Introduction: Iron overload in patients who received hematopoietic cell transplantation (HCT) is one of the major clinical issues. Although deferasirox is well known to be an iron chelating agent, its safety for the patients who received HCT is unknown. Then, we designed a multicenter prospective study (phase 1) to evaluate the safety and efficacy of deferasirox in patients with iron overload after HCT.

Methods: The eligibility criteria includes the duration at least 6 month after HCT, serum ferritin more than 1,000 ng/ml, red blood cell (RBC) transfusions more than 20 units, disease remission, normal renal function, performance status of 0 or 1, and the unfit of phlebotomy. The exclusion criteria were history of iron chelating therapy after HCT, presence of moderate or severe chronic graft-versus-host disease (GVHD), uncontrollable complications, and the history of hepatitis B or C virus infection. A registration target was set at 20 patients including 5 ineligibles. Safety of deferasirox was assessed by the dose escalation methods in the individual. After the registration, deferasirox was started at a dose of 5 mg/kg for four weeks. Then, the dose was increased to 7.5 mg/kg and 10 mg/kg. The patient attended every two weeks for the safety evaluation. Cessation criteria were any grade 2 to 4 of adverse event or early disease relapse. Namely, 4 weeks medication within grade 1 of adverse events was defined as tolerable and successful medication for the identical dose. Primary endpoint was the maximum tolerate dose of deferasirox and defined from the dose in which 50 to 80% of the eligible patients were tolerable.

Results: A total of 16 patients were enrolled to the study from March 2013 to January 2016. One case was excluded out of analysis due to the early relapse and 15 were eligible. Median age was 42 years old (range: 22-68). Disease included acute myeloid leukemia (n=6), acute lymphoblastic leukemia (n=2), aplastic anemia (n=2), non-Hodgkin's lymphoma (n=2), and others (n=3). Median duration from HCT to deferasirox administration was 9 months (range: 6-84). Median amount of RBC transfusions was 54 units (range: 20-156). Median value of serum ferritin was 1,537 ng/ml (range: 1,027-7,655). Regarding to the dose escalation test, 9 cases succeeded in taking from the initial 5mg/kg to the final 10mg/kg and 6 resulted in withdrawal during the treatment: abnormality of clinical test in 5 mg/kg (n=3), late relapse in 7.5 mg/kg (n=1), self-cessation and gastrointestinal event in 10 mg/kg (n=2). Achievement rates of successful medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in10 mg/kg (9 of 15), respectively. Among 10 evaluable cases, mean value of ferritin decreased from 1,605 ng/ml at pre-treatment to 1,303 ng/ml at post-treatment. The change of other markers were as follows: hemoglobin from 12.0 g/dl to 12.6 g/dl, aspartate aminotransferase (AST) from 24.9 IU/L to 28.3 IU/L, alanine aminotransferase (ALT) from 25.8 IU/L to 28.4 IU/L, creatinine (Cr) from 0.80 mg/dl to 1.05 mg/dl. Liver iron content (LIC) was examined only in 3 cases and the mean LIC was did not change before and after the treatment at 200 μmol/g. Main of grade 1 of adverse events were elevation of clinical test including Cr (60%), AST (40%), ALT (40%), and alkaline phosphatase (33%), diarrhea (27%), abdominal pain (20%), skin rash (20%), constipation (20%), nausea (13%). None of the patients developed the exacerbation of GVHD.

Conclusion: This dose escalating method of deferasirox treatment for transplant patients may be feasible. Ten mg/kg of deferasirox may be maximum tolerated dose when given after HCT. The efficacy of iron chelation would be inadequate due to the low dose and short term of deferasirox. Validation of phase 2 study is warrant.


Morita:Bristol-Myers Squibb: Speakers Bureau. Kanda:Otsuka Pharmaceutical: Honoraria, Research Funding. Okamoto:Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Astellas Pharma Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.