Has introduction of azacytidine in everyday clinical practice improved survival in late-stage Myelodysplastic syndrome? A single center experience
Introduction
The introduction of azacytidine has radically transformed the therapeutic approach of patients with late-stage Myelodysplastic syndrome (MDS) patients and has led to a significant prolongation of overall survival, as repeatedly demonstrated in clinical trials [1]. However, the so-called “real-life” experience often differs significantly from the results of randomized trials for several reasons. Well-controlled, explanatory trials measure the efficacy of a given intervention in limited populations by using strict selection criteria and operating in a controlled-and somehow artificial medical environment. As a result, the applicability and generalization of the results from such trials in an extended patient population and the everyday clinical setting is questionable [2].
In particular, the actual effectiveness of azacytidine in real life settings is a debatable issue. In the landmark AZA-001 trial the median OS of azacytidine treated patients reached 24 months [3]. By contrast, most real-world data published by institutional series and national registries show a median overall survival ranging from less than a year to up to 19 months depending on the cohort characteristics [4], [5], [6]. In keeping with these data, extended follow up in 282 patients of the GFM compassionate program, the largest series so far, revealed a median OS of only 13.5 months [7]. Though these results cannot be directly compared with prospective data, they underscore the grave prognosis of individuals with late-stage MDS in everyday practice even after the introduction of azacytidine.
Apart from the above, only about half of the patients achieve a response, while azacytidine evokes considerable toxicity, predominantly in old and frail individuals, leading to a discontinuation rate of 5% even in clinical trials [3]. Although not being officially stipulated in the recommendations of most drug regulatory agencies, it is becoming increasingly evident that comorbidities may seriously compromise the outcome of patients treated with azacitidine and should rather be placed first in the treatment algorithm to determine patient eligibility for azacytidine [8], [9], [10], [11]. Thus, it remains obscure which patients benefit most from azacytidine rendering the latter a typical paradigm of the need for distinction between the efficacy of an intervention in clinical trials and the effectiveness in the real-world daily practice.
We retrospectively compared the outcome of two well-balanced cohorts of late-stage MDS patients managed in our institution in a non clinical trial setting. The first cohort consisted of patients treated with azacytidine and the second of patients treated with other therapies.
Section snippets
Patients
Eighty-seven MDS patients managed in our institution from November 2000 to May 2013 were included in the study after Institutional Review Board approval. All patients had late-stage MDS as defined based on either International Prognostic Scoring System (IPSS) or WHO Classification-Based Prognostic Scoring System (WPSS), an ECOG performance status of 0–2 and were managed in a non-clinical trial setting.
Treatment
In the first cohort azacytidine was initiated at 75 mg/m2 SC for 7 days on 28-day cycles. Dose
Study cohorts
Patients’ characteristics are presented analytically in Table 1. Two groups were defined based on whether patients were treated or not with azacytidine. The first cohort included forty-six consecutive patients treated with azacytidine (hereafter named AZA cohort). Median follow up and number of completed cycles were 38.5 months and 6 (1–33), respectively, whereas 57% (26/46) of the patients had received ≥6 cycles. Time from diagnosis to first line treatment with azacytidine ranged from 0 to
Discussion
Nine years after its formal approval by U.S. Food and Drug Administration (FDA) azacytidine remains the mainstay in therapy of late-stage MDS. Nevertheless, setting aside the cost of treatment, there are still many unresolved issues relating to azacytidine therapy. Due to the complex epigenetic landscape of MDS, the mechanism of action of azacitidine remains to be established and both the genetic and cellular level where the drug exerts its effects are still under investigation. As a
Funding
No funding to declare.
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgements
Contributions: IK was the principal investigator and takes primary responsibility for the paper. MP, ED, ES, DM and CT recruited the patients. IK and VP performed the statistical analysis. ED and MP collected patient data and IK coordinated the research. MP, ED, and IK wrote the paper. MP and ED contributed equally to this manuscript.
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