Daily alternating deferasirox and deferiprone therapy successfully controls iron accumulation in untreatable transfusion‐dependent thalassemia patients
Authors: Valeria Maria Pinto, Manuela Balocco, Sabrina Quintino, Lorenzo Bacigalupo, Barbara Gianesin, Monica Rizzi, Roberto Malagò, Lucia De Franceschi, Gian Luca Forni
Journal: American Journal of Hematology (2018)

Chelation therapy to treat iron overload has beneficial impact on the prognosis of patients with transfusion-dependent thalassemia (TDT). Three different chelating agents are currently available: deferoxamine (DFO) which is given subcutaneously, and two oral agents, deferasirox (DFX) and deferiprone (DFP). Combination of two different iron chelators is common practice in patients with severe iron burden, or for those in which monotherapy is not adequately effective. Combination of DFO and DFP is well established as a treatment for severe iron overload in heart dysfunction.1 More recently, the combination of DFO and DFX has been shown to be safe and efficacious in treating iron overload in TDT patients nonresponder to standard treatment regimens.2 Successful combination therapy with DFX and DFP has been reported previously,3 as being effective in reducing iron overload and superior in improving cardiac T2*, compliance and patient satisfaction compared with the deferoxamine/deferiprone combination.4 The use of combination therapy to address intolerance to monotherapy is not common practice, due to the expectations that patients will continue to exhibit similar or worse lack of tolerance. Some TDT patients do not tolerate either mono or combined therapy, resulting in worsening iron overload and in poor prognosis in term of life expectancy. The main described side effects are persistent proteinuria (deferasirox) or gastro-intestinal symptoms (deferasirox or deferiprone). These TDT patients are at high risk to develop life-threatening complications related to iron overload. We previously reported safe and effective treatment of two TDT patients treated with alternating regimens of DFP and DFX over 1 year.5 We have subsequently extended this daily alternating approach to other six previously untreatable TDT subjects. Patients were defined as intolerant due to the presence of the following side effects during monotherapies or classical combined therapy: significant proteinuria persistent after re-challenge; arthralgia with functional limitation; neutropenia resolved after DFP discontinuation; gastrointestinal intolerance; systemic reactions. A total of eight TDT patients (4 males and 4 females) have been placed so far on DFP (starting dose 75 mg/kg/day, three doses/day) combined with DFX (starting dose 25 mg/kg/day) administrated as alternating chelation therapy. Patients' mean age was 28 years (ranging from 17 to 36). Figure 1A reports the demographic, clinical conditions of TDT patients on daily alternating chelation therapy and the doses of chelators. The median adherence, calculated as the percentage of drug taken in respect to the one issued, was 90%. Median iron intake from blood transfusions was 9.9 mg/year. Mean follow-up was 52 months (ranging from 12 to 104). The mean value of serum ferritin was 1632 at baseline and 1045 ng/mL at follow-up (P = .2), Figure 1C reports the evaluations of serum ferritin during the follow-up. Figure 1B,C reports the performed MRI-T2* evaluations (1.5 T GE HDxt scanner) of liver, heart and pancreas during the follow-up for seven patients; one patient was excluded from analysis due to lack of MRI follow-up. The mean value of cardiac MRI-T2* was 27 and 37 millisecond (ms) at baseline and follow-up, respectively (P = .21). Three patients showed cardiac iron overload at baseline (1 pt with T2* < 10 ms, 2 pts with T2* > 10 and <20 ms) that disappeared at follow-up (Figure 1B). Mean values of liver MRI-T2* were 5.8 and 12.8 ms at baseline and follow-up, respectively (P = 0.19). Five patients showed liver iron overload at baseline (1 moderate-severe, 4 mild) which is almost disappeared at the follow-up (Figure 1B). Mean values of the MRI-T2* of pancreas were 12.6 and 17 ms at baseline and follow-up, respectively (P = .47). None of the patients' developed iron overload in liver and heart during alternate-combined iron chelation therapy. None of the patients experienced any of the safety problems previously experienced with daily monotherapy with either DFO, DFX, or DFP alone or combined. The alternating-combined iron chelation therapy was designed to improve patient tolerance and achieve the desired therapeutic efficacy by allowing continued exposure to iron chelator and efficient iron clearance coverage. In our case series, daily alternating regimen of DFP and DFX was effective in removing iron from heart and liver as well as in maintaining the optimal MRI-T2* values in heart, liver and even pancreas during the follow-up period6 (8 years). None of the TDT patients experienced moderate to severe adverse events. This new schedule for oral iron chelators administration exploits the peculiarity of pharmacokinetic and pharmacodynamics of both DFP and DFX, synergizing and reducing their possible side effects. Our data generate the rationale to design larger studies to investigate this combined schedule as a potential treatment option for a broader spectrum of TDT patients.