Improvements in hematologic parameters and/or reductions in transfusion requirements have been associated with iron chelation therapy in transfusion-dependent patients with MDS; however, data has been limited to case reports/small studies (Jensen P et al. Br J Hematol 1996; Messa E et al. Acta Haematol 2008; Okabe H et al. Rinsho Ketsueki 2009; Oliva E et al. Transfusion 2010; n=1–11). The 1-year prospective EPIC study (Cappellini MD et al. Haematologica 2010) enrolled 341 transfusion-dependent MDS patients with iron overload. Patients were chelated with deferasirox leading to reductions in serum ferritin, an indicator of body iron burden (Gattermann N et al. Leuk Res 2010). During the EPIC study, transfusions were recorded and pretransfusion blood counts were assessed. Here we report a post-hoc analysis evaluating hematologic responses in a large cohort of MDS patients enrolled in EPIC using the IWG 2006 criteria (Cheson B et al. Blood 2006).
Full study design and inclusion/exclusion criteria for EPIC have previously been described (Cappellini MD et al. Haematologica 2010; Gattermann N et al. Leuk Res 2010). Patients with a life expectancy of <1 year were excluded. Deferasirox dose was initiated at 20 mg/kg/day with adjustments of 5–10 mg/kg/day up to 40 mg/kg/day. MDS patients with pretreatment hemoglobin (Hb) levels <11 g/dL or red blood cell (RBC) transfusion requirements >4 units every 8 weeks and not receiving erythropoietin were eligible for erythroid response analysis. Patients with pretreatment platelet counts of <100 × 109/L or platelet-transfusion dependence, and absolute neutrophil counts of <1.0 × 109/L and not receiving GCSF were selected to assess platelet and neutrophil responses, respectively. Erythroid response: Hb increase '1.5 g/dL or reduction of ≥4 RBC transfusions/8 weeks compared with previous 8 weeks before treatment start. Platelet response: increase ≥30 × 109/L for patients with >20 × 109/L platelets, increase from <20 × 109/L to >20 × 109/L and by at least 100%. Neutrophil response: ≥100% increase and an absolute increase >0.5 × 109/L. All responses to last ≥8 weeks (IWG 2006).
Of the 341 iron-overloaded MDS patients enrolled in the EPIC study, 279, 121 and 56 patients were included in erythroid, platelet and neutrophil response analyses, respectively. Mean deferasirox dose for erythroid, platelet and neutrophil analysis groups were 19.2, 19.4 and 18.4 mg/kg/day, respectively; no significant difference in dose was observed between responders and non-responders. During deferasirox treatment, erythroid responses were observed in 22.6% (63/279) of patients. Median time to response was 113.0 days. Of these erythroid responses, a transfusion reduction-only response with maintenance of Hb level was observed in 10.8% (n=30) of patients, Hb improvement-only response in 10% (n=28) of patients and both transfusion and Hb response observed in 1.8% (n=5) of patients. Platelet and neutrophil responses were observed in 14.0% (n=17) of patients after a median of 169.0 days and 19.6% (n=11) of patients after a median of 226 days, respectively.
This is the first large study to show that, alongside reducing iron overload, deferasirox may affect hematologic parameters in MDS patients. Overall erythroid response was 22.6% with deferasirox; although cross-trial comparisons should be interpreted with caution, a study in patients with low- and intermediate-1-risk MDS (IPSS) treated with valproic acid for a median of 4 months showed a major hematological response (IWG 2000 criteria) of 29% (Kuendgen A et al. Ann Hematol 2005). A limitation of the current analyses is the lack of a control arm comparing to best supportive care. The exact mechanism by which deferasirox can lead to improved hematological response in MDS remains to be determined. The effect may be attributed to reduction in iron overload, a specific pharmacological effect of the drug on hematopoiesis such as the ability to inhibit nuclear factor κB (Messa E et al. Haematologica 2010; Epub), or both. Other implicated mechanisms include the ability to sequester iron in a particular target or to affect the neoplastic clone or bone marrow microenvironment (Messa E et al. Acta Haematol 2008). Confirmation of these results and greater insights into mechanisms will require larger prospective trials specifically investigating hematologic responses in deferasirox-treated patients.
Gattermann:Novartis: Honoraria, Research Funding. Finelli:Celgene: Consultancy. Fenaux:CELGENE: Honoraria, Research Funding; JANSSEN CILAG: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; GSK: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; MERCK: Honoraria, Research Funding; CEPHALON: Honoraria, Research Funding. Guerci-Bresler:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Habr:Novartis: Employment. Marcellari:Novartis: Employment. Roubert:Novartis: Employment.
Asterisk with author names denotes non-ASH members.