Outcome of azacitidine treatment in patients with therapy-related myeloid neoplasms with assessment of prognostic risk stratification models
Introduction
The 2008 World Health Organization (WHO)-defined therapy-related myeloid neoplasms (t-MN) span a continuum of clinically similar hematologic malignancies, including therapy-related myelodysplastic syndrome (t-MDS), therapy-related acute myelogenous leukemia (t-AML), and t-MDS/myeloproliferative neoplasms [1]. These diseases arise as complications from prior radiation and/or chemotherapy for prior neoplastic or non-neoplastic disorders, often leading to characteristic cytogenetic abnormalities. Prognosis is generally poor when compared to their de novo counterparts due to several factors, including poor risk karyotype, older age, poor performance status, number of comorbidities, and resistance to conventional cytotoxic chemotherapies. One series reported a median overall survival of 8 months after diagnosis and less than 10% five-year survival rate [2].
t-MDS accounts for up to 20% of patients with MDS, and patients may present at any age [3], [4], [5], [6]. The clinical presentation varies by agent, with a latency of 5–7 years and frequent chromosome 5 and 7 abnormalities with prior exposure to alkylating agents and a latency of months to years with 11q23 abnormalities more common after topoisomerase II inhibitors.
Azacitidine, a DNA methyltransferase inhibitor, is currently the preferred agent for patients with MDS, particularly those with higher-risk International Prognostic Scoring System (IPSS) score owing to two large, randomized clinical trials [7], [8]. The first trial, conducted by the Cancer and Leukemia Group B, compared azacitidine to best supportive care, reporting significantly higher overall response rates and a trend toward overall survival benefit, leading to its approval by the U.S. Food and Drug Administration. Six percent of patients received prior radiotherapy and 14% received prior chemotherapy; however, results for patients with t-MDS were not reported separately [8]. The landmark AZA-001 study demonstrated increased time to leukemic transformation and an overall survival benefit with azacitidine compared to three different conventional care regimens in patients with higher-risk MDS, oligoblastic AML, and CMML, but patients with t-MN were excluded from the trial [7].
A recently presented model for t-MDS by Quintás-Cardama and colleagues identified and validated seven prognostic factors that predict survival: age at least 65 years, ECOG performance status greater than 1, monosomy 7 or complex cytogenetics, WHO MDS subtype of refractory anemia with ringed sideroblasts (RARS) or refractory anemia with excess blasts (RAEB)-1 or -2, hemoglobin less than 11 g/dL, platelets less than 50,000 (μL)−1, and transfusion dependency [9]. Patients in the good (0–2 factors), intermediate (3–4 factors), and poor (5–7 factors) risk categories had median survival of 34, 12, and 5 months, respectively. However, only a fraction of patients were treated with hypomethylating agent-based therapy, and the number of patients treated specifically with azacitidine was not reported [9].
Outcomes using azacitidine in patients with t-MN have not been well-documented in the literature. One study of a compassionate-use azacitidine program reported a 43% overall response rate and a median overall survival of 9.2 months in a subset of patients with t-MDS [10], and one recent retrospective study of patients with t-MN documented a 42% overall response rate and a 21-month median survival [11]. Otherwise, the data are limited to small retrospective series with limited analyses [12], [13] and case reports [14], [15]. In this retrospective study, we investigated the outcomes of t-MN patients treated with azacitidine at the Moffitt Cancer Center.
Section snippets
Methods
This was a retrospective review of t-MN patients treated at the Moffitt Cancer Center with azacitidine. Patients were identified through the Moffitt MDS database, individual charts were reviewed, and clinical data were extracted. Patients were required to have a diagnosis of MDS, chronic myelomonocytic leukemia, or AML with less than 30% bone marrow blasts (refractory anemia with excess blasts in transformation by French–American–British criteria) confirmed by bone marrow biopsy. Patients were
Patient characteristics
Between July 2004 and December 2011, 84 t-MN patients were identified who were treated at the Moffitt Cancer Center with azacitidine. Baseline characteristics of these patients are shown in Table 1. The median age of the cohort was 65 years, with a slight male predominance (56%). The vast majority (88%) was Caucasian, and 72% had an ECOG performance status of 1 or better. Fifty-two percent had a previous hematologic malignancy, 43% had a history of a solid tumor, and 5% had a history of both
Discussion
Although the efficacy of azacitidine has been well-established in patients with de novo MDS and oligoblastic AML, data in the literature regarding its efficacy specifically in t-MN are limited. To our knowledge, this study is the largest reported experience with azacitidine in this patient population. We found an overall response rate of 43% and a median survival of 14.5 months, the latter of which is higher than previously reported for therapy-related myeloid neoplasms prior to the
Conflicts of interest
RSK was on the Speaker's Bureau and had research funding from Celgene. JEL was a Consultant (Celgene) and received grant funding to institution for efforts from Celgene. AFL was a Consultant and received research funding from Celgene.
Contributions. RSK was the principal investigator and takes primary responsibility for the paper. VHD, EA, and NHA performed the analysis for this study. VHD, JEL, EA, NHA, JP, TF, PKE, LZ, AFL, and RSK participated in the research. RSK coordinated the research.
Acknowledgments
We thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance. This study did not receive any external funding.
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