Elsevier

Leukemia Research

Volume 37, Issue 6, June 2013, Pages 637-640
Leukemia Research

Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): A report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM)

https://doi.org/10.1016/j.leukres.2013.02.014Get rights and content

Abstract

The effect of azacitidine (AZA) in therapy related MDS and AML (t-MDS/AML) is not well established. 54 patients (42 t-MDS and 12 t-AML), 71% of whom had complex karyotype, received AZA for at least one cycle (median 4 cycles). The overall response rate (ORR) was 39% in the whole cohort and 62% in patients who received ≥4 cycles. One, 2 and 3 year OS was 36%, 14% and 8% respectively. Female gender (p = 0.01) and ECOG 0–1 (p = 0.04) were associated with significantly better OS, while karyotype and marrow blast percentage had no significant impact. By comparison with de novo MDS/AML treated in the same program, t-MDS/AML had a similar response rate (38% vs 45% in de novo MDS/AML, p = 0.53), but significantly shorter OS (2 year OS of 14% vs 33.9%, p = 0.0005). However, in a multivariate analysis performed in all patients (de novo and therapy related cases), only complex karyotype and high IPSS, and not etiology (i.e. de novo versus therapy related), had a significant impact on OS. Nine (15%) patients received allogeneic stem cell transplantation, 4 of whom were still alive.

Introduction

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis leading to blood cytopenias and by a high incidence of progression to acute myeloid leukemia (AML) [1]. MDS and AML can arise de novo or be secondary to the administration of antineoplastic agents (therapy related MDS/AML or t-MDS/AML). Main prognostic factors of MDS include the number and depth of cytopenias, the percentage of marrow blasts and bone marrow cytogenetic abnormalities, combined in an International Prognostic Scoring System (IPSS) that distinguishes 4 subgroups with significantly different risk of progression to AML and survival [2]. Other prognostic factors have been identified, including having therapy related disease, myelofibrosis, LDH, and somatic mutations [3], [4], [5]. The poor prognosis of t-MDS/AML is due in particular to the high prevalence of complex karyotype in this sub-group [6].

In 2008, azacitidine (AZA) was approved in Europe for the treatment of high risk MDS and AML with 20–30% marrow blasts, following the results of a phase III randomized trial showing a survival advantage over conventional treatments including chemotherapy [7]. Nevertheless, therapy related cases were excluded from that phase III trial, and the impact of azacitidine in those patients has not been well studied.

Recently, we published overall results of a compassionate patient named program of AZA in 282 patients with higher risk MDS and AML with 20–30% marrow blasts [8]. In the present study, we focused on the 54 patients which, in that program, were therapy related.

Section snippets

Patients

Following approval of AZA by the US Food and Drug Administration (FDA) for the treatment of MDS in 2004 and before European Medicines Agency (EMA) approval at the end of 2008, the French health agency (French Health Products Safety Agency; AFSSAPS) opened a compassionate, patient-named program (authorization for temporary utilization [ATU] program) of AZA in IPSS intermediate-2 or high-risk MDS and poor-risk AML, in cooperation with the Groupe Francophone des Myelodysplasies (GFM). Patients

Baseline patient characteristics

Of the 282 patients with higher risk MDS or AML with 20–30% marrow blasts included in the French ATU program, fifty-four had t-MDS/AML, including 21 males and 33 females, with a median age of 68.5 years (range, 20–87). The primary disease was a lymphoid malignancy (n = 17, including non-Hodgkin's lymphoma in 6 patients, chronic lymphoid leukemia in 5, Hodgkin's lymphoma in 4, and acute lymphoblastic leukemia in 2 patients), breast carcinoma (n = 15), other solid tumors (n = 21) being represented by

Discussion

By comparison with de novo MDS treated in the same French ATU program [8], the 54 t-MDS/AML had a higher frequency of complex karyotype (71 vs 43%), received fewer cycles of AZA (mean 4 vs 6 cycles) due to more frequent discontinuation of AZA before 4 cycles (41.7% vs 25% in de novo MDS/AML) mainly related to a higher incidence of early deaths. Despite those poor features, t-MDS/AML had a similar ORR (38% vs 45% in de novo MDS/AML, p = 0.53), but significantly shorter OS (2 year OS of 14% vs

Acknowledgments

LA, CB, PF conceived the study, analyzed the data and drafted the manuscript. LA performed statistical analysis. All authors treated the patients, collected the data, read and approved the manuscript.

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