Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia

Abstract

T he prognosis of patients with acute myeloid leukemia in whom primary treatment fails remains very poor. In order to improve such patients' outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen, combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure were included. Cytogenetic risk was poor in 15 patients (62%) and intermediate in nine (38%). The sequential regimen consisted of clofarabine (30 mg/m 2 /day) and cytosine arabinoside (1 g/m 2 /day) for 5 days, followed, after a 3-day rest, by reduced-intensity conditioning and allogeneic stem-cell transplantation combining cyclophosphamide (60 mg/kg), intravenous busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Patients in complete remission at day +120 received prophylactic donor lymphocyte infusion. Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI: 33-71) at 1 year and 38% (95% CI: 18-46) at 2 years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI: 26-64) at 1 year and 29% (95% CI: 13-48) at 2 years. The cumulative incidence of non-relapse mortality was 8% (95% CI: 1-24) at 1 year and 12% (95% CI: 3-19) at 2 years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, which warrants further investigation. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174. IntroductionThe prognosis of patients with acute myeloid leukemia (AML) in primary treatment failure remains very poor. Primary treatment failure or primary refractory AML is defined by failure to achieve a complete hematologic remission (CR) after one or two courses of induction chemotherapy.1,2 For these patients, the chance of achieving a CR with another standard or conventional treatment, including the use of intermediate-or high-dose cytosine arabinoside (Ara-C) alone or in combination with an ABSTRACT © Ferrata Storti Foundationanthracycline, fludarabine or gemtuzumab-ozogamicin, is 10-20% at best. The overall survival rate at 1 year is less than 20%, with a median survival of less than 6 months.3-5

Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

“…Our results showing a 2‐year OS of about 40% compared favorably with previous series of MAC and sequential HSCT in relapsing or refractory AML . Patients from two groups did not differ in regards to their major characteristics, especially the distribution between refractory and relapsed leukemia.…”

“…Another way of reducing post‐transplant relapse in SEQ approach could be to reinforce the pretransplant cytoreduction by using news drugs. A second generation of purine analog, clofarabine, which also shown to be relevant in first line or in relapsed of AML, was thus evaluated in the setting of sequential transplant . In our series there is no superiority of a clofarabine/cytarabine‐RIC compared with a more classic FLAMSA‐RIC regimen.…”

“…Prophylactic donor lymphocyte infusions (DLI) are systematically planned, in the absence of graft versus host disease (GVHD) to reinforce the graft versus leukemia (GVL) effect . Sequential approaches are associated to 30%‐45% long‐term survival in advanced AML patients . Conversely, major advances in the supportive care of HSCT, such as fungal and viral infections prevention and treatment, or HLA‐typing in unrelated transplants, have reduced NRM after MAC transplants .…”

Phase I/II multisite trial of optimally dosed clofarabine and low‐dose TBI for hematopoietic cell transplantation in acute myeloid leukemia

“…Among 24 older patients with AML (median age 59‐60 years), Chevallier et al retrospectively observed similar NRM (12.5% vs 20.8%, P = .58) but lower 2 year relapse incidence (16.7% vs 41.2%, P = .05) and better 2 year LFS (70.8% vs 38%, P = .03) and OS (79.2% vs 38%, P = .01) with clofarabine‐2‐day busulfan HCT conditioning, compared to 248 who received fludarabine‐2‐day busulfan . Other trials found that clofarabine, as part of bridging chemotherapy or combined with myeloablative busulfan or melphalan conditioning, could salvage a proportion of patients with primary induction failure and those with chemosensitive relapse . Median ages of patients those trials were 47 to 61 years.…”

Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy

“…A similar, sequential approach was recently reported by Mohty et al 26 In this study, 24 patients with primary refractory AML were treated with a sequential regimen consisting of clofarabine and cytarabine, followed by a 3-day rest, and then an allogeneic HCT utilizing a reduced-intensity conditioning regimen combining cyclophosphamide, busulfan (for 2 days) and antithymocyte globulin for 2 days. Patients in CR on posttransplant day +120 received prophylactic DLI.…”