November-December 2019, Volume 16, Issue 6
Does Your MDS Treatment Have Mettle? The Utility of Iron Chelation Is Always a Point of Discussion in MDS
Published on: September 23, 2019
Hoeks M, Yu G, Langemeijer S, et al. Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry. Haematologica. 2019; doi: 10.3324/haematol.2018.212332. [Epub ahead of print].
Despite numerous advances in the care of patients with myelodysplastic syndrome (MDS) in recent years, chronic red blood cell (RBC) transfusions remain the mainstay of therapy for all patients, especially anemic patients with lower-risk disease.1 RBC transfusion provides prompt, symptomatic relief for lower hemoglobin and improves health-related quality of life. Unfortunately, transfusion dependence is also associated with less favorable prognosis in MDS.2 Chronic transfusion therapy is associated with the risk of iron overload, which has the potential to cause substantial organ toxicity. No controlled prospective studies have demonstrated a benefit from iron chelation in MDS, but several retrospective or observational studies have suggested improved survival with chelation.3 The long-awaited TELESTO trial, a randomized controlled trial of deferasirox compared to placebo was published as an abstract (#234) at the 2018 ASH Annual Meeting; it showed a risk reduction in the treatment arm, but no overall survival (OS) benefit with chelation. Thus, there remains no consensus regarding the optimal iron chelation regimen in MDS, making this a regular manuscript topic in the literature as we try to optimize outcomes in our patients.
In this study, Dr. Marlijn Hoeks and colleagues used the robust European Union MDS (EUMDS) registry to investigate the role of iron chelation therapy in patients with lower-risk MDS. For this analysis, prospectively collected, observational data from recently diagnosed lower-risk4 patients were included. The investigators analyzed all patients, chelated or nonchelated, who were eligible for chelation based on at least one of the following criteria: at least 15 cumulative RBC units, transfusion intensity of a one or more units per month during a six-month period, or serum ferritin level greater than 1,000 μg/L. The registry was queried July 2017 for patients diagnosed between December 2007 and April 2017. This cohort ultimately included 689 eligible patients — 199 chelated and 490 nonchelated. There were many significant differences between chelated and nonchelated patients including older age and increased deaths for nonchelated patients but with longer follow-up for chelated patients. Nonchelated patients had more cumulative units transfused than chelated subjects (4 vs. 2 units) at baseline, but the chelated patients had higher median ferritin levels. The median time on chelation was 13 months (range, 3-41 months). Unfortunately, recording of reasons for cessation of chelators was not possible in this cohort.
A Cox proportional hazards model showed a hazard ratio (HR) for OS in chelated patients (adjusted for multiple appropriate covariates) of 0.50 (95% CI, 0.34-0.74). Additionally, a propensity score–matched model demonstrated a further significantly improved OS for chelated patients, with an HR of 0.42 (95% CI, 0.27-0.63) compared to nonchelated patients. Of the 199 chelated patients, 150 received deferasirox as the initial chelating agent (of the 3 available in Europe at the time). Interestingly, patients who were initially treated with deferoxamine had inferior OS compared with deferasirox-treated patients. Compelling analyses were run to investigate improvements in hematopoiesis and even transfusion independence. More than 80 percent of the 77 chelated patients who responded were also on an erythropoiesis-stimulating agent or lenalidomide. Further analysis showed that 39 percent of chelated patients reached an erythroid response. The authors concluded that these results suggest that iron chelation may improve OS and hematopoiesis in transfusion-dependent MDS patients.
This report from a very experienced group of MDS investigators uses registry data to advance our knowledge about iron chelation therapy for lower-risk patients with MDS. Their conclusions are consistent with previous reports3,5,6; several features of the cohort and analyses make it highly applicable to this patient population in whom chelation must be considered at the bedside. The cohort represents a very “real-world” lower-risk, transfusion-dependent group of patients in their seventh and eighth decades with all the anticipated comorbidities that could be excluded from a trial population. Given its conduct in Europe and not the United States, these lower-risk patients were not routinely treated with hypomethylating agents, and thus their effect on response or myelosuppression did not contribute to the results. Additionally, the propensity score–matched analysis can incorporate more confounding factors into their model. The authors also make the salient point that there will always be limitations to performing a randomized controlled trial for the use of chelators in MDS due to staunchly held beliefs by both providers and patients on the topic. The noted benefit in deferasirox is interesting, but unfortunately, there was no further information provided on the choice of chelation agent.
In summary, chelation therapy in MDS is expensive, cumbersome, and may be associated with significant adverse effects such as gastrointestinal symptoms and nephrotoxicity, among others, and thus its potential benefits require more studies, even prospective and observational ones such as this, to guide our treatment decisions.
Fenaux P, Adès L. How we treat lower-risk myelodysplastic syndromes. Blood. 2013;121:4280-4286.
Waszczuk-Gaida A, Madry K, Machowicz R, et al. Red blood cell transfusion dependency and hyperferritinemia are associated with impaired survival in patients diagnosed with myelodysplastic syndromes: results from the First Polish MDS-PALG Registry. Adv Clin Exp Med. 2016;25:633-641.
Zeidan AM, Giri S, DeVeaux M, et al. Systematic review and meta-analysis of the effect of iron chelation therapy on overall survival and disease progression in patients with lower-risk myelodysplastic syndromes. Ann Hematol. 2019;98:339-350.
Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2072088.
Rose C, Brechignac S, Vassilief D, et al. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myélodysplasies). Leuk Res. 2010;34:864-870.
Delforge M, Selleslag D, Beguin Y, et al. Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes. Leuk Res. 2014;38:557-563.
Conflict of Interests
Dr. DeZern indicated no relevant conflicts of interest.
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