Prospective Evaluation of the Effect of Deferasirox on Hematologic Response in Transfusion-Dependent Patients with Low-Risk MDS and Iron Overload: The Rythmex Study

Background:Long-term blood transfusions remain the mainstay of supportive care in patients with low-risk myelodysplastic syndromes (MDS). Blood transfusions can result in iron overload, which can lead to impaired organ function, significant morbidity and mortality. Although debate exists around its use in patients with MDS, iron chelation therapy is recommended in patients with low-risk MDS to prevent iron-overload toxicities and to improve survival. In addition, hematologic improvement has been reported during chelation therapy (Jensen PD 1996, Gattermann N 2012). Here we report results from a prospective, observational study that evaluated a hematologic response to deferasirox in a large population of regularly transfused patients with low- or intermediate-1-risk MDS.

Methods:inclusion criteria: Transfusion-dependent (at least 4 packed red blood cells (PRBC)/8 weeks) adult patients with IPSS low- or intermediate-1-risk MDS who had initiated or had been receiving chelation therapy for less than 3 months. Primary endpoint was reduction in transfusion requirements at 3 month, (i.e. the number of PRBC received during the 8 weeks before deferasirox initiation compared with the 8 weeks before month 3). Secondary endpoints included: hematologic improvement (HI; IWG 2006 criteria for erythroid [HI-E], platelet [HI-P] and neutrophil [HI-N]) at 3, 6 and 12 months, duration of response, serum ferritin levels and safety.

Results: 70 patients were included, 57 were evaluable. Most exclusions (19%) were related to a low level of transfusion before inclusion. Median age was 78.3 years. The cytologic subtypes were: sideroblastic anemia, 31.6%; refractory anemia, 19.3%; refractory anemia with excess blasts-1, 17.5%; refractory cytopenia with multilineage dysplasia, 17.5%; 5q syndrome, 10.5%; unclassified SMD, 3.6%. Median time since diagnosis was 2.79 years (33 months). Before inclusion, 87% patients had received a treatment for MDS (erythropoiesis-stimulating agents, 72%; lenalidomide, 17%;G-CSF, 16%; azacitidine, 7%; thalidomide: 2%). Patients received a median of 5.8 ± 2.8 PRBC during the 8 weeks before inclusion. The mean number of PRBC received per month during the 6 months before inclusion was 2.11. The median serum ferritin level at inclusion was 1 543 ng/ml.The mean number of PRBC received in the whole population post inclusion (eight weeks before month 3) was 5.9, which was not significantly different from the number of PRBC given during the 8 weeks before inclusion (5.8). However at 3 months, 4 patients had a positive effect on transfusion requirement. At 6 and 12 months, positive effect occurred in 3 and 4 additional patients, respectively. 10 patients achieved HI-E during the study and according to Kaplan-meier analysis, the probability of HI-E was 12.7% at 6 months and 24.2% at 1 year. During the study, 17 patients (32%) achieved an erythroid response, i.e positive effect on transfusion requirement and/or HI-E; 19% had an erythroid response at month 12. Median duration of erythroid response was 123 days. 3.5%, 10%, 21% of patients had received a concomitant treatment with deferasirox at 3, 6, and 12 months, respectively. However,deferasirox was the sole specific treatment received in 12/17 patients with erythroid response. 27 patients experienced adverse events (AEs) related to deferasirox, among them 4 patients with grade > 2 . 32 patients underwent deferasirox dosing modifications, and 20 patients had discontinued treatment by 3 months ( median duration of treatment 11.3 months). In patients receiving deferasirox for more than 9 months, the median serum ferritin level at 12 months was 1 438 ng/ml . In contrast, the median serum ferritin level at 12 months was 2247 ng/ml in the whole group. There were no predictive factors of erythroid response (cytologic classification, time since diagnosis, level of ferritin at inclusion, the number of PRBC transfused before inclusion), but the number of responders was low.

Conclusions: After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused low risk MDS patients. However, deferasirox could induce 19% of specific erythroid response at 12 months. These results suggest that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a small subset of patients with MDS and iron overload.