Up-front Blinatumomab Improves MRD Clearance and Outcome in Adult Ph− B-lineage ALL: the GIMEMA LAL2317 Phase 2 Study

• To improve MRD response and outcome, blinatumomab was added to the early consolidation of a risk-oriented program for adult Ph- B-ALL.

• After blinatumomab, MRD negativity rate was 93%; 3-year survival rate was 93% and 65% in chemotherapy and HSCT patient groups, respectively.

The GIMEMA LAL2317 protocol investigated the frontline chemotherapy-blinatumomab combination in adult Philadelphia- CD19+ B-lineage acute lymphoblastic leukemia (Ph- B-ALL) to improve minimal residual disease (MRD) response and clinical outcome. Two cycles of intravenous blinatumomab were administered after chemotherapy cycles 3 and 6. The primary endpoint was the rate of molecular MRD negativity following blinatumomab 1. One hundred and forty-nine patients were enrolled (median age 41 years, range18-65); 132 entered remission, 122 received blinatumomab and 109 had a pre- and post-blinatumomab 1 MRD assessment. MRD negativity increased from 72% to 93% (P<0.001) after blinatumomab, with 23/30 MRD+ patients (73%) becoming MRD-, fulfilling the primary endpoint. At a median follow-up of 38.1 months (0.5-62.8), the median overall and disease-free survivals (OS, DFS) were not reached and the estimated 3-year OS and DFS were 71% and 65%, with an excellent outlook for the patients aged 18-40 years who achieved an early MRD negativity (DFS 92%). Pre-blinatumomab MRD predicted a worse outcome, especially in genetics high-risk patients. Notably, the 3-year survival of blinatumomab-treated patients was 82%. Survival and relapse rates were 91% and 15% in patients assigned to standard chemotherapy, 59% and 35% in patients assigned to HSCT, and 69% and 19% in transplant recipients. Blinatumomab toxicity was manageable, with only 8 permanent discontinuations. This chemotherapy-blinatumomab risk-oriented program yielded remarkable results that need further improvement in higher-risk patients displaying early MRD persistence. Blinatumomab should be considered as a standard component of induction/consolidation for adult Ph- B-ALL. ClinicalTrials.gov # NCT03367299.