Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

We have previously reported on the efficacy and tolerability of hyper-CVAD regimen (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib followed by imatinib-based consolidation/maintenance therapy in 20 patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Here, we present the 13-year follow up of our study. Fifty-four patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia were enrolled: 39 (72%) with de novo disease, 6 (11%) whose disease was primary refractory after induction (without a tyrosine kinase inhibitor), and 9 (17%) in complete remission after one course of induction therapy (without tyrosine kinase inhibitor). Forty-two (93%) of the 45 patients treated for active disease achieved complete remission, one achieved complete remission with incomplete recovery of platelets, one achieved partial remission and one died during induction. Nineteen (35%) patients are alive and 18 are in complete remission. The 5-year overall survival rate for all patients was 43%. Significant negative predictors of overall survival were age over 60 years, p190 molecular transcript, and active disease at enrollment. Sixteen (30%) patients underwent allogeneic stem cell transplantation. Median overall survival was not significantly greater for patients who underwent transplant. Patients with residual molecular disease at three months had improved complete remission duration with transplant. The median time to hematologic recovery and severe toxicities with combination were not significantly different from those observed with conventional chemotherapy. Only one patient discontinued therapy due to toxicity. HyperCVAD chemotherapy and imatinib is an effective regimen for Philadelphia-positive acute lymphoblastic leukemia. Transplant may not be indicated in all patients with Philadelphia-positive acute lymphoblastic leukemia. (clinicaltrials.gov identifier: NCT00038610).

Figure 1.

All 54 patients enrolled on the protocol and treated with imatinib in combination with hyper-CVAD chemotherapy are evaluated for overall survival (OS) (A) and disease-free survival (DFS) (B) from the time of initiation of protocol therapy. This includes newly diagnosed untreated patients (n=39) or patients previously treated with induction therapy without tyrosine kinase inhibitors (TKI): either failing after one course of chemotherapy without TKI (n=6) or in complete remission after up to two courses of chemotherapy without TKI (n=9). (C) Evaluation of OS censored for allogeneic stem cell transplant (ASCT).

Figure 2.

Overall survival (A) and disease-free survival (B) for patients enrolled on the protocol and treated with imatinib in combination with hyper-CVAD chemotherapy is evaluated from the time of initiation of protocol therapy for newly diagnosed untreated patients (de novo, n=36) or patients previously treated with induction therapy without tyrosine kinase inhibitors (TKI): either failing after one course of chemotherapy without TKI (primary refractory, n=6) or in complete remission after up to two courses of chemotherapy without TKI (CR at start, n=9). The OS, DFS, and OS censored for allogeneic stem cell transplant (ASCT) in the 36 de novo patients are shown separately in C, D and E.

Figure 3.

Disease-free survival in patients treated with hyper-CVAD and imatinib followed by imatinib-based consolidation/maintenance therapy by transplant versus no transplant for all patients under 60 years of age (A) and by transplant versus no transplant for patients aged 40 years or under and patients aged 41–60 years (B).

Figure 4.

Disease-free survival in patients treated with hyper-CVAD and imatinib followed by imatinib-based consolidation/maintenance therapy by molecular response status [deep molecular remission (CMR/MMR) versus no deep molecular remission] at three months.