Deferasirox Treatment Interruption in a Transfusion-Requiring Myelodysplastic Patient Led to Loss of Erythroid Response

Abstract

Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy in both adult and pediatric patients with transfusional iron overload [1]. Clinical trials have demonstrated the efficacy of deferasirox for up to 2 years of treatment in patients with myelodysplastic syndromes (MDS) [2,3]. The drug is able to reduce key indicators of total body iron levels (serum ferritin, liver iron concentration and toxic labile plasma iron) and has also demonstrated a good tolerability profile, which renders it a suitable therapeutic option for patients with chronic conditions requiring ongoing iron chelation therapy. Current guidelines indicate to suspend deferasirox treatment in MDS patients once serum ferritin is below 1,000 ng/ml [4]. Some interesting observations have been reported on the effect of deferasirox on erythroid improvement, and it is still a matter of debate when the drug has to be suspended [5,6,7]. Here, we describe a MDS patient with a transfusional requirement, who under deferasirox treatment showed an erythroid improvement; however, after interruption of the drug lost the response, but regained it when the drug was resumed.A 50-year-old man was referred to our institution in November 2006 for fever, anemia (9 g/dl), thrombocytopenia (50 × 109/liter) and abdominal pain. Bone marrow morphological analysis showed trilinear dysplasia, with 4% of blast cells. Cytogenetic conventional analysis showed a normal karyotype and a FISH panel did not detect the most common aberrations related to MDS [5q–, 7q–, +8 and del(20q)]. A diagnosis of refractory cytopenia with multilineage dysplasia (RCMD) according to WHO classification, with low-risk IPSS, was made. At that time, a CT scan revealed the presence of multiple calculi in the gallbladder. Treatment with erythropoietin was started in March 2007, but despite this treatment, the patient started to present a transfusional requirement and erythropoietin was definitively suspended after 3 months. At that time, the serum ferritin level was 650 ng/ml. The patient received only supportive therapy with a median transfusional requirement of 3 red blood cell units/month until May 2008, when serum ferritin increased to 4,640 ng/ml. Deferasirox treatment at the dose of 20 mg/kg was started in June 2008 and the patient experienced only a moderate skin rash during the first 2 weeks of treatment, which spontaneously resolved with no requirement of drug suspension or alternative treatments. We did observe a progressive decrease of serum ferritin, which reached 1,002 ng/ml after 6 months of treatment. Concomitantly, the transfusional requirement decreased and the Hb level increased up to 10 g/dl after 3 months of treatment. Transfusions were no longer required after 6 months of treatment. When the patient reached a serum ferritin level <1,000 ng/ml, we reduced the deferasirox dose to 10 mg/kg/day, with the erythroid response being maintained. After 15 months of treatment, the patient developed an acute infection of the gallbladder, with an increase in transaminases, requiring systemic antibiotic therapy and surgery. During this period and for the four subsequent months, the patient suspended deferasirox. The hemoglobin level lowered to 6 g/dl, with transfusion being required and the serum ferritin level raising to 2,060 ng/ml. Deferasirox was then resumed at the dose of 20 mg/kg/day and, after 2 months, serum ferritin again lowered to 1,000 ng/ml and the Hb level increased to >10 g/dl without transfusions. At present, the patient remains transfusion free with a stable Hb level >10 g/dl and serum ferritin <1.000 ng/ml on deferasirox at the dose of 10 mg/kg/day (fig. 1).Iron overload is a well-recognized prognostic factor for survival in MDS patients [8]. A small number of observations have been reported on the beneficial effect of iron chelation therapy on erythropoiesis [5,6,7,9], but the mechanisms of this effect are not completely clear. Jensen et al. [9] observed erythropoietic improvement in 7 of 11 MDS patients treated with deferoxamine, with good compliance, of which four of these patients lost the transfusional requirement. Until now, four MDS cases and two primary myelofibrosis cases were reported in the literature with erythroid response due to deferasirox treatment [5,6,7]; the reduction or suspension of transfusion need was not in all instances concomitant to serum ferritin reduction. It has been postulated that deferasirox could act not only through a rapid reduction of non-transferrin bound iron, whose toxic effects are well known, but also via a possible direct effect on a neoplastic clone or on the bone marrow microenvironment [7]. Messa et al. [10 ]found that deferasirox is also an active NF-ĸB inhibitor in MDS transfusion-requiring patients, as compared to deferoxamine and deferiprone, independently from the chelation efficacy. Through NF-ĸB inhibition, the drug may reduce the transcription of anti-apoptotic factor, cytokines/enzymes or adhesion molecules that may have an effect on erythroid inefficacy.Rachmilewitz et al. [11 ]reported on the improvement of oxidative stress parameters in MDS iron-overloaded patients treated with deferasirox, such as red blood cells and platelets, intra-labile iron pool and extracellular labile plasma iron, which is well known as being responsible for the development of reactive oxygen species which correlate with the severity of inefficient erythropoiesis. In the absence of biological data to prove the reduction of labile plasma iron in our case, hypothetical clinical erythroid improvement by deferasirox is suggested. In fact, the suspension of the drug for a 5-month period was accompanied by the loss of a previously reached erythroid response and the increase of serum ferritin. Because of the persistent effect during deferasirox therapy and loss of response at its withdrawal, we can hypothesize that this was responsible for erythroid improvement. It is also possible that the concomitant gallbladder infection, which was responsible for deferasirox suspension, might have contributed to hemoglobin reduction. In light of the cases reported, it remains to be clarified which is the best time to start and to suspend the drug as well as the exact schedule in MDS patients who present hematological improvement.