High Dose Cytarabine and Mitoxantrone in Combination with Dasatinib As Active Induction Therapy in Adult Patients with Philadelphia Chromosome Positive (ph+) Acute Lymphoblastic Leukemia (ALL)

• Published in: Blood 2012-11, Vol.120 (21), p.4293-4293
• Main Authors: Lamanna, Nicole, Weiss, Mark, Berman, Ellin, Frattini, Mark G., Heaney, Mark, Jurcic, Joseph G., Rosenblat, Todd L., Landau, Heather, Weissbrot, Hanna, Maslak, Peter G.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.4293.4293

Abstract 4293 The Philadelphia chromosome is the most frequent cytogenetic abnormality in adult ALL, with an overall incidence of 20–30%. When treated with conventional therapy, adult patients with Ph+ ALL have an extremely poor prognosis. While current chemotherapy regimens typically induce complete responses (CRs) in the majority of patients, the quality of remission is poor as most patients relapse within 6–11 months of treatment and subsequently die from the disease. The 1 and 5-year overall survival rates for patients treated with imatinib-based chemotherapy regimens is approximately 60% and 30%, respectively. Previously we in collaboration with others have reported a Phase III randomized study of high-dose cytarabine and mitoxantrone (ALL-2 regimen) as induction therapy versus a more traditional treatment regimen with vincristine-prednisone based induction therapy in newly diagnosed adult ALL patients (Weiss, ASCO 2005). This study was conducted prior to the routine use of tyrosine kinase inhibitors (TKIs) for Ph+ disease. In that randomized study, there were 16 patients with Ph+ ALL treated with the frequency of CRs on the ALL-2 regimen 85% compared to 47% of patients treated on the vincristine-prednisone based arm. At 6 year follow-up, 26% of Ph+ patients treated with the ALL-2 regimen were alive compared to 0% of Ph+ ALL patients treated on the vincristine-prednisone induction arm. Based on this initial favorable response seen with the ALL-2 regimen in Ph+ patients and the emerging use of TKI therapy in Ph+ALL, dasatinib was added to this therapeutic regimen. This is the first report of this combination in newly diagnosed patients with Ph+ ALL or blastic phase CML patients. Eligible patients included previously untreated or treated adults with a diagnosis of Ph+ ALL or lymphoid blast crisis of known CML. Patients must have evidence of t(9;22) in leukemic cells based on chromosomal or molecular analysis. Patients received induction therapy with high-dose cytarabine (3000 mg/m2 IVPB daily, days 1–5) and mitoxantrone (80mg/m2 IVPB on day 3 for patients ≤ 65 yrs or 40mg/m2 for patients >65 yrs) in combination with dasatinib. Patients in the phase I portion of the study were assigned to one of 3 successive dose cohorts of dasatinib: dose level 1: 70mg daily, dose level 2: 100mg daily; dose level 3: 140mg daily, starting on day 1. Patients then received treatment with Consolidation A: vincristine, dexamethasone, and dasatinib. Following consolidation A,