Fast track — ArticlesEfficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study
Introduction
Myelodysplastic syndromes are malignant diseases of bone-marrow stem-cells, characterised by ineffective haemopoiesis leading to peripheral-blood cytopenias and, in many patients, progression to acute myeloid leukaemia.1, 2 Myelodysplastic syndromes are categorised morphologically with the French–American–British (FAB) and, more recently, WHO3, 4 classifications. Individual prognosis is determined using the international prognostic scoring system.5
Patients with myelodysplastic syndromes who had intermediate-2 or high-risk scores on the international prognosis scoring system (known as higher-risk myelodysplastic syndromes) have a median survival of 1·2 years or 0·4 years, respectively,5 and a high-risk for progression to acute myeloid leukaemia.5 Although increasing survival and suppression of leukaemic transformation are the primary goals of treatment,6 no treatment strategies other than allogeneic stem-cell transplantation offer meaningful potential to change the natural history of the disease.7, 8, 9, 10, 11, 12, 13, 14, 15 Results of a Cancer and Leukemia Group B (CALGB) trial comparing treatment with azacitidine, a DNA methyltransferase inhibitor, with best supportive care suggested improved overall survival with azacitidine, but the study was inconclusive because of its crossover design and absence of an active comparator.16
This large, prospective, randomised, phase III, clinical trial was done to assess the effect of treatment on overall survival with azacitidine. The control arm included the three most commonly used treatments in higher-risk myelodysplastic syndromes (best supportive care, low-dose cytarabine, or intensive chemotherapy).6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17
Section snippets
Patients
Patients were eligible for enrolment if they were aged 18 years or older, with higher-risk myelodysplastic syndromes (an international prognosis scoring system rating of intermediate-2 or high risk) and FAB-defined refractory anaemia with excess blasts, refractory anaemia with excess blasts in transformation, or chronic myelomonocytic leukaemia3 with at least 10% bone-marrow blasts and a white-blood-cell count lower than 13×109 cells per L. Patients needed an Eastern Cooperative Oncology Group
Results
Between Feb 13, 2004, and Aug 7, 2006, 358 patients (intention-to-treat population) at 79 sites from 15 countries were randomly assigned to receive either azacitidine (n=179) or conventional care regimens (n=179). Of those assigned to conventional care, 105 were to receive best supportive care, 49 low dose cytarabine, and 25 intensive chemotherapy (figure 2). Median age was 69 years (range 38–88 years) with 258 (72%) of 358 patients age 65 years or older. Baseline characteristics were well
Discussion
Treatment with azacitidine prolongs overall survival and lowers the risk of progression to acute myeloid leukaemia in patients with higher-risk myelodysplastic syndrome compared with treatment with conventional care regimens.
The previous CALGB trial16 included a heterogeneous population of patients, best-supportive care as the only comparator, and a crossover design, and 53% of patients who received best-supportive care subsequently received azacitidine. Our study aimed to include only patients
References (38)
Myelodysplastic syndromes: introduction
Semin Hematol
(2008)- et al.
Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts
Blood
(2001) - et al.
Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS
Blood
(2001) - et al.
Report of an international working group to standardize response criteria for myelodysplastic syndromes
Blood
(2000) - et al.
Allogeneic stem cell transplantation for myelodysplastic syndrome
Semin Hematol
(2008) Standard and low-dose chemotherapy for the treatment of myelodysplastic syndromes
Leuk Res
(1998)- et al.
Hypomethylation and apoptosis in 5-azacytidine-treated myeloid cells
Exp Hematol
(2008) - et al.
Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: consensus statements and report from a working conference
Leuk Res
(2007) - et al.
Proposals for the classification of the myelodysplastic syndromes
Br J Haematol
(1982) - et al.
World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997
J Clin Oncol
(1999)
International scoring system for evaluating prognosis in myelodysplastic syndromes
Blood
Myelodysplastic syndromes
Hematology Am Soc Hematol Educ Program
Low-dose ara-C in acute nonlymphocytic leukemia and myelodysplastic syndromes: a review of 20 years' experience
Semin Oncol
Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome
J Clin Oncol
S-HAM induction chemotherapy with or without GM-CSF in patients with high-risk myelodysplastic syndromes
Ann Hematol
A phase II study of intensive chemotherapy with fludarabine, cytarabine, and mitoxantrone in P glycoprotein-negative high-risk myelodysplastic syndromes
Hematol J
Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome
Cancer
Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes
Cancer
Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia
Ann Hematol
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