Safety of Combined Chelation Therapy with Deferasirox and Deferoxamine in Transfusion-Dependent Thalassemia.
Authors: Lal Ashutosh , Sweeters Nancy , Herz Matt , Foote Dru , Neumayr Lynne , Kurio Greg , Harmatz Paul R , Vichinsky Elliott P 
Published: October 2019

Abstract
Abstract 2021
Poster Board I-1043
Therapeutic regimens that combine two chelators have the potential to improve iron excretion while avoiding toxicities associated with high doses of single agents. This pilot study was designed to explore the safety of the combined treatment with deferasirox (DFX) and deferoxamine (DFO) in individuals with transfusion-dependent thalassemia and iron overload who had failed standard therapy. Subjects underwent baseline evaluation of liver iron, cardiac iron, cardiac function and target organ damage, and were enrolled in 3 groups (n=5 in each group) - Group B: adults with liver iron concentration (LIC) >15 mg/g dry weight, group A: adults with LIC >5 and <15 mg/g plus iron-related organ dysfunction, and Group C: children between 8-18 years with LIC >5 mg/g dry weight plus iron related organ dysfunction. The duration of therapy was 52 weeks, with DFX (20-30 mg/Kg) given daily and (DFO 35-50 mg/Kg/infusion) given for 3-5 days/week (groups A and C), or 5-7 days/week (group B). Subjects were monitored for hepatic and renal toxicity, visual or auditory changes, and development of new symptoms. Changes in serum ferritin, LIC (ferritometer), cardiac function (MRI) and myocardial iron (MRI T2*) were monitored. We have enrolled 14 subjects (target 15 subjects) with a median follow up of 29 weeks (range 18-52). The mean daily dose of DFO was 16, 33, and 17 mg/Kg/day for groups A, B and C, respectively, at the start of the study. The corresponding mean DFX dose was 21, 25 and 22 mg/Kg/day. At the end of 26 weeks, the mean LIC (mg/g dry wt) in evaluable patients declined from 13.0 (3.9-21.7) to 10.6 (0.60-18.3, p=0.015), and the mean ferritin (ng/mL) fell from 2631 (1000-5230) to 2158 (319-5845, p=n.s.). Cardiac evaluation revealed that mean MRI T2* (msec) improved from 22.7 (6.7-32.6) to 25.5 (10.7-38.1) and the mean LVEF (%) from 63.4 (47.5-68.5) to 64.3 (53.4-72.2), but these changes were not statistically significant. No subject developed evidence of significant myocardial iron (T2* <20 msec) loading during the trial. Elevation of serum creatinine or ALT was not observed in any subject. One subject from group B died 9 weeks after start of therapy from sepsis. One subject interrupted DFX therapy because of abdominal pain. In all other cases the treatment was well tolerated and no dose adjustment or suspension of therapy was required owing to toxicity. Protocol mandated modification of treatment (temporary cessation of DFX) occurred in two subjects resulting from a marked fall in serum ferritin and LIC. This suggests that simultaneous administration DFX and DFO at these doses is well tolerated and has low potential for toxicity. From these preliminary data, this combination seems to be effective in lowering body iron in high-risk patients. A larger clinical trial will be needed to assess the benefits of long-term combined chelation therapy on iron balance and end-organ damage in chronically transfused patients with thalassemia.

Disclosures:
Lal: Novartis: Research Funding. Harmatz:Novartis: Research Funding. Vichinsky:Novartis: Consultancy, Research Funding.