Combination of the hyperCVAD Regimen with Dasatinib Is Effective in Patients with Relapsed Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL) and Lymphoid Blast Phase Chronic Meyloid Leukemia (CML-LB)

The dual Src and Abl inhibitor dasatinib is ~325 times more potent in vitro against BCR-ABL kinase activity and has significant clinical activity in patients with imatinibresistant lymphoid blast phase CML (CML-LB) and Ph+ ALL. In this study, patients with relapsed Ph+ ALL or CML-LB received dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in CR continued to receive dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. To date 14 patients with relapsed Ph+ ALL or CML-LB have received a median of 3 cycles (range 1–8); 1 patient in complete remission (CR) is receiving maintenance therapy. Median age was 43 years (range 21–69); 4 (29%) patients were older than 50 years. Median WBC at start of treatment was 6.8 × 10⁹/L (range, 0.4 – 27.2 × 10⁹/L). Median blast percentage was 45% (range 0–96%) Three patients had CNS involvement. Median number of previous therapies was 1 (range, 1–4) including hyperCVAD and imatinib, tyrosine kinase inhibitor monotherapy, investigational agents and transplantation. All patients were evaluable for response. 10 patients (71%) achieved CR and 4 patients (29%) achieved CR with incomplete platelet recovery (CRp). Twelve of 14 (86%) patients achieved a major cytogenetic response, complete in 11, 1 (7%) had insufficient metaphases, and 1 (7%) had no response. Overall, 9 (64%) patients had achieved a major molecular response, complete in 5. Median time to neutrophil and platelet recovery during the first course was 18 and 22 days and 18 and 26 days, respectively after subsequent courses. Four patients relapsed after median response duration of 19 weeks (range, 9–38); two of them had acquired ABL kinase domain mutations: One patient lost his baseline mutation, Y253H, and acquired T315I and E450G; the second lost his 3 baseline mutations, Y253H, F359V, and E459K, and acquired T315I.Two patients received an allogeneic transplantation and one patient received a donor lymphocyte infusion. Grade 3 and 4 toxicities included 7 episodes of bleeding (4 GI, 1 GU, and 2 subdural hematomas), 4 episodes of pleural effusions, 2 episodes of pericardial effusions, infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and hyperbilirubinemia. With a median follow up of 6 months (range, 1–13 months), 9 patients are alive; 7 in CR/CRp. Two patients died after disease relapse, 1 died post transplant and 2 died in CR/CRp from infections. In conclusion, the hyperCVAD regimen with dasatinib is feasible and effective in patients with relapsed Phpositive ALL and CML-LB.