A Phase II, Multicenter, Single-Arm Study to Evaluate the Safety and Efficacy of Deferasirox after Hematopoietic Stem Cell Transplantation in Children with β-Thalassemia Major

Abstract

We conducted a prospective, phase II, multicenter, single-arm study to evaluate the efficacy and safety of deferasirox in patients age >2 to <18 years with β-thalassemia major (TM) who underwent hematopoietic stem cell transplantation (HSCT) and had evidence of iron overload (serum ferritin >1000 µg/L; cardiac MRI T2* <20 ms, or liver iron concentration [LIC; by MRI R2] ≥5 mg/g). Patients received deferasirox at an initial dose of 10 mg/kg/day, with up-titration to a maximum of 20 mg/kg/day. The study continued for 52 weeks and included a total of 27 patients (mean age, 9.1 ± 3.8 years; 70.4% male). One patient (3.7%) was lost to follow-up. The majority of patients (n = 20; 74.1%) were able to achieve the intended dose of 20 mg/kg/day. No deaths occurred. A total of 134 adverse events (AEs) were reported in 25 patients (92.6%) during the study. The majority of patients had grade 1 or 2 AEs, with only 8 patients (29.6%) experiencing grade 3 AEs. Only 10 AEs occurring in 4 patients (14.8%) were suspected to be related to deferasirox (ALT/AST increase, n = 4; urinary tract infection, n = 1). The deferasirox dose had to be adjusted or interrupted for 6 AEs occurring in 4 patients (14.8%). A total of 6 serious AEs occurred in 3 patients (11.1%), none of which were suspected to be related to deferasirox. From baseline to week 52, there were decreases in median concentrations of alanine aminotransferase (ALT), from 30.0 to 17.0 IU/L, and aspartate aminotransferase (AST), from 35.5 to 26.0 IU/L. Median serum creatinine and cystatin C concentrations were similar at baseline and week 52. There was a continuous and significant decrease in median serum ferritin level from 1718.0 µg/L at baseline to 845.3 µg/L following 52 weeks of therapy (P < .001); 9 patients (33.3%) achieved a level of <500 µg/L. There was also a significant decrease in median LIC (from 8.6 to 4.1 mg/g; P < .001) and an increase in median cardiac T2* (from 26.0 to 28.0 ms; P = .520) from baseline to week 52. Our findings indicate that deferasirox treatment at doses up to 20 mg/kg/day reduces the iron burden in children with TM post-HSCT, with a manageable safety profile.

Serum ferritin is not a reliable predictor to determine iron overload in thalassemia major patients post‐hematopoietic stem cell transplantation

“…In 5 of 18 (28%) patients, the SF levels were <1000 µg/L and would not meet the criteria for further diagnostic procedure. Performing further assessment in these patients, 30,31 However, its inappropriate use in patients with low body iron can cause organ toxicity, particularly in patients with pre-existing renal or hepatic impairment. In our study, we identify patients with high SF but normal iron stores.…”

“…Coexisting anemia (many matched sibling donors suffer from thalassemia minor) and limited venous access, especially in small children, can hamper this procedure. Iron chelation therapy is effective in reducing iron overload post‐HSCT . However, its inappropriate use in patients with low body iron can cause organ toxicity, particularly in patients with pre‐existing renal or hepatic impairment.…”

“…Once IO has been proven and the SF/LIC‐ratio is known for an individual patient, regular analysis of SF can temporarily serve as a useful monitoring parameter. Phlebotomy and iron chelation therapy are effective and safe for the reduction of IO post‐HSCT , and should aim to reduce LIC to <5 mg/g dw. Iron chelation or phlebotomy should be changed or even terminated only on the basis of LIC measurement by MRI or SQUID.…”

Guest Editor: Raffaella Origa IRON TOXICITY AND HEMOPOIETIC CELL TRANSPLANTATION: TIME TO CHANGE THE PARADIGM.

“…There was also a significant decrease in median LIC and an increase in median cardiac T2* from baseline to week 52. A manageable safety profile was observed 42…”

Development of Gene Editing Strategies for Humanβ-Globin (HBB) Gene Mutations

“…Allogeneic stem cell transplantation, a promising treatment for SCD and similar blood diseases, is based on the availability of suitable donors, harvesting of healthy HSCs and their transplantation to the patients (Kahraman et al, 2014;Ozdogu et al, 2018b;Shenoy, 2011;Yesilipek, 2007;Yesilipek et al, 2018). Even though there are successful results of this method, it is not a universal treatment because of insufficiency of available donors, the immune issues like graft versus host disease (GVHD) and other toxicities (Ozdogu et al, 2018a;Ozdogu et al, 2018b).…”