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 NCT00390793.

Figures

Figure 1

Levels of residual disease after 1 cycle of protocol therapy in CR. MRD after 1 cycle at CR by (A) BCR-ABL/ABL percentage and (B) flow cytometry.

Figure 2

MRD status by PCR and by flow cytometry with follow-up. (A) MRD by time from therapy according to BCR-ABL/ABL percentage. The line connects the median values of the patients at the stated time points. Several patients at different time intervals had overlapping values. In 1 patient, BCR-ABL was undetectable at presentation by RT-qPCR and was detected by fluorescence in situ hybridization. (B) MRD by time from therapy according to multiparameter flow cytometry.

Figure 3

Event-free survival, CR duration, DFS, and overall survival of the patients. (A) Event-free survival, (B) CR duration, (C) DFS, and (D) overall survival. Numbers of patients at risk are indicated on the horizontal axis.

Figure 4

CR duration and overall survival by age and transplant status. (A) CR duration, excluding patients who underwent allogeneic stem cell transplantation in first CR. (B) Overall survival, excluding patients who received transplants in first CR. (C) CR duration by age. (D) Overall survival by age. Numbers of patients at risk are indicated on the horizontal axis.