AALL2131/EsPhALL2022, An International Pilot Study of Chemotherapy and Tyrosine Kinase Inhibitor with Blinatumomab in Patients with Newly Diagnosed Philadelphia Chromosome Positive or ABL-class Philadelphia Chromosome-Like B-cell Acute Lymphoblastic Leukemia

This study evaluates a modified chemotherapy regimen incorporating blinatumomab and tyrosine kinase inhibitors in pediatric, adolescent, and young adult patients with newly diagnosed Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) or ABL-class Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (ABL-class Ph-like B-ALL). The primary objectives are to estimate the 3-year event-free survival (EFS) in patients with Ph+ B-ALL treated with modified Berlin-Frankfurt-Münster (mBFM) chemotherapy backbone incorporating three cycles of blinatumomab without traditional consolidation chemotherapy in combination with continuous dasatinib, to estimate the 3-year EFS in patients with ABL-class Ph-like B-ALL treated with the same modified chemotherapy approach combined with continuous imatinib for those with PDGFRB gene fusions or dasatinib for those without PDGFRB gene fusions, and to describe the safety and toxicity profile including infections, mucositis, neurotoxicity, cytokine release syndrome, hypogammaglobulinemia, therapy delays exceeding 14 days, and treatment-related mortality for patients treated with this novel chemo-immunotherapy backbone with continuous tyrosine kinase inhibitor. The secondary objectives include estimating the 3-year overall survival (OS) of patients with Ph+ and ABL-class Ph-like B-ALL, estimating the 3-year EFS, disease-free survival (DFS), cumulative incidence rates (CIR) of relapse, treatment-related mortality, and OS of patients with ABL-class Ph-like B-ALL stratified by their underlying ABL-class fusion subtypes, describing rates of end of consolidation (EOC)/timepoint 2 (TP2) minimal residual disease (MRD) negativity defined as <1×10⁻⁴ or <0.01% for patients with Ph+ B-ALL, and describing rates of EOC/TP2 MRD negativity defined as <1×10⁻⁴ or <0.01% for patients with ABL-class Ph-like B-ALL collectively and based on their ABL-class fusion subtypes.

This clinical trial enrolled a total of **10 participants** with newly-diagnosed **Philadelphia chromosome positive** (Ph+) or **ABL-class Philadelphia chromosome-like B-cell acute lymphoblastic leukemia**. The study population included both **male** and **female** subjects ranging from **children** to **adults**, with specific age eligibility varying by participating consortium: patients aged over 365 days to under 18 years for AIEOP-BFM sites, over 365 days to under 22 years for COG sites, and over 365 days to under 46 years for ALLTogether sites. The trial population was classified as a **vulnerable population**. Participants were selected based on confirmed diagnosis of Ph+ B-ALL documented by a clinically-validated assay or ABL-class Ph-like B-ALL with leukemic blasts expressing **CD19** and rearrangements involving ABL1, ABL2, CSF1R, or PDGFRB genes. Eligible patients were required to have adequate **liver function**, **renal function**, and **cardiac function**, as well as a performance status corresponding to ECOG scores of ≤2 or Karnofsky and Lansky performance scores ≥50%. For Ph+ B-ALL, patients must have previously started standard induction therapy but not received more than 14 days of systemic treatment, while those with ABL-class Ph-like B-ALL must have completed 4 or 5 weeks of multiagent induction chemotherapy prior to enrollment.

This international pilot study investigates a modified chemotherapy regimen combined with tyrosine kinase inhibitor therapy and blinatumomab in patients with newly diagnosed Philadelphia Chromosome positive B-cell acute lymphoblastic leukemia or ABL-class Philadelphia Chromosome-like B-cell acute lymphoblastic leukemia. The trial is designed as a Phase III study to evaluate the efficacy and safety of this novel chemo-immunotherapy approach. The study employs a modified Berlin-Frankfurt-Münster chemotherapy backbone that incorporates three cycles of blinatumomab without traditional consolidation chemotherapy, administered in combination with continuous tyrosine kinase inhibitor treatment. Patients with Philadelphia Chromosome positive disease receive dasatinib, while those with ABL-class Philadelphia Chromosome-like disease receive either imatinib for PDGFRB gene fusions or dasatinib for other ABL-class fusions.

The primary objectives are to estimate the 3-year event-free survival in children, adolescents, and young adults treated with this regimen, and to describe the safety and toxicity profile including infections, mucositis, neurotoxicity, cytokine release syndrome, hypogammaglobulinemia, therapy delays exceeding 14 days, and treatment-related mortality. Secondary objectives include estimation of 3-year overall survival, disease-free survival, cumulative incidence rates of relapse, and treatment-related mortality, as well as assessment of minimal residual disease negativity rates at specified timepoints.

Eligible participants include patients aged more than 365 days and less than 18 years for AIEOP-BFM sites, less than 22 years for COG sites, and less than 46 years for ALLTogether sites at enrollment. Patients must have newly diagnosed Philadelphia Chromosome positive or ABL-class Philadelphia Chromosome-like B-cell acute lymphoblastic leukemia with leukemic blasts expressing CD19. ABL-class fusions are defined as rearrangements involving ABL1, ABL2, CSF1R, and PDGFRB genes predicted to be sensitive to imatinib and dasatinib. Evidence of BCR::ABL1 fusion must be documented by a clinically validated assay prior to study entry on Day 15 from the first dose of vincristine during induction therapy. Patients with Philadelphia Chromosome positive disease must have previously started induction therapy including vincristine, a corticosteroid, pegaspargase or calaspargase pegol, with or without anthracycline, and must not have received more than 14 days of systemic induction therapy. Patients with ABL-class Philadelphia Chromosome-like disease must have completed 4 or 5 weeks of multiagent induction chemotherapy. Additional inclusion criteria require adequate liver, cardiac, and renal function, and a performance status corresponding to ECOG scores of 2 or less, or Karnofsky and Lansky performance scores of 50 or greater.

The investigational medicinal product blinatumomab is administered as a solution for infusion via intravenous administration. The maximum daily dose is 28 micrograms with a maximum total dose of 2352 micrograms over a maximum treatment period of 12 weeks. The estimated recruitment start date is December 1, 2025, with an estimated study completion date of November 30, 2030. The study duration reflects the long-term follow-up required to assess 3-year event-free survival and overall survival outcomes. Participants may be withdrawn from the study based on safety considerations, treatment-related toxicities requiring discontinuation, disease progression, or other protocol-specified criteria for early termination.

**Blinatumomab** is administered as the experimental medicinal product in this clinical trial for patients with newly diagnosed **Philadelphia chromosome positive** or **ABL-class Philadelphia chromosome-like B-cell acute lymphoblastic leukemia**. The investigational medicinal product is supplied as BLINCYTO 38.5 micrograms **powder for concentrate** and **solution for solution for infusion**, which is prepared as a **solution for infusion** for administration. The active substance, blinatumomab, is a **recombinant antibody derivative** against human **CD19** and **CD3**, classified as a protein-based therapeutic agent. The medicinal product is manufactured by AMGEN EUROPE B.V. and holds marketing authorization number EU/1/15/1047/001.

Blinatumomab is administered via **intravenous administration** as a continuous infusion. The maximum daily dose is 28 micrograms, with a maximum total dose of 2352 micrograms over the treatment period. The treatment regimen incorporates three cycles of blinatumomab without traditional **consolidation chemotherapy**, integrated into a modified **Berlin-Frankfurt-Münster chemotherapy backbone**. The maximum treatment period for blinatumomab administration extends to 12 weeks. The dosing schedule is designed to be administered in combination with continuous **tyrosine kinase inhibitor** therapy and modified chemotherapy agents.

Participants receive concomitant treatment with tyrosine kinase inhibitors as part of the therapeutic regimen. Patients with **BCR::ABL1-rearranged** Philadelphia chromosome positive disease receive continuous **dasatinib** throughout the treatment period. For patients with ABL-class Philadelphia chromosome-like disease, the choice of tyrosine kinase inhibitor depends on the specific genetic abnormality: continuous **imatinib** is administered to those with **PDGFRB gene fusions**, while continuous dasatinib is given to those without PDGFRB gene fusions. These targeted agents are administered concurrently with the blinatumomab cycles and the modified chemotherapy backbone.

Participant compliance monitoring includes assessment of therapy delays exceeding 14 days and evaluation of treatment-related toxicities. The safety profile is monitored through systematic evaluation of **infections**, **mucositis**, **neurotoxicity**, **cytokine release syndrome**, **hypogammaglobulinemia**, and **treatment-related mortality**. The study protocol incorporates specific monitoring procedures to track adherence to the dosing schedule and to document any deviations from the planned treatment regimen.

Efficacy will be assessed through the evaluation of **3-year event-free survival (EFS)** as the primary endpoint for patients with newly-diagnosed Philadelphia chromosome positive (Ph+) **B-cell acute lymphoblastic leukemia** treated with a modified Berlin-Frankfurt-Münster chemotherapy backbone incorporating three cycles of **blinatumomab** without traditional consolidation chemotherapy in combination with continuous **dasatinib**. The 3-year EFS will also be estimated for patients with newly-diagnosed ABL-class Philadelphia chromosome-like (Ph-like) B-cell acute lymphoblastic leukemia treated with the same modified chemotherapy backbone and blinatumomab regimen, combined with continuous **imatinib** for those with PDGFRB gene fusions or dasatinib for those without PDGFRB fusions. Additionally, the safety and toxicity profile will be described, including the assessment of infections, **mucositis**, **neurotoxicity**, **cytokine release syndrome**, **hypogammaglobulinemia**, therapy delays exceeding 14 days, and treatment-related mortality for patients treated on this chemo-immunotherapy backbone with continuous tyrosine kinase inhibitor.

Secondary efficacy parameters include the estimation of **3-year overall survival (OS)** for patients with Ph+ and ABL-class Ph-like B-cell acute lymphoblastic leukemia. The 3-year EFS, **disease-free survival (DFS)**, cumulative incidence rates of relapse, treatment-related mortality, and overall survival will be estimated for patients with ABL-class Ph-like B-cell acute lymphoblastic leukemia stratified by their underlying ABL-class fusion subtypes. Rates of **minimal residual disease (MRD)** negativity, defined as less than 1x10-4 or less than 0.01%, will be described for patients with ABL-class Ph-like B-cell acute lymphoblastic leukemia collectively and based on their ABL-class fusion subtypes at end of consolidation/therapy phase 2 timepoint.