Addition of Blinatumomab to Consolidation Therapy Among Older Newly Diagnosed Patients (pts) with BCR::ABL1 Negative B-Lineage Acute Lymphoblastic Leukemia (ALL) in the ECOG-ACRIN E1910 Randomized Phase III Trial

Introduction

E1910 randomized pts with ALL aged 30-70 years who were measurable residual disease negative (MRD-) by multi-color flow cytometry (FC) after intensification to conventional chemotherapy (chemo) with or without blinatumomab (blina). The addition of blina resulted in improved overall survival (OS) (Litzow, NEJM 2024) and led to a new standard of care.

Older ALL pts have inferior outcomes when compared to younger pts in part due to increased treatment toxicity. In E1910, exposure to dexamethasone and pegasparagase was reduced for older pts (age >55 years). We present results of subgroup analyses describing outcomes of older pts enrolled in E1910.

Methods

Details of the E1910 protocol remission induction (step 1), high dose methotrexate with pegaspargase intensification (step 2), blina randomization (step 3), and maintenance (step 4) or allogeneic hematopoietic stem cell transplant (HCT) were previously presented (Litzow, NEJM 2024). MRD status was determined after step 2 centrally with 6-color FC with MRD- defined as <0.01% in the bone marrow (BM). Following approval of blina in the US for MRD positive (MRD+) disease in 2018, MRD+ pts were assigned to the blina arm and no longer randomized.

The primary objective was to compare the OS and relapse free survival (RFS) among older pts aged >55 years (pre-specified stratification factor) who received chemo + blina to that of pts who received chemo alone (step 3 treatment). Estimates of OS and RFS were calculated using the Kaplan-Meier method. Comparison of OS and RFS between treatment arms was conducted using the two-sided stratified log-rank test and Cox model with CD20 status, rituximab use, and whether pts intended to receive HCT or not as stratification factors. Stratified Multivariate Cox models of OS and RFS were used to further evaluate the effect of step 3 treatment, adjusted by gender, white blood cell count (WBC), platelets, hemoglobin, peripheral blood blasts, BM blasts, performance status and combined molecular risk category.

Results

Among the 488 enrolled pts, 211 were ≥55 years old with median age of 61 (range 55-70). Among older pts, 49.3% were female and 83.4% were white, 17 (8.1%) pts had WBC >30.000/uL at the time of diagnosis. 156 (73.9%) pts had CD10+ early B-ALL and 46 (21.8%) had CD10- B-ALL immunophenotype. The most common genetic subgroups were low hypodiploid (n=58, 27.5%), BCR::ABL1-like (n=34, 16.1%) and KMT2A rearranged (n=26, 12.3%). 8.1% of pts had low, 9.0% intermediate, 63.5% high combined molecular risk disease and in 19.4% of pts risk could not be assigned. Baseline characteristics were not significantly different in chemo + blina and chemo only pts. The median follow-up for this analysis from step 1 registration was 54.6 months.

Complete response with (CR) or without (CRi) count recovery after induction was observed in 174 (82.5%) pts (167 CR, 7 CRi). 93 (44%) pts were MRD-. 32 (15.1%) pts received HCT on study and 24 (11.4%) pts received it off study.

Among MRD- pts (n=93), 46 were randomized to and 45 received blina: 6 (13.3%) pts had 1, 14 (31.1%) had 2, 2 (4.4%) had 3 and 23 (51.1%) had 4 cycles. 3-year OS were 71% and 67% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.37-1.50; multivariate model: HR 0.56, 95% CI: 0.25-1.27). 3-year RFS were 69% and 59% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.39-1.45; multivariate model: HR 0.67, 95% CI: 0.32-1.42).

Among MRD+ pts (n=25), 14 were randomized to and 11 received blina: 7 (63.6%) pts had 2, and 4 (36.4%) had 4 cycles. 3-year OS were 66% and 44% for the blina vs the chemo only arm (univariate model: HR 0.66, 95% CI: 0.12-3.64). 3-year RFS were 64% and 31% for the blina vs the chemo only arm (univariate model: HR 0.64, 95% CI: 0.15-2.74).

Frequency of treatment-related toxicities among older pts during different study phases and treatment assignments will be presented.

Conclusion

Despite evidence of improved outcomes in the whole study cohort, the addition of blina to consolidation chemo for older pts with ALL was not associated with statistically significant improvement of OS or RFS in this exploratory analysis not powered to detect the difference in subgroups. This is possibly due to sample size but may be due to biologic differences in the older adult population. Further studies are needed to definitively determine tolerance and benefit of blina addition to consolidation for older pts with ALL.

Podoltsev:Astex Pharmaceuticals: Research Funding; Aptose Biosciences: Consultancy, Honoraria, Research Funding; CTI BioPharma/Sobi: Consultancy, Honoraria, Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria, Research Funding; Kartos Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria; Constellation pharmaceuticals/MorphoSys: Consultancy, Honoraria, Research Funding; Sunesis Pharmaceuticals, Inc.: Research Funding; Arog Pharmaceuticals: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; Celgene: Research Funding; AI Therapeutics: Research Funding; Cogent Biosciences: Honoraria, Other: IDMC; Pfizer: Research Funding; Boehringer Ingelheim: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Astellas Pharma: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; PharmaEssentia: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; MorphoSys: Research Funding; Blueprint Medicines: Consultancy, Honoraria. Litzow:Abbvie: Research Funding; Amgen: Research Funding, Speakers Bureau; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Sanofi: Research Funding; Beigene: Speakers Bureau; Biosight: Other: Data Safety Monitoring Committee. Lazarus:Jazz Pharmaceuticals: Speakers Bureau; Pfizer: Speakers Bureau; CSL Behring: Consultancy; BioSight: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Consultancy; Partner Therapeutics: Consultancy, Current holder of stock options in a privately-held company; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pluristem Therapeutics, Inc: Consultancy; Geron: Speakers Bureau; Amgen: Speakers Bureau; Seattle Genetics: Speakers Bureau; GlycoMimetics: Consultancy. Rowe:BioSight: Consultancy. Liedtke:Biomea: Research Funding; Allogene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum/Alexion: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Nexcella: Membership on an entity's Board of Directors or advisory committees; Seagen: Research Funding. Wood:Cellnomics LLC: Current equity holder in private company; Amgen: Consultancy. Pratz:Immunogen: Consultancy; Kura Oncology: Research Funding; AbbVie: Consultancy, Research Funding. Dinner:Pfizer: Consultancy; Rigel: Consultancy; Kite: Consultancy. Atallah:Novartis Pharmaceuticals Corporation: Honoraria. Jeyakumar:Jazz Pharma: Research Funding; Pfizer: Research Funding. Lin:Aptevo; Bio-Path Holdings; Ciclomed; Cleave; Jazz; Jazz Pharmaceuticals; Leukemia & Lymphoma Society; Kura Oncology; Trovagene: Research Funding; Jazz Pharmaceuticals; Servier: Consultancy. DeAngelo:AbbVie, Blueprint, GlycoMimetics, Novartis: Research Funding; Amgen, Autolus, Blueprint, Gilead, Incyte, Jazz, Novartis, Pfizer, Servier, Takeda: Consultancy; Daiichi-Sankyo, Fibrogen: Other: DSMB; Mt Sinai MPN Consortium: Other: Mt Sinai MPN Consortium; Dana-Farber Cancer Institute: Current Employment. Advani:Novartis: Consultancy; MD Education: Honoraria; Amgen: Research Funding; Kura: Research Funding; Servier: Research Funding; Seattle Genetics: Research Funding; Wiley: Honoraria; Immunogen: Research Funding; American Society of Hematology: Honoraria; Springer: Honoraria; Incyte: Research Funding; OBI: Research Funding; BEAM: Other: Research support, Research Funding; Pfizer: Other: Manuscript help, Research Funding; Macrogenics: Research Funding; Glycomimetics: Research Funding; Emmes: Honoraria; PER: Honoraria; Web MD: Honoraria; Wolters Kluwer: Honoraria; Kite: Consultancy, Research Funding; MJH Life: Honoraria. Vachhani:Cogent Biosciences: Consultancy; GenenTech: Consultancy; CTI BioPharma Corp (now Sobi): Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Research Funding; GlaxoSmith Kline: Consultancy; Gilead/Forty Seven: Research Funding; Kartos Therapeutics: Research Funding; Blueprint Medicines: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astex Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Daiichi Sankyo: Consultancy; Stemline: Consultancy; Novartis: Consultancy; MorphoSys: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Sharon:Mallinckrodt Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; D.E. Shaw Research: Consultancy. Erba:Taiho Oncology: Research Funding; PTE: Research Funding; Oryzon: Research Funding; Ascentage: Research Funding; Aptose: Research Funding; ALX Oncology: Research Funding; Trillium: Consultancy, Other: Advisory Board/Consultant; Takeda: Consultancy, Other: Advisory Board/Consultant; Syros: Consultancy, Other: Advisory Board/Consultant; Sumitomo Pharma: Consultancy, Other: Advisory Board/Consultant, Research Funding; Stemline: Consultancy, Other: Advisory Board/Consultant; Servier: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Schrodinger: Consultancy, Other: Advisory Board/Consultant; Pfizer: Consultancy, Other: Advisory Board/Consultant; Novartis: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Macrogenics: Consultancy, Other: Advisory Board/Consultant, Research Funding; Kura Oncology: Consultancy, Other: Advisory Board/Consultant, Research Funding; Jazz: Consultancy, Other: Advisory Board/Consultant, Speakers Bureau; Incyte: Consultancy, Other: Advisory Board/Consultant; Immunogen: Consultancy, Other: Advisory Board/Consultant; Glycomimetics: Consultancy, Other: Advisory Board; Steering Committee member, Research Funding; Daiichi Sankyo: Consultancy, Other, Research Funding; Celgene: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Research Funding, Speakers Bureau; BMS: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Speakers Bureau; Astellas: Consultancy, Other: Advisory Board; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Chair, Independent Review Committee for VIALE A and VIALE C, Research Funding; Genentech: Consultancy, Other: Advisory Board. Stone:Ligand Pharma: Consultancy; Epizyme: Consultancy, Other: DSMB; Syndax: Other: Research funding to my institution; Novartis: Other: Research funding to my institution; Redona therapeutics: Consultancy; Rigel: Consultancy; AbbVie: Consultancy, Other: Research funding to my institution; Glycomimetrics: Consultancy; Syntrix: Other: DSMB; ENSEM: Consultancy; Aptevo: Consultancy; Janssen: Other: Research funding to my institution; Hermavant: Consultancy; Kura Oncology: Consultancy; Bristol Meyers Squibb: Consultancy; Curis Oncology: Consultancy; Daiichi Sankyo: Consultancy; Lava Therapeutics: Consultancy; AMGEN: Consultancy; Glaxosmithkline: Consultancy; Cellarity: Consultancy; CTI Biopharma: Consultancy; AvenCell: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy; Takeda: Other: DSMB. Tallman:Adjudication Committee Foghorn Therapeutics FG286: Membership on an entity's Board of Directors or advisory committees; Moleculin: Membership on an entity's Board of Directors or advisory committees; UpToDate: Other: Royalties. Luger:Astellas: Consultancy; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.