Introduction: ECOG ACRIN E1910 is a randomized phase III trial that showed that adults with newly diagnosed BCR::ABL1 negative acute lymphoblastic leukemia (ALL) who become MRD negative (<0.01%) after induction chemo who receive blinatumomab with conventional chemotherapy (chemo) have improved survival compared with those who received chemo only (Litzow et al, Blood (2022) 140: Supplement 2, LBA-1). However, not all pts were able to receive all four planned cycles of blinatumomab in consolidation. In this report we assessed outcomes of pts in the blinatumomab arm of the trial who received all 4 cycles of blinatumomab compared to those who received 1-2 cycles.
Methods: Patient 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 pegaspargase (after induction only for patients >=55 years of age) and addition of rituximab for CD20 positive patients. After remission induction (step 1) pts in morphologic complete remission (CR/CRi) received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). At the conclusion of step 2, remission and MRD status were determined centrally by 6-color flow cytometry with MRD negativity defined as <0.01%. In the primary analysis subset, MRD negative patients were randomized to receive an additional 4cycles of consolidation chemo or 2 cycles of blinatumomab at 28 mcg/day (flat dose) for 28 days each cycle followed by 3 cycles of consolidation chemo, another 4-week cycle of blinatumomab (3rd cycle of blinatumomab) followed by an additional cycle of chemo and then a 4th cycle of blinatumomab (step 3). Following completion of consolidation chemo +/- blinatumomab, pts were given 2.5 years of POMP maintenance therapy timed from the start of the intensification cycle (step 4). 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. As the number of cycles needed to optimize outcome has not been studied, an unplanned landmark analysis was used to compare OS of pts in the blinatumomab arm who received all 4 cycles o those who received 1-2 cycles. Time 0 was chosen as 9 months post step 3 randomization (the time that patients were supposed to complete 4 cycles of blina). Four pts who received blinatumomab but died within 9 months post step 3 randomization were therefore excluded from this analysis.
Results: The study was activated on December 17, 2013 and closed to enrollment on October 15, 2019. 772 pts were screened for the trial and 488 were enrolled on step 1 induction therapy. The median age of the pts was 51 years (range 30-70). 224 MRD negative pts were randomized, 112 pts to each arm. In the blinatumomab arm 12 pts received 1 cycle (11%), 32 pts received 2 cycles (29%), 4 pts received 3 cycles (4%) and 63 pts received 4 cycles (57%). The OS of pts who received 1-2 cycles of blinatumomab was compared to control (Figure 1) The difference was not significant (hazard ratio 0.62, 95% CI 0.28 to 1.34, p=0.22). Fig 2 compares the survival of those who received 1-2 cycles to those who received 4 cycles ( (HR: 0.39, 95% CI 0.12 to 1.16, p=0.076).
Conclusion: The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival compared to chemotherapy alone in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification. This represents a new standard of care for pts aged 30-70 years with BCR::ABL1 negative ALL. The optimal dose and number of cycles is however unknown. In this unplanned subgroup analysis we demonstrate that a survival benefit can only be confirmed in patients who receive the intended 4 cycles of blinatumomab during consolidation. Further studies will be needed to determine if fewer cycles can provide a similar benefit.
OffLabel Disclosure:
Luger:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Novartis: Consultancy; Marker Therapeutics: Membership on an entity's Board of Directors or advisory committees; Onconova: Research Funding. Mattison:Nkarta: Membership on an entity's Board of Directors or advisory committees. Lazarus:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Liedtke:Kite: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Allogene: Other: Grants or contracts; Abbvie: Other: Grants or contracts; BMS: Other: Grants or contracts; Participation on a Data Safety Monitoring Board or Advisory Board; Seagen: Other: Grants or contracts; Adaptive: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Janssen: Other: Grants or contracts; Participation on a Data Safety Monitoring Board or Advisory Board; Caelum: Other: Grants or contracts. Bergeron:BMS: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Taiho: Honoraria; Gilead: Honoraria. Wood:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional Laboratory Services Agreement; Kite: Other: Institutional Laboratory Services Agreement; Novartis: Other: Institutional Laboratory Services Agreement; Beckman-Coulter: Honoraria; Becton-Dickinson: Honoraria; Beam: Other: Institutional Laboratory Services Agreement; Wugen: Other: Institutional Laboratory Services Agreement; Macrogenics: Other: Institutional Laboratory Services Agreement; Biosight: Other: Institutional Laboratory Services Agreement. Pratz:Roche: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz Pharamceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding. Dinner:Kite/Gilead: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Rigel: Research Funding; BMS: Research Funding. Frey:Kite Pharma: Consultancy; Sana Biotechnology: Consultancy. Atallah:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding. Uy:Jazz: Other: Advisory Board. Lin:Bio-path Holdings: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Celyad: Research Funding; Aptevo Therapeutics: Research Funding; Cleave Biosciences: Research Funding; Ciclomed: Research Funding; Jazz Pharmaceuticals: Research Funding. DeAngelo:GlycoMimetics: Research Funding; AbbVie: Research Funding; Novartis: Research Funding; Blueprint: Research Funding; Servier: Honoraria; Autolus: Honoraria; Amgen: Honoraria; Blueprint: Honoraria; Gilead: Honoraria; Incyte: Honoraria; Jazz: Honoraria; Kite: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria. Erba:Servier: Consultancy, Honoraria, Research Funding; Syros: Consultancy; Takeda: Consultancy; Ascentage: Research Funding; Trillium: Consultancy; ALX Oncology: Research Funding; Amgen: Research Funding; Pfizer: Consultancy; Forma: Research Funding; Forty-Seven: Research Funding; Sunesis Pharmaceuticals: Honoraria; Celgene: Consultancy, Honoraria, Other: Chair, Myeloid Neoplasms Repository Study, Research Funding; Daiichi Sankyo Inc.: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; BMS: Consultancy, Honoraria, Other: Chair, Myeloid Neoplasms Repository Study; Genentech: Consultancy; Glycomimetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunogen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria, Research Funding; Kura Oncology: Consultancy, Research Funding; Macrogenics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; PTE: Research Funding; Sumitomo: Research Funding. Stone:Abbvie: Consultancy; CTI Biopharma: Consultancy; Aptevo: Other: DSMB; Epizyme: Other: DSMB; GSK: Consultancy; Hermavant: Consultancy; Ligand Pharma: Consultancy; Lava Therapeutics: Consultancy; Takeda: Other: DSMB; Amgen: Consultancy; AvenCell: Consultancy; BerGenBio: Consultancy; Cellularity: Consultancy; Jazz: Consultancy; Kura One: Consultancy; Rigel: Consultancy; Syntrix: Other: DSMB. Mullighan:Illumina: Honoraria; Amgen: Honoraria; Pfizer: Research Funding; Abbvie: Research Funding. Tallman:UpToDate: Patents & Royalties; American Society of Hematology: Honoraria, Membership on an entity's Board of Directors or advisory committees; HOVON: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Innate Pharmaceuticals: Consultancy; Ipsen Biopharmaceuticalas: Consultancy; Kura: Consultancy; Foghorn: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; BioSight: Research Funding; Orsenix: Research Funding; AbbVie: Research Funding.
Blinatumomab for MRD negative ALL
