Iron Chelation Therapy With Deferasirox in the Management of Iron Overload in Primary Myelofibrosis

Abstract

Deferasirox (DSX) is the principal option currently available for iron-chelation-therapy (ICT), principally in the management of myelodysplastic syndromes (MDS), while in primary myelofibrosis (PMF) the expertise is limited. We analyzed our experience in 10 PMF with transfusion-dependent anemia, treated with DSX from September 2010 to December 2013. The median dose tolerated of DSX was 750 mg/day (10 mg/kg/day), with 3 transient interruption of treatment for drug-related adverse events (AEs) and 3 definitive discontinuation for grade 3/4 AEs. According to IWG 2006 criteria, erythroid responses with DSX were observed in 4/10 patients (40%), 2 of them (20%) obtaining transfusion independence. Absolute changes in median serum ferritin levels (Delta ferritin) were greater in hematologic responder (HR) compared with non-responder (NR) patients, already at 6 months of ICT respect to baseline. Our preliminary data open new insights regarding the benefit of ICT not only in MDS, but also in PMF with the possibility to obtain an erythroid response, overall in 40 % of patients. HR patients receiving DSX seem to have a better survival and a lower incidence of leukemic transformation (PMF-BP). Delta ferritin evaluation at 6 months could represent a significant predictor for a different survival and PMF-BP. However, the tolerability of the drug seems to be lower compared to MDS, both in terms of lower median tolerated dose and for higher frequency of discontinuation for AEs. The biological mechanism of action of DSX in chronic myeloproliferative setting through an independent NF-κB inhibition could be involved, but further investigations are required.

Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase

“…Conversely, there were scarce and erratic data concerning the use of DFX in patients with FP-MPN and transfusional iron overload prior to this report (14,15). Similar observations to those presented in our data set have been observed in some case reports (10,(14)(15)(16)(17) and more recently in a small singlecenter study (18). However, these studies are small and therefore have a limited potential impact on clinical practice.…”

Transfusion Independency and Histological Remission in a Patient with Advanced Primary Myelofibrosis Receiving Iron-Chelation Therapy with Deferasirox

“…Whether this improvement is caused by the reduction of oxidative stress and DNA damage due to ICT with deferasirox or another deferasirox-mediated effect is unclear [18,20]. The patient, however, reported no other drug intake, and we consider this to be further evidence of improved hematopoiesis with ICT leading to sustained transfusion independence as described in several case reports in patients with primary myelofibrosis [2,5,12,13,14,15,18]. Restoration of trilineage hematopoiesis with ICT with deferasirox was also described in several patients with aplastic anemia [12,23,24].…”

“…However, for patients with myeloproliferative syndromes, especially PMF, no clear benefit of chelation therapy has been shown [12]. Current treatment guidelines in PMF do not recommend ICT in patients with transfusion dependency and iron overload [1], although an increasing number of publications indicate possible positive effects on hematopoiesis and also possible transfusion independency during ICT with deferasirox [2,9,13,14,15]. …”

Deferasirox in the management of iron‐overload in patients with myelofibrosis: a multicentre study from the Rete Ematologica Lombarda (IRON‐M study)

“…Myelofibrosis (MF) is a clonal myeloproliferative neoplasm with a high prevalence of transfusion‐dependent (TD) anaemia, which may lead to iron overload (IOL) (Tefferi et al , ). At present, very few data are available on the role of iron chelation therapy (ICT) with deferasirox (DFX) in MF (Elli et al , ; Latagliata et al , ). In this study, we assessed the efficacy of DFX, in terms of iron chelation response (ICR), haematological improvement (HI), impact on survival and leukaemic evolution, on 45 consecutive MF patients fulfilling the inclusion criteria (Data S1).…”

“…Our preliminary data open new insights regarding the benefit of DFX in MF patients with TD anaemia. Several emerging lines of evidence indicated that DFX can improve haematopoiesis, however, these data come from single case descriptions (Di Tucci et al , ; Piro et al , ) or small retrospective studies (Elli et al , ; Latagliata et al , ). DFX, probably independently of its iron‐chelating property but through the interference on its reactive oxygen species (ROS) signalling activation, may influence key factors involved in self‐renewal/differentiation of haematopoietic stem cells (HSC; Zhang et al , ).…”