Effects of azacitidine compared with conventional care regimens in elderly (≥75 years) patients with higher-risk myelodysplastic syndromes

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Abstract

This analysis compared azacitidine (AZA) to conventional care regimens (CCR) and their associated overall survival (OS) and tolerability in the subset of 87 elderly (≥75 years) patients with higher-risk MDS (FAB: RAEB, RAEB-t, CMML and IPSS: Int-2 or High) from the AZA-001 trial. Patients were randomized to AZA (75 mg/m2/day subcutaneously × 7 days every 28 days) (n = 38) or CCR (n = 49) and had median ages of 78 and 77 years, respectively. AZA significantly improved OS vs CCR (HR: 0.48 [95%CI: 0.26, 0.89]; p = 0.0193) and 2-year OS rates were 55% vs 15% (p < 0.001), respectively. AZA was generally well tolerated compared with CCR, which was primarily best supportive care (67%). Grade 3–4 anemia, neutropenia, and thrombocytopenia with AZA vs CCR were 13% vs 4%, 61% vs 17%, and 50% vs 30%, respectively. Given this efficacy and tolerability, AZA should be considered the treatment of choice in patients aged ≥75 years with good performance status and higher-risk MDS.

Introduction

Myelodysplastic syndromes (MDS) are common and prevalent hematologic disorders. The estimated annual incidence of MDS in North American and European populations is approximately 3.3–4.5 cases per 100,000 [1]. However, the incidence increases with age, and over the age of 70, the annual incidence of MDS is as high as 15–50 cases per 100,000/year [2]. MDS is associated with impaired quality-of-life, and severe cytopenias can lead to potentially fatal bleeding or infections [3]. Patients with more advanced MDS subtypes are at high risk of progression to acute myeloid leukemia (AML), and unless patients are able to receive allogeneic stem cell transplant, or have competing comorbidities, MDS is their most likely cause of death [4], [5], [6].

Treatment options for elderly patients with MDS are very limited, and many factors increase the likelihood that they will not receive any active MDS treatment. These include the presence of age-related comorbidities and functional impairment, poor tolerability and/or ineffectiveness of available cytotoxic therapies, and patient preferences combined with physician reluctance. Results of a large cross-sectional survey of physicians treating older patients with MDS (most patients were >70 years of age) indicated that 27% of newly diagnosed patients with higher-risk disease and 24–49% of patients with established higher-risk MDS received supportive care only [7]. Moreover, unlike experience in younger patients with MDS, when elderly patients do receive active treatment, there is little evidence for any improvement in survival [8].

The most commonly applied treatments for patients with MDS are hypomethylating agents, intensive chemotherapy, low-intensity cytotoxic regimens, or palliative care, and it is difficult to determine which treatment approach may benefit elderly patients most [3]. There is a paucity of clinical trials in elderly patients and a general lack of data regarding outcomes of cytotoxic therapy for older patients with higher-risk MDS [9]. Even the definition of “elderly” varies widely, with patients over age 60, 65, or 70 years of age considered “elderly” in published studies [10], [11], [12]. In the absence of clear guiding data, clinical decisions may be extrapolated from data in older patients with AML [12], as it has been suggested that in older patients, higher-risk MDS and AML are two points on the biological continuum of the same disease [2]. Many patients who meet the FAB classification for RAEB-t also meet the WHO classification for AML (≥20% marrow blasts) [13]. Moreover, higher-risk MDS and AML have comparable prognoses and treatment is often similar [3].

The international multicenter randomized phase III AZA-001 trial established that the demethylating agent, azacitidine, significantly improves overall survival (OS) in patients with higher-risk MDS, including patients whose disease meets the definition of WHO-AML (20–30% marrow blasts) [14]. Patients in the AZA-001 trial tended to be older, with a median age of 69 years (range 38–88). Approximately one quarter of all randomized patients were ≥75 years or age. To further explore toxicity and outcomes in elderly patients with higher-risk MDS or AML with 20–30% marrow blasts, these analyses were performed for the prospectively defined subgroup of patients in AZA-001 who were ≥75 years of age at entry.

Section snippets

Patients

Patients aged ≥18 years with higher-risk MDS (FAB-defined refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-t], or chronic myelomonocytic leukemia [CMML] with more than 10% marrow blasts and a white blood count <13 × 109/L, and an IPSS risk of Intermediate-2 or High [5]) were eligible. Patients must have had an ECOG performance status of 0–2 and an estimated life expectancy of ≥3 months. Patients with therapy-related MDS, prior azacitidine treatment, or who were planned to

Patient disposition

Eighty-seven patients in the AZA-001 study were ≥75 years of age at entry and comprise the intent-to-treat (ITT) population for this analysis. The median age of this subgroup was 78 years (range 75–88) and mean time (±SD) from diagnosis was 1.0 ± 1.7 years. Thirty-eight patients were randomized to azacitidine and 49 to CCR, with the difference in numbers due to the fact that initial randomization was not stratified by age. Two patients (1 randomized to BSC and 1 to intensive chemotherapy) did not

Discussion

Azacitidine significantly improved OS compared with the most commonly used conventional care regimens in these elderly (≥75 years) patients with higher-risk MDS, approximately one-third of whom also fulfilled criteria for WHO-defined AML (20–30% blasts). At a median follow-up of 17.7 months, the median OS in the azacitidine group was not reached, and the proportion of patients who received azacitidine and were alive at 2 years (55%) was more than threefold that of the CCR cohort (15%). This is

Conflict of interest statement

John F. Seymour consulted with Celgene, received honoraria and research funding (participation as clinical trial investigator) from Celgene, and participated in advisory board meetings for Celgene. Pierre Fenaux received research funding (participation as clinical trial investigator) from Celgene, Amgen and Roche; received honoraria from Roche, Celgene, Amgen, Cephalon, Merck Sharp and Dohme, GlaxoSmithKline, and Johnson and Johnson. Lewis R. Silverman has received honoraria from Celgene.

Reviewers

Jamile M. Shammo, M.D., Rush University Medical Center, Chicago, IL 60612, United States.

Bart L. Scott, M.D., University of Washington Medical Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, United States.

Acknowledgments

The study was funded by Celgene Corporation. The paper was written by John F. Seymour and other co-authors who had access to all data and controlled all content. Sheila Truten, B.S. and Neil Malone, M.A., provided editorial assistance and Indrasiri Fernando, Ph.D., provided statistical support during manuscript development. ST is employed by MC2, Wynnewood, PA, and was compensated by Celgene Corporation; NM and IF are employed by Celgene Corporation, Summit, NJ.

Professor John Seymour is Head of the Department of Haematology, Peter MacCallum Cancer Centre. Dr. Seymour received his M.B., B.S. degrees from the University of Melbourne in 1987, pursued training in Haematology including a fellowship at the M.D. Anderson Cancer Center in Houston.

Dr. Seymour successfully completed his Ph.D. studies at the Ludwig Institute for Cancer Research. He is a member of several national and international scientific committees including, Cancer Australia Advisory

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  • Cited by (0)

    Professor John Seymour is Head of the Department of Haematology, Peter MacCallum Cancer Centre. Dr. Seymour received his M.B., B.S. degrees from the University of Melbourne in 1987, pursued training in Haematology including a fellowship at the M.D. Anderson Cancer Center in Houston.

    Dr. Seymour successfully completed his Ph.D. studies at the Ludwig Institute for Cancer Research. He is a member of several national and international scientific committees including, Cancer Australia Advisory Groups, the Scientific Advisory Committee for the International Workshop on NHL, International Conference on Malignant Lymphoma, and the International Workshop on Myelodysplasia and Board of Directors of the International Extranodal Lymphoma Study Group. He is the current Chairman of the major national clinical trials co-operative group in hematologic malignancies in Australia, the Australasian Leukaemia & Lymphoma Group, and previous board member of the Leukaemia Foundation of Victoria (2000–2005).

    He is frequent invited speaker nationally and internationally, member of numerous professional societies, and the Editor-in-Chief of Leukemia and Lymphoma and on the editorial boards of the Journal of Clinical Oncology, British Journal of Haematology, and Leukemia Research. He has also authored 13 book chapters, more than 250 peer-reviewed publications, and approximately 350 conference abstracts. Actively involved in research, Dr. Seymour has received more than $2.5 million dollars of competitive grant funding in the last 5 years and is national study chairman for 13 ongoing national or international clinical trials.

    This study is registered with ClinicalTrials.gov, number NCT00071799.

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