Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome

Abstract

BackgroundThis report focuses on the adaptive phase I trial design aimed to find the clinically applicable dose for decitabine maintenance treatment after allogeneic hematopoietic stem cell transplantation in patients with higher-risk myelodysplastic syndrome and secondary acute myeloid leukemia.MethodsThe first cohort (three patients) was given the same initial daily dose of decitabine (5 mg/m2/day, five consecutive days with 4-week intervals). In all cohorts, the doses for Cycles 2 to 4 were individualized using pharmacokinetic-pharmacodynamic modeling and simulations. The goal of dose individualization was to determine the maximum dose for each patient at which the occurrence of grade 4 (CTC-AE) toxicities for both platelet and neutrophil counts could be avoided. The initial doses for the following cohorts were also estimated with the data from the previous cohorts in the same manner.ResultsIn all but one patient (14 out of 15), neutrophil count was the dose-limiting factor throughout the cycles. In cycles where doses were individualized, the median neutrophil nadir observed was 1100/mm3 (grade 2) and grade 4 toxicity occurred in 5.1 % of all cycles (while it occurred in 36.8 % where doses were not individualized). The initial doses estimated for cohorts 2 to 5 were 4, 5, 5.5, and 5 mg/m2/day, respectively. The median maintenance dose was 7 mg/m2/day.ConclusionsWe determined the acceptable starting dose and individualized the maintenance dose for each patient, while minimizing the toxicity using the adaptive approach. Currently, 5 mg/m2/day is considered to be the most appropriate starting dose for the regimen studied.Trial registrationClinicaltrials.gov NCT01277484

Graft-versus-Host Disease–Free, Relapse-Free Survival after Allogeneic Stem Cell Transplantation for Myelodysplastic Syndrome

“…All patients received allogeneic HSCT after conditioning consisting of fludarabine and busulfan with or without total body irradiation. Excluded patients were as follows: 4 patients without marrow examination at the time of HSCT, 19 patients who enrolled in a previous phase I trial designed to administer post-HSCT preemptive chemotherapy [19], and 1 patient who received different GVHD prophylaxis consisting of alemtuzumab. After that, the final study cohort included 324 patients with MDS or secondary AML arising from MDS.…”

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…Only one retrospective case series recently reported on a maintenance approach in 18 patients, who were envisaged to receive Aza continuously until progression or intolerability [40]. In contrast, 5 prospective single-arm studies have been performed so far investigating consolidation therapy with either Aza (n = 3) or DAC (n = 2) for patients with AML or MDS after allo-SCT [41][42][43][44][45]. These early-phase studies covered 130 patients and demonstrated feasibility.…”

Do hypomethylating agents prevent relapse after Allo-HCT?

“…So far, the evidence for the use of HMA as prophylactic approach to avoid relapse after allo‐HCT is based on five prospective single‐arm studies and one retrospective case series investigating Aza (n = 4) or DAC (n = 2) in a total of 148 patients . All of them fulfill the formal definition criteria of consolidation therapy reflecting a treatment phase defined by a limited time interval and/or number of cycles.…”