Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial

Josep-Maria Ribera, Albert Oriol, Marcos González, Belén Vidriales, Salut Brunet, Jordi Esteve, Eloy Del Potro, Concepción Rivas, Maria-José Moreno, Mar Tormo, Victoria Martín-Reina, Josep Sarrá, Ricardo Parody, Jaime Pérez de Oteyza, Encarna Bureo, Maria-Teresa Bernal, Programa Español de Tratamiento en Hematología, Grupo Español de Trasplante Hemopoyético Groups, Josep-Maria Ribera, Albert Oriol, Marcos González, Belén Vidriales, Salut Brunet, Jordi Esteve, Eloy Del Potro, Concepción Rivas, Maria-José Moreno, Mar Tormo, Victoria Martín-Reina, Josep Sarrá, Ricardo Parody, Jaime Pérez de Oteyza, Encarna Bureo, Maria-Teresa Bernal, Programa Español de Tratamiento en Hematología, Grupo Español de Trasplante Hemopoyético Groups

Abstract

Background: Imatinib, given concurrently or alternating with chemotherapy, has improved the response and survival of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) but relapses are still frequent. The aim of this study was to evaluate the feasibility and results of giving imatinib concurrently with intensive chemotherapy, stem cell transplantation and post-transplant imatinib maintenance therapy in patients with newly diagnosed Ph(+) ALL.

Design and methods: This was a phase II study of patients with newly diagnosed Ph(+) ALL given standard chemotherapy, together with imatinib (400 mg/day) until stem cell transplantation, followed by imatinib maintenance therapy for all patients regardless of the molecular status of the disease.

Results: Of the 30 patients included, 27 (90%) achieved complete remission, one was resistant to treatment and two died during induction therapy. The percentages of major and complete molecular responses were 86% and 21% after induction, and 81% and 65% after consolidation, respectively. Similar results were observed assessing minimal residual disease by flow cytometry. Of the 27 patients who achieved complete remission, 21 underwent stem cell transplantation (16 allogeneic, 5 autologous). Imatinib (400 mg/day) could be administered after transplantation for a median of 3.9 months in 12 patients, although it was interrupted in 10 patients (in 2 cases because of side effects of the drug). Nine patients relapsed, four before and five after stem cell transplantation and eight patients died of transplant-related causes. With a median follow-up of 4.1 years, the probabilities (95% CI) of disease-free and overall survival were 30% (15% to 45%) and 30% (16% to 45%), respectively.

Conclusions: These results confirm that imatinib is an effective first-line treatment for adult Ph(+) ALL when given concurrently with chemotherapy, making stem cell transplantation feasible in a high proportion of patients. However, post-transplantation imatinib administration was limited, mainly because of transplantation-derived complications rather than drug-specific toxicity.

Figures

Figure 1.
Figure 1.
Flow chart of the patients included in the trial. MUD: matched unrelated donor; RIC: reduced intensity conditioning; UCB: unrelated cord blood; TRM transplant-related mortality.
Figure 2.
Figure 2.
Progression of MRD of individuals assessed by RT-PCR. Values are expressed on a logarithmic scale and negative values set at 0. Boxes represent medians and quartiles; dots represent patients with outlier values. Rounded asterisks represent values for individual patients who relapsed after that control. Out of eight patients in sustained complete remission only one had a positive PCR in a pre-SCT evaluation and another a single positive PCR in a post-SCT control.
Figure 3.
Figure 3.
Progression of MRD of individuals as assessed by flow cytometry. Values are expressed on a logaritmic scale and negative values set at minus 4. Boxes represent medians and quartiles; dots represent patients with outlier values. Rounded asterisks represent values for individual patients who relapsed after that control. Out of eight patients in sustained complete remission only one had positive flow cytometry in a pre-SCT evaluation and none was positive in any post-SCT controls.
Figure 4.
Figure 4.
Probabilities of overall survival (A) and disease-free survival (B) of the patients included in the CSTIBES02 trial. Black dots in figures A and B indicate patients alive and alive in complete remission, respectively.

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