Up-front blinatumomab improves MRD clearance and outcome in adult Ph– B-lineage ALL: the GIMEMA LAL2317 phase 2 study
Renato Bassan, Sabina Chiaretti, Irene Della Starza, Alessandra Santoro, Orietta Spinelli, Manuela Tosi, Loredana Elia, Deborah Cardinali, Maria Stefania De Propris, Matteo Piccini, Federico Lussana, Mario Annunziata, Patrizia Chiusolo, Patrizia Zappasodi, Erika Borlenghi, Matteo Leoncin, Catello Califano, Monica Bocchia, Francesco Di Raimondo, Francesco Grimaldi, Mario Tiribelli, Anna Candoni, Albana Lico, Ernesta Audisio, Monia Lunghi, Anna Maria Mianulli, Mariangela Di Trani, Valentina Arena, Monica Messina, Alfonso Piciocchi, Paola Fazi, Alessandro Rambaldi, Robin Foà
Abstract
ABSTRACT: The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Leucemia Acuta Linfoblastica (LAL) 2317 protocol investigated the frontline chemotherapy-blinatumomab combination in adult Philadelphia chromosome/BCR::ABL1 rearrangement-negative (Ph-) CD19+ B-lineage acute lymphoblastic leukemia (B-ALL) to improve minimal residual disease (MRD) response and clinical outcome. Two cycles of IV blinatumomab were administered after chemotherapy cycles 3 and 6. The primary end point was the rate of molecular MRD negativity after blinatumomab 1. One hundred forty-nine patients were enrolled (median age, 41 years [range, 18-65]); 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 < .001) after blinatumomab, with 23 of 30 MRD-positive patients (73%) becoming MRD negative, fulfilling the primary end point. At a median follow-up of 38.1 months (range, 0.5-62.8), the median overall survival (OS) and disease-free survival (DFS) were not reached, and the estimated 3-year OS and DFS were 71% and 65%, respectively, with an excellent outlook for the patients aged 18 to 40 years who achieved an early MRD negativity (DFS, 92%). Pre-blinatumomab MRD predicted a worse outcome, especially in genetically 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 hematopoietic stem cell transplantation, and 69% and 19% in transplant recipients, respectively. 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. This trial was registered at www.ClinicalTrials.gov as #NCT03367299.