First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia

Abstract

The combination of cytotoxic chemotherapy and imatinib has improved the outcome for patients with Philadelphia chromosome-positive (Ph ؉ ) acute lymphoblastic leukemia (ALL). Dasatinib has significant clinical activity in patients with imatinib resistance. We examined the efficacy and safety of combining chemotherapy with dasatinib for patients with Ph ؉ ALL. Newly diagnosed patients received dasatinib 50 mg by mouth twice per day (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyper-CVAD, and high-dose cytarabine and methotrexate. Patients in complete remission received maintenance daily dasatinib and monthly vincristine and prednisone for 2 years, followed by dasatinib indefinitely. Thirty-five patients with untreated Ph ؉ ALL with a median age of 53 years (range, 21-79 years) were treated; 33 patients (94%) achieved complete remission. Two patients died of infections before response assessment. Grade 3 and 4 adverse events included hemorrhage and pleural and pericardial effusions. With a median follow-up of 14 months (range, 4-37 months), the median disease-free survival and median overall survival have not been reached, with an estimated 2-year survival of 64%. The combination of chemotherapy with dasatinib is effective in achieving long-term remissions in patients with newly diagnosed Ph ؉ ALL. This study was registered at www.ClinicalTrials.gov as

A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study

“…We continue, therefore, to support a strategy that allows a CHR to be obtained in virtually all patients, including the elderly, based on this chemotherapy-free approach. Furthermore, our study confirms the importance of MRD, the negativity of which should be a major objective in this disease: a higher rate of MRD negativity is likely to be achieved with the inclusion of 2 nd -and, more likely, 3 rd -generation TKI such as ponatinib, which have been proven to have a greater debulking effect, 9,14,16,55 and might possibly be more active in patients with the BCR-ABL p210 form, given the lower MRD clearance observed in this subgroup of patients. As far as ponatinib is concerned, a recent study from the MDACC 55 on 37 patients has indeed shown that its use as upfront therapy, combined with chemotherapy, is able to induce extremely promising results with 2-year event-free survival (EFS) and OS of 81% and 80%, respectively, although 6 toxic deaths were recorded.…”

“…5,6,10,12,13,15,[18][19][20][21]34,35 Furthermore, our schedule has the advantage that there are fewer deaths during induction treatment, in contrast to the majority of the combination studies in which, with few exceptions, 5 toxic deaths were recorded in 2%-7% of cases. 6,8,[12][13][14][18][19][20] Indeed, toxicity was recorded in the initial combination protocol (imatinib+chemotherapy) that led to the final amendment to a sequential strategy. These results indicate that the induction treatment for adult Ph + ALL can be effectively based on the administration of imatinib plus steroids, without systemic chemotherapy, which enables a CHR to be obtained in virtually all patients with no deaths in induction.…”

“…[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Prior to the introduction of TKI, prognosis was very poor, with virtually no adult patients (<5%) cured with standard chemotherapy; median survival was 8-10 months unless an allogeneic hematopoietic stem cell transplant (allo-SCT), the only potentially curative strategy, could be performed. [22][23][24][25] Today, treatment with TKI, with [5][6][7][8][9][10][12][13][14][15][18][19][20][21] or without 11,16,17 systemic chemotherapy, represents the most appropriate first-line management of patients with Ph + ALL in terms of rates of complete hematologic remission (CHR) and disease-free survival (DFS). Imatinib has been incorporated into different schedules either in induction [5][6][7]10,[12][13][14][18]…”

“…[22][23][24][25] Today, treatment with TKI, with [5][6][7][8][9][10][12][13][14][15][18][19][20][21] or without 11,16,17 systemic chemotherapy, represents the most appropriate first-line management of patients with Ph + ALL in terms of rates of complete hematologic remission (CHR) and disease-free survival (DFS). Imatinib has been incorporated into different schedules either in induction [5][6][7]10,[12][13][14][18][19][20][21] or following induction 8,10 in cohorts including also elderly patients, 8 with CHR rates varying from 72% to 96%. Moreover, the use of imatinib can also act as a "bridge" to an allo-SCT for those patients eligible.…”

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

“…Response rates with combinations of TKIs and chemotherapy are 40% in nonlymphoid BP CML and 70-80% in lymphoid BP CML [81][82][83]. Median survival times are 6-12 months, and 12-24 months, respectively.…”