Durable Molecular Remissions in Patients with Relapsed CML Post Allogeneic Stem Cell Transplantation upon Treatment with Imatinib-Mesylate (Glivec®, STI-571). Follow-Up Results of a Phase II Open-Label Study.

Purpose: In a phase II clinical trial we have previously reported on the safety and efficacy of imatinib mesylate (IM) to induce hematologic, cytogenetic and molecular remissions in case of relapse post allogeneic stem cell transplantation (SCT) in patients with chronic myelogenous leukaemia (CML). Here we report on an extended follow-up phase, which was performed to monitor stability of responses and further disease course in patients enrolled.

Patients and Methods: Within the trial, patients, transplanted in chronic phase (CP) CML with molecular or cytogenetic relapse (n=37), received IM at a starting dose of 400mg. Close monitoring was performed, which, besides evaluation of side effects, included hematology, chimerism, bone marrow analysis and quantitative/qualitative PCR for Bcr-Abl. After completion of the study phase, pts were treated by the discretion of their physician, which could include continuation or cessation of IM or application of DLI.

Results: During the entire observation period the rate of reported side effects was low, only one mild reactivation of Graft versus Host Disease (GvHD) occurred upon IM treatment. Response rates reflected high efficacy of IM in this patient population: in 16/22 (72.7%) evaluable patients a complete chimerism in peripheral blood was demonstrated. Complete cytogenetic response (CCR) was seen in 11/13 (84.6%) of patients with cytogenetic relapse and follow-up samples available. Importantly, 25/37 patients (67%) achieved a complete molecular response (CMR) (defined as nested PCR-negativity for 3 consecutive samples) within the primary study phase or during follow-up. Cessation of IM in 10 patients with CMR during follow-up resulted in molecular relapse of 6 patients (60%). However, importantly in 4/10 (40%) patients, CMR were durable even after cessation of the study drug with a median follow-up of 381 days after discontinuation of IM. In 7 patients, donor lymphocyte infusions (DLI) were given without major toxicities. This established CMR in 4 of these patients. One episode of mild GvHD reactivation did occur in the context of DLI. At the median follow-up of 1.7 years, OS is 100% in the study cohort; one patient has died due to progressive disease 2 years after inclusion into the study.

Conclusion: In CP-CML patients with relapse post allogeneic SCT IM treatment established CMR in a majority of patients. Importantly, CMR were noted even after cessation of the study drug, suggesting the possibility of definite tumor control in selected patients. Therefore, weighing the risk of aggravation of GvHD and/or induction of bone marrow aplasia using DLI against the favourable toxicity profile of IM, in case of MRD post allogeneic SCT relapse and primary IM-treatment seems to be justified. In particular in patients with poor performance status or active GvHD early therapy instead of postponed treatment may lead to superior results. Further clinical trials are warranted to optimize sequential or concurrent use of IM and DLI in this patient population.