Robin Foà1, Renato Bassan1, Antonella Vitale1, Loredana Elia1, Alfonso Piciocchi1, Maria-Cristina Puzzolo1, Martina Canichella1, Piera Viero1, Felicetto Ferrara1, Monia Lunghi1, Francesco Fabbiano1, Massimiliano Bonifacio1, Nicola Fracchiolla1, Paolo Di Bartolomeo1, Alessandra Mancino1, Maria-Stefania De Propris1, Marco Vignetti1, Anna Guarini1, Alessandro Rambaldi1, Sabina Chiaretti1. 1. From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.
Abstract
BACKGROUND: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment. METHODS: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment. RESULTS: Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%). CONCLUSIONS: A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).
BACKGROUND: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment. METHODS: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment. RESULTS: Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%). CONCLUSIONS: A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).