Phase 2 study of brexu-cel in minimal residual disease positive B-cell acute lymphoblastic leukemia Free

Recent data suggest that identification of low burden disease (minimal residual disease, MRD) following induction therapy, below the classical cut-off for “complete remission” (5% blasts) can stratify those with long term remission free survival from those prone to relapse. MRD post induction impacts approximately 30% of patients, and is associated with poor long-term outcomes, with one meta-analysis highlighting a 10-year OS of only 15%. Notably, subsequent studies have demonstrated that later conversion to MRD negativity by flow cytometry or more sensitive next generation sequencing (NGS) assays failed to significantly improve outcomes.

Accordingly, efforts to intervene on MRD have been explored. Data generated with blinatumomab in those with MRD demonstrated an 80% conversion rate to MRD negativity. However, continuous remission was contingent on subsequent allogeneic transplantation, which in turn was accompanied by high treatment related mortality, impacting approximately 1/3 of patients. Efforts to intervene with blinatumomab for those without detectable MRD by flow cytometry (presumably with MRD below this threshold) after consolidation proved more active than chemotherapy alone, but ultimately only 58% (286/488) of patients were able to proceed to randomization, and of these, only 53% were able to proceed to maintenance (151/286) – highlighting a need for earlier and more potent intervention.

Three CAR T-cell products, tisagenlecleucel (tisa-cel), obecabtagene autoleucel (obe-cel), and brexucabtagene autoleucel (brexu-cel) are approved for relapsed and refractory (R/R) B-ALL. Registrational trial and consortium data show improved outcomes, both as they relate to toxicity and benefit, when integrated for those with MRD in these R/R settings and highlight an opportunity for earlier intervention. We have therefore designed this study to explore the efficacy of brexu-cel for adult B-ALL patients who are MRD positive by NGS following induction chemotherapy (NCT06144606).

This is a planned U.S. multicenter single arm phase 2 study of adult patients showing MRD by NGS after induction chemotherapy. There is no upper age limit, and both Philadelphia positive (PH+) and negative (PH-) patients may enroll, though, those with ALL arising from CML and those with known or suspected mixed phenotype, biphenotypic, or stem cell leukemia are excluded. Patient may receive a single dose of vincristine with four days of dexamethasone (PH-) or continue tyrosine kinase inhibitor therapy (PH+) if enrolling with 0.1%-4.9% blasts. Patients undergo restaging marrow prior to lymphodepletion with fludarabine (25mg/m2 x3 days) and cyclophosphamide (900mg/m2 x1 day) and cell infusion at 1x10⁶ cells per kg. Patients may receive consolidation allogeneic transplant or tyrosine kinase inhibitor maintenance at the discretion of the treating physician. The primary endpoint is relapse free survival (RFS). The analysis for RFS is event driven, with a planned accrual of 60, and interim analysis for futility after 11 events.

Secondary and endpoints include safety, molecular and clinical response rates, duration of remission, molecular RFS, allogeneic transplantation rate and overall survival. Exploratory endpoints include brexu-cel expansion and persistence kinetics, cytokine profiling, immunoglobulin recovery, T-cell and B-cell recovery, anti-KTE-X19 antibodies.

Status:The trial opened to accrual November 15, 2023, with first subject infused January 22, 2024. To date 16 of 60 have been infused. Accrual is ongoing with plans to extend enrollment to MD Anderson Cancer Center, Montefiore Einstein Cancer Center, and the University of Pennsylvania.