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 Myeloid Leukemia (CML-LB).

The dual Src and Abl inhibitor dasatinib is ∼325 times more potent than imatinib in vitro against the kinase activity of BCR-ABL and has significant clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL. Prognosis of patients with relapsed Ph+ ALL and CML-LB is poor with few effective options other than allogeneic stem cell transplant.

To investigate the feasibility of and response to a combination of chemotherapy and dasatinib to patients with relapsed Ph+ ALL or CML-LB.

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 maintenance with dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely.

To date, 23 patients with relapsed Ph+ ALL (n=14) or CML-LB (n=9) have received a median of 3 cycles of this regimen (range 1-8 cycles). Median age was 49 years (range 21-69); 10 (43%) patients were older than 50 years. Median WBC at start of treatment was 9.6 × 10⁹/L (range, 0.4 – 295.5 × 10⁹/L). Median bone marrow blast percentage was 80% (range 0-98%). Six patients had CNS involvement. Pre-treatment ABL mutations included: 1 patient with F317L, 1 M351T, 1 T315I, 1 Y253F, 1 Y253H, and 1 with Y253H, F359V, and E459K). Median number of previous therapies was 1 (range, 1-4); these include hyperCVAD plus imatinib (n=8), other combination chemotherapy regimens (n=8), monotherapy with tyrosine kinase inhibitors other than dasatinib (n=7), investigational agents (n=2) and allogeneic stem cell transplantation (n=2). All patients were evaluable for response. 15 patients (65%) achieved CR, 6 patients (26%) achieved CR with incomplete platelets recovery (CRp), 1 patient (4%) did not have day 21 bone marrow to assess response, and 1 patient (4%) died during induction. Nineteen of 21 (90%) patients have achieved a major cytogenetic response after 1 cycle of therapy, complete in 17, 1 (5%) had insufficient metaphases, and 1 (5%) had no response (still had 95% Ph+ metaphases after 1 cycle). Overall, so far 15 (65%) patients had achieved a major molecular response, complete in 10. Median time to neutrophil and platelet recovery for the first cycle was 18 and 22 days, and for subsequent cycles, 18 and 26 days, respectively. Nine patients have relapsed after median response duration of 26 weeks (range, 8-49); six of them had acquired ABL kinase domain mutations (1 T315I and E450G; 3 T315I; 1 F317L, and 1 G303fs). Three patients proceeded to an allogeneic transplantation and one previously transplanted patient received a donor lymphocyte infusion. Grade 3 and 4 adverse events included bleeding (GI, GU, and subdural hematomas)(9), pleural effusions (5), pericardial effusions (2), as well as infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and hyperbilirubinemia. With a median follow up of 13 months (range, 5-52 months), 10 patients are alive; 8 are in CR/CRp. Seven patients died after disease relapse, 1 died post transplant, 4 died in CR/CRp from infections, and 1 died of unknown causes. The median survival was 39 weeks (range, 2 to 226 weeks) with 42% of patients alive at 1 year.

The combination of the hyperCVAD regimen with dasatinib is feasible and effective in patients with relapsed Ph-positive ALL and CML-LB and can provide a bridge to an allogeneic stem cell transplant.

Ravandi:Bristol Myers Squibb: Honoraria, Research Funding. Kantarjian:Bristol Myers Squibb: Research Funding. Cortes:Bristol Myers Squibb: Research Funding. O'Brien:Bristol Myers Squibb: Research Funding.