Title: Comment on “deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5‐year long‐term <scp>I</scp>talian multicenter randomized clinical trial”
Abstract: We read with interest the article by Calvaruso et al. reporting on the long-term efficacy and safety of deferiprone (DFP) as compared to deferoxamine (DFO) in patients with thalassemia intermedia (TI) 1. Although this clinical trial was registered prior to the availability of results from the THALASSA study 2, we would like to point out that the design of studies evaluating the efficacy of iron chelators in non-transfusion-dependent thalassemia (NTDT) should include a comparison with deferasirox (DFX), the current gold-standard for iron chelation in this group of thalassemias. The doses of DFP (75 mg/kg/day daily) and DFO (50 mg/kg/day for 5 days per week) used in this trial are based on the usual doses in transfusion-dependent thalassemia (TDT). These doses may not be ideal in NTDT, since DFX doses needed to achieve adequate chelation were lower in NTDT than in TDT 2. In addition, the transfusion requirements of both groups of TI patients, as reported in Table 1, are higher than the usual requirements of TDT patients. As the pathophysiology and clinical complications of NTDT differ from TDT, and as many patients with TI may be transfusion-dependent later in their life, the ideal study design should include transfusion requirements and make sure that patients are phenotypically similar from that standpoint 3. The authors tried to account for transfusion requirements through the generalized linear mixed effects model; however, in order to be able to extrapolate the results of the trial to the clinical setting, study design should categorize patients according to transfusion requirements before inclusion. Concerning the primary endpoint of the trial, randomized controlled trials assessing the efficacy of iron chelation therapy should have the change in liver iron concentration (LIC) by magnetic resonance imaging (MRI) as a primary endpoint. LIC by MRI is a safe and reliable means to assess iron overload in NTDT. LIC should also be part of the inclusion criteria, in addition to or instead of serum ferritin, which may underestimate iron burden in NTDT and fluctuate with inflammation 4. The manuscript reports a similar proportion of patients with serum ferritin ≤ 400 ng/mL in both the DFP and DFO groups. This cutoff is not supported by the available literature. The literature suggests that 300 ng/mL is an appropriate cutoff to discontinue iron chelation therapy as none of the patients have NTDT-related complications below that cutoff 4, 5. A final point to be taken into consideration when interpreting the results of the trial is the high 5-year attrition rate, which may limit the reliability of the results. Antoine N. Saliba, Ali T. Taher* Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon