a surrogate marker of treatment effects that can capture incremental improvements sooner than survival outcomes, such as disease measure–based end points (e.g., DFS, EFS), which may take 5 to 6 years to appreciate (or OS at 10 years). However, there was uncertainty in the results due to the potential risk of bias, small sample size (especially in the SWOG-S1318 cohort of patients with Ph-positive ALL who were untreated), and substandard reporting (no data were reported on the number of patients with events, number of patients censored, or reasons for censoring). There was limited information from the MDACC study about patients with Ph-positive ALL who were untreated. Results for OS, EFS, and response were not available at the longest follow-up in this population subgroup. Data on baseline characteristics, outcomes (e.g., RFS, occurrence of relapse), and AEs were reported for all patients, including those with newly diagnosed disease who had been previously treated and enrolled in CR.

The included studies varied in terms of geographical location (Italy versus US); number of sites (1 versus multicentre); enrolment time frame (2017 to 2019 in the GIMEMA LAL2116 D-ALBA study, 2015 to 2022 in the SWOG-S1318 study, and 2018 to 2024 in the MDACC study); sample size (range, 24 to 63); and follow-up duration (range, 29 to 53 months). The GIMEMA LAL2116 D-ALBA study enrolled a broader population of adults than the SWOG-S1318 study, which focused on older patients. Although the MDACC study and treatment protocol were designed to target older patients with Ph-positive ALL, the study later broadened its enrolment to include all adult patients based on early positive results. The testing method used to determine MRD status for assessing CMR differed across the studies (i.e., RT-PCR was used in the GIMEMA LAL2116 D-ALBA study; 8-colour flow cytometry was used in the SWOG-S1318 study; and both 6-colour multiparameter flow cytometry and NGS were used in the MDACC study). The included response outcomes and their definitions also varied across the studies (CMR in the GIMEMA LAL2116 D-ALBA study and MDACC study; CR in the SWOG-S1318 and MDACC studies; CHR was also reported in the GIMEMA LAL2116 D-ALBA study). Altogether, the variability in treatment protocols (including drugs and the timing and duration of treatment), selection of outcomes, and outcome measurements (including testing methods, timing and frequency of assessments, and outcome definitions) makes it challenging to compare the results and precludes the ability to make meaningful comparisons across studies. Notwithstanding the importance of expert opinion to help understand and interpret the evidence, the available evidence is limited to uncontrolled phase II studies, with the appraisal and interpretation of results hampered by differences across studies, missing data, and substandard reporting. Comparative studies and longer follow-ups may help to better inform survival outcomes for adult patients with Ph-positive ALL.

There were several gaps in the evidence, including the absence of information on HRQoL, which is important to patients. In addition, the efficacy of blinatumomab plus a TKI compared with chemotherapy and a TKI is unknown in the absence of evidence.

Harms

While data on harms were not reported exclusively for patients who were untreated in the MDACC study, these data may be viewed as more generalizable to different patient populations than data on efficacy; the study authors noted that these were similar to the full reported population. Information was not available at the longest follow-up in the GIMEMA LAL2116 D-ALBA study for the number of patients with AEs overall, SAEs, AEs of grade 3 or higher, and withdrawals due to AEs. The interpretation of harms was hampered by missing information in the SWOG-S1318 study for the number of patients with AEs overall and AEs of grade 3 or higher.

In the SWOG-S1318 study, all 24 patients had experienced nonserious AEs after 32 months of follow-up; some of these AEs occurred in 50% or more of patients during induction (i.e., decreased platelet or neutrophil count, fatigue, anemia, hypoalbuminemia, decreased WBCs, and dyspnea), during postremission treatment (i.e., anemia, edema in the limbs, fatigue, fever, anorexia, hyperglycemia, decreased neutrophil count, decreased WBC count, dyspnea, and diarrhea), and during maintenance (i.e., diarrhea, anemia, nausea, edema in the limbs, fatigue, and dyspnea). In the GIMEMA LAL2116 D-ALBA study, 43% of patients had experienced SAEs or AEs of grade 3 or higher after 53 months of follow-up. These commonly included pleural effusion, infection, pulmonary hypertension, cardiac failure, and diarrhea. In the SWOG-S1318 study, 58% of patients experienced SAEs. These commonly included dyspnea and pleural effusion across treatment phases. Few patients (< 5%) had discontinued the GIMEMA LAL2116 D-ALBA study after about 18 months of follow-up. Five patients died in the first CHR in the GIMEMA LAL2116 D-ALBA study, and 3 patients died in the SWOG-S1318 study. However, these harms are estimated with uncertainty because the estimates were based on small numbers of patients, particularly for the SWOG-S1318 study, and reflect the detection of commonly occurring events rather than less common or rare harms that are unlikely to be observed. The clinical experts were not concerned about the AEs reported in the studies, noting that even though the rates appeared to be high, many AEs were likely disease-related rather than treatment-related. The experts added that patients tend to experience higher rates of AEs with intensive chemotherapy regimens, and that the AEs observed in the trials were as expected.

The comparative safety of blinatumomab plus a TKI versus chemotherapy and a TKI is unknown in the absence of evidence.

Other Considerations

The current evidence base is informed by studies of blinatumomab in combination with 2 TKIs (dasatinib and ponatinib); the latter drug is informed by limited data for patients with Ph-positive ALL in the first-line setting. Results of the ongoing, phase III GIMEMA ALL2820 study (NCT04722848; completion expected in September 2027), once published, may help inform the findings for blinatumomab plus ponatinib compared with chemotherapy plus imatinib in adults with Ph-positive ALL. Finally, CDA-AMC located no evidence to provide information on the potential benefits and harms of blinatumomab plus TKI in children. The noncomparative COG AALL2131 international study of combined chemotherapy with TKI and blinatumomab in children with newly diagnosed, Ph-positive or Ph-like B-cell ALL is ongoing.

Conclusion

Patients with ALL and their caregivers seek new treatments that offer prolonged disease remission and help patients maintain their quality of life while imposing minimal toxicity. Clinicians agreed that patients with Ph-positive ALL need first-line treatments that help them to achieve deep, sustained molecular remission, thereby prolonging survival, reducing the risk of relapse, minimizing the need for second- or later-line therapies, and limiting both acute and long-term toxicities. Evidence was available from 3 phase II, open-label, single-arm trials that included a total of 140 adult patients aged 18 years or older with newly diagnosed, Ph-positive ALL who were previously untreated. The purpose of phase II studies is typically to provide preliminary evidence for efficacy and to characterize safety. Accordingly, there was a lack of formal hypothesis testing, and the noncomparative nature of these trials makes the efficacy and safety of blinatumomab plus a TKI versus relevant comparators challenging to quantify. The findings for response and remission outcomes were favourable, according to the clinical experts consulted, and can likely be attributed to blinatumomab plus a TKI despite the single-arm design because responses do not typically occur spontaneously; in addition, the experts noted that these outcomes represent a substantial improvement over current standards of care. The interpretation of these results was limited by risk of bias due to the open-label designs and missing outcome data and because the uncertainty around the estimates was not quantified (i.e., no CIs were reported). Single-arm designs cannot support causal conclusions for time-to-event end points, and interpretation is limited to clinical opinion. The clinical experts consulted by the review team noted that the OS, DFS, and EFS results (at differing time points ranging from 1 to 4 years, depending on the study) were favourable compared to their observations in current clinical practice. Interpretation was limited by reporting deficiencies, small sample sizes, and potential risk of bias in the measurements of DFS and EFS due to the open-label trial designs. Evidence to inform the impact of the treatment on HRQoL was unavailable. The rate of SAEs was high, but the clinical experts consulted believed that the reported harms were as expected. The trials were not adequate in size to capture less common AEs. The efficacy and safety of blinatumomab plus a TKI in pediatric patients are unknown in the absence of evidence. The efficacy and safety of blinatumomab plus a TKI compared with chemotherapy plus a TKI in adult or pediatric patients with Ph-positive ALL are unknown in the absence of evidence.

Economic Review

Methods

The economic review consisted of a cost comparison for blinatumomab compared with the DFCI regimen for patients aged 60 years or older, the DFCI regimen for patients aged 59 years or younger, and hyper-CVAD regimens administered in the consolidation phase of first-line treatment of Ph-positive ALL in adult patients. No cost comparisons were conducted for the pediatric population, given the absence of clinical evidence on the use of blinatumomab in this population.

Based on public list prices, blinatumomab is expected to have a cost of $14,440 per patient per 28 days (refer to Supplemental Material, Appendix 4). The DFCI regimen for patients aged 60 years or older, the DFCI regimen for patients aged 59 years or younger, and the hyper-CVAD regimen are expected to have costs of $1,235, $1,251, and $3,648 per patient per 28 days, respectively. Therefore, the incremental costs of blinatumomab compared with these 3 regimens are $13,205, $13,189, and $10,792 per patient per 28 days, respectively. As such, the reimbursement of blinatumomab for the first-line treatment of Ph-positive ALL in adult patients is expected to increase overall drug acquisition costs. Additional items for consideration are as follows:

• TKIs can also be administered during the first-line treatment of Ph-positive ALL, and would add costs of $583 to $9,829 per patient per 28 days (refer to Table 6 of Supplemental Material) for blinatumomab or hyper-CVAD. Of note, imatinib is part of the DFCI regimens; therefore, the cost of the regimen already includes the cost of the TKI. The reimbursement of blinatumomab for the indication of this review is not expected to affect the use of TKIs for this population, given that these drugs are already part of the standard of care.

• According to the clinical review, the evidence from 3 single-arm, phase II trials demonstrated favourable molecular response and MRD negativity rates as well as DFS and OS for treatment with blinatumomab plus dasatinib or ponatinib. The interpretation of the results is limited due to the single-arm designs of the studies and risk of bias. No evidence was identified regarding the efficacy and safety of blinatumomab versus active comparators.

• As of November 2025, blinatumomab is available only as a brand name product in Canada (Blincyto). There are no biosimilars currently under review at Health Canada.

• The clinical experts consulted for this review provided the following considerations on the possible impacts on health care resources of reimbursing blinatumomab: blinatumomab is expected to have lower administration-related costs compared with DFCI and hyper-CVAD, given that the latter regimens require regular hospital admissions for treatment. However, blinatumomab requires more frequent outpatient visits for administration. In addition, compared to blinatumomab, DFCI and hyper-CVAD regimens are expected to be associated with more unscheduled outpatient visits and hospitalizations, given that these are myelosuppressive treatments; therefore, AEs are more likely to occur during their administration.

• Blinatumomab was not previously reviewed by CDA-AMC for the first-line treatment of Ph-positive ALL. As of November 2025, there are no drugs under review for Ph-positive ALL.

• No cost-effectiveness studies conducted in Canada that included blinatumomab for the first-line treatment of patients with Ph-positive ALL were identified in a literature search conducted on October 2, 2025, with alerts maintained until the Formulary Management Expert Committee meeting on January 22, 2026.

Conclusion

The reimbursement of blinatumomab for the first-line treatment of Ph-positive ALL in adult patients is expected to increase overall drug acquisition costs. There were no direct or indirect comparisons of blinatumomab with active regimens used in the first-line treatment of Ph-positive ALL in adult patients; as such, the comparative efficacy of blinatumomab versus identified comparators is unknown.

Given that blinatumomab is associated with increased drug acquisition costs and unknown clinical benefit, reimbursement of blinatumomab will add costs to the public health care system, with unknown benefit.

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