Consolidation Therapy with Blinatumomab Improves Overall Survival in Newly Diagnosed Adult Patients with B-Lineage Acute Lymphoblastic Leukemia in Measurable Residual Disease Negative Remission: Results from the ECOG-ACRIN E1910 Randomized Phase III National Cooperative Clinical Trials Network Trial

Introduction: Adults with newly diagnosed acute lymphoblastic leukemia (ALL) can achieve a high rate of complete remission (CR) with conventional chemotherapy (CC), but frequently relapse and have suboptimal survival rates even if their measurable residual disease (MRD) status is negative after induction. Blinatumomab (blin) is a bispecific T cell engager molecule that is FDA-approved for patients with relapsed/refractory B-lineage ALL or patients in morphologic CR who are MRD positive (>0.1%). We conducted a phase III trial randomizing patients to CC with or without blin to determine if patients who become MRD negative (<0.01%) after induction chemotherapy (chemo) can have improved outcomes with the addition of blin.

Methods: Patients (pts) between the ages of 30 and 70 with newly diagnosed BCR::ABL1 negative B-lineage ALL were enrolled and initially received 2.5 months of combination induction chemo utilizing a BFM-like regimen adapted from the E2993/UKALLXII clinical trial with extended remission induction, addition of pegaspargase for patients <55 years of age and addition of rituximab for CD20 positive patients (figure 1). After remission induction (step 1), if pts were in morphologic complete remission (CR/CRi), they continued on-study and received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). Subsequently, their remission and MRD status were determined centrally by 6-color flow cytometry with MRD negativity defined as <0.01%. All patients were then randomized to receive an additional four cycles of consolidation chemo or two cycles of blin for 28 days each cycle followed by 3 cycles of consolidation chemo, another 4-week cycle of blinatumomab (3^rd cycle of blinatumomab) followed by an additional cycle of chemo and then a 4^th cycle of blinatumomab (step 3). Patients in each arm received the same number of cycles and doses of chemo. Following completion of consolidation chemo +/- blin, pts were given 2.5 years of POMP maintenance therapy timed from the start of the intensification cycle (step 4). Patients proceeded to allogeneic hematopoietic cell transplant (HCT) at the discretion of the treating physician which was suggested to be done after the first two cycles of blin in the blin arm or at any time following intensification chemo in the control chemo arm. Following the FDA approval of blin for MRD positive disease in March, 2018 pts who were MRD positive after intensification were assigned to the blin arm of the trial and no longer randomized. The primary objective of the trial was to compare the overall survival (OS) in MRD- patients who received blin in conjunction with chemo to that of patients who received chemo alone. With a minimum of 190 MRD negative pts, the study had an 80% power to detect a 45% reduction in hazard rate in the blinatumomab arm relative to the control chemo arm, using one-sided log rank test at the significance level of 0.025 and assuming 2 years of follow-up. Estimates of OS were calculated using the Kaplan-Meier method. Comparison of OS between treatment arms were conducted using the stratified log-rank test and Cox proportional-hazards model with age, CD20 status, rituximab use, and whether pts intend to receive HSCT or not as stratification factors.

Results: The study activated on December 17, 2013. 772 pts were screened for the trial and 488 were enrolled on step 1 induction therapy. The study closed to enrollment on October 15, 2019. The median age of the pts was 51 years (range 30-70). 224 MRD negative pts were randomized, 112 pts to each arm. 22 pts in each arm proceeded to allogeneic BMT. The CR/CRi rate after induction chemo was 81%. Among the MRD negative pts, at the third interim efficacy analysis, 56 pts had died, 17 in the blin arm and 39 in the control chemo arm. The upper boundary for efficacy analysis was crossed in favor of blin with a significant improvement in overall survival in favor of the blin arm as shown in figure 2 (median OS: not reached vs. 71.4 months; Hazard ratio 0.42, 95% CI: 0.24 - 0.75; two-sided p=0.003). Median follow-up was 43 months.

Conclusion: The addition of blin to consolidation chemo resulted in a significantly better overall survival in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification chemo. No significant safety concerns were noted. The addition of blin to consolidation chem in adult pts aged 30-70 years represents a new standard of care for BCR::ABL1 negative ALL pts.

Litzow:Actinium: Research Funding; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Novartis: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Pluristem: Research Funding; Biosight: Consultancy, Other: Data Monitoring Board. Lazarus:Pluristem: Consultancy, Honoraria. Rowe:Biosight: Consultancy. Wieduwilt:Reata: Current holder of stock options in a privately-held company; Sorrento: Other: Data monitoring committee; BMS, Jazz, Gilead/Kite: Membership on an entity's Board of Directors or advisory committees. Liedtke:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Allogene: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Natera: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Research Funding; Seagen Inc.: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees. Pratz:AbbVie, Agios, Daiichi Sankyo, Millennium: Research Funding; AbbVie, Astellas, Boston BioMedical, BMS, Celgene, Novartis, Jazz Pharmaceuticals, and Servier.: Membership on an entity's Board of Directors or advisory committees. Frey:Novartis: Research Funding; Sana Biotechnology, Kite Pharma, and Syndax Pharmaceuticals: Consultancy. Atallah:Novartis: Consultancy, Research Funding; Takeda: Research Funding; Abbvie: Consultancy, Research Funding, Speakers Bureau; Blueprint: Speakers Bureau; BMS: Consultancy, Speakers Bureau. Jeyakumar:Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding. Lin:AbbVie, Aptevo, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Mateon Therapeutics, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Tallman:Roche: Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Ipsen Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; KAHR-Adv Bd: Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Glycomimetics: Research Funding; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Abbvie: Research Funding; Orsenix: Research Funding; UpToDate: Patents & Royalties: Royalties; Innate Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Blinatumomab