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

Abstract

In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase together with chemotherapy. Due to the toxicity of this combined approach, the protocol was further amended to a sequential scheme based on imatinib plus steroids as induction, followed by consolidation with chemotherapy plus imatinib and, when applicable, by a hematopoietic stem cell transplant. Fifty-one patients (median age 45.9 years) were enrolled in the final sequential protocol. At the end of induction (day +50), 96% of evaluable patients (n=49) achieved a complete hematologic remission; after consolidation, all were in complete hematologic remission. No deaths in induction were recorded. Overall survival and disease-free survival at 60 months are 48.8% and 45.8%, respectively. At day +50 (end of imatinib induction), a more than 1.3 log-reduction of BCR-ABL1 levels was associated with a significantly longer disease-free survival (55.6%, 95%CI: 39.0-79.3 vs. 20%, 95%CI: 5.8-69.1; P=0.03), overall survival (59.1%, 95%CI: 42.3-82.6 vs. 20%, 95%CI: 5.8-69.1; P=0.02) and lower incidence of relapse (20.5%, 95%CI: 7.2-38.6 vs. 60.0%, 95%CI: 21.6-84.3; P=0.01). Mean BCR-ABL1 levels remained significantly higher in patients who subsequently relapsed. Finally, BCR-ABL1^p190 patients showed a significantly faster molecular response than BCR-ABL1^p210 patients (P=0.023). Though the study was not powered to evaluate the role of allogeneic stem cell transplant, allografting positively impacted on both overall and disease-free survival. In conclusion, a sequential approach with imatinib alone in induction, consolidated by chemotherapy plus imatinib followed by a stem cell transplant is a feasible, well-tolerated and effective strategy for adult Philadelphia positive acute lymphoblastic leukemia, leading to the best long-term survival rates so far reported. (clinicaltrials.gov identifier: 00458848).

Trial registration: ClinicalTrials.gov NCT00458848.

Figure 1.

Schematic representation of the GIMEMA 0904 3^rd amendment. Steroid pre-phase: oral prednisone at increasing doses (10–60 mg/m²/day) for seven days. Induction therapy: oral imatinib at a dose of 600 mg daily for 50 days; prednisone (60 mg/m²/day) until day +24, then tapered and stopped at day +32; intrathecal methotrexate (15 mg) on days +21 and +35. Consolidation treatment: HAM regimen plus oral imatinib at a dose of 600 mg daily. Post consolidation: a hematopoietic SCT, either allogeneic or autologous (if no donor was available) was offered; otherwise, patients continued treatment with imatinib. Patient flow-chart is also provided. pts: patients; CR: complete remission; Progr: progression; allo-SCT: allogeneic stem cell transplantation; Auto-SCT: autologous stem cell transplantation; AraC: cytarabine.

Figure 2.

Minimum residual disease (MRD) monitoring during treatment. MRD monitoring was performed by quantitative real-time PCR (Q-RT-PCR) and BCR-ABL1 expression levels converted into a logarithmic (base 10) scale. A highly significant (P<0.0001) disease reduction was observed between the onset and day (d) +35, and an additional decrease [P=not significant (ns)] between days +35 and +50. Consolidation chemotherapy induced a further reduction (P=ns) of the BCR-ABL1 levels compared to those obtained at the end of induction.

Figure 3.

Cumulative incidence of relapse (CIR) on the basis of reduction in minimum residual disease (MRD). Patients were stratified according to the 1.3 log reduction at day +50 (cut-point 1.3 log). CIR was significantly lower in patients with an MRD reduction of 1.3 log or over (continuous line) at day +50 vs. those with an MRD reduction less than 1.3 log (dashed line) (60.0%, 95%CI: 21.6–84.3 vs. 20.5%, 95%CI: 7.2–38.6, respectively; P=0.01). CR: complete remission.

Figure 4.

Survival of the whole study population. Median follow up is 51.8 months. (A) Disease-free survival (DFS) at 60 months is 45.8% (95%CI: 33.6–62.5), with a median DFS of 40.1 months. (B) Overall survival (OS) at 60 months is 48.8% (95%CI: 36.4–65.3), with a median OS of 48.8 months. CR: complete remission.

Figure 5.

Survival at 60 months on the basis of the reduction in minimal residual disease (MRD). (A) Disease-free survival (DFS) was significantly better for patients with BCR-ABL1 log reduction levels of 1.3 log or over (55.6%, 95%CI: 39.0–79.3, continuous line) than for patients with log reduction levels less than 1.3 log (20.0%, 95%CI: 5.8–69.1, dashed line) (P=0.03). (B) Overall survival (OS) at 60 months is 59.1% (95%CI: 42.3–82.6) for patients with BCR-ABL1 log reduction levels of 1.3 log or over, and 20% for patients with log reduction levels less than 1.3 log (95%CI: 5.8–69.1). CR: complete remission.