European Journal of Haematology 95 (545–550)
ORIGINAL ARTICLE
Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study Rodolfo Cancßado1, Murilo R. Melo2, Roberto de Moraes Bastos3, Paulo C. J. L. Santos4, Elivira M. Guerra-Shinohara5, Carlos Chiattone1, Samir K. Ballas6 1
Department of Hematology/Oncology, Santa Casa Medical School, Sao Paulo; 2Molecular Medicine Laboratory, Santa Casa Medical School, Sao Paolo; 3Radiology Department, Santa Casa Medical School, Sao Paolo; 4Laboratory of Genetics and Molecular Cardiology, Heart Institute (InC0r), University of Sao Paolo Medical School, Sao Paolo; 5Department of Clinical Chemistry and Toxicology, Pharmaceutical Sciences School, University of Sao Paolo, Sao Paolo, Brazil; 6Cardeza Foundation for Hematological Research; Jefferson Medical College, Thomas Jefferson University Philadelphia, Philadelphia, PA, USA
Abstract This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 5 mg/ kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients. Key words iron overload; hereditary hemochromatosis; transfusional siderosis; deferasirox; chelation therapy; phlebotomy; erythrocytapheresis Correspondence Rodolfo Cancado, MD, Hematology/Oncology Department, Santa Casa Medical School, Rua Marques de Itu, 579, CEP 01221-003 Sao Paulo, SP, Brazil. Tel: +551121767255; Fax: +551121767255; e-mail: [email protected] Accepted for publication 2 February 2015
Hereditary hemochromatosis (HH) is one of the most common inherited causes of non-transfusional iron overload (IOL) (1, 2). The majority of cases are associated with mutations in the HFE gene which results in reduced hepcidin expression and up-regulation of both dietary iron absorption and mobilization (1–3). Untreated IOL may lead to hepatic cirrhosis, diabetes mellitus, hypogonadotrophic hypogonadism, arthropathy, cardiomyopathy, and increased risk of hepatocellular carcinoma (1, 3, 4). Nevertheless, early diagnosis of HH and the initiation of therapy with phlebotomy on a regular basis largely prevent the adverse consequences of iron overload (4–6). Patients with poor venous access and patients with congestive heart failure, however, may not tolerate therapeutic phlebotomy (3). In addition, compliance with phlebotomy may be variable over time as a result of
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12530
the inconvenience of frequent visits and the discomfort associated with the procedure (7–9). Erythrocytapheresis has also been reported as effective in the treatment of HH, but it was not studied in large randomized trials and is not as widely available as phlebotomy (10–13). Moreover, surveys of patients with HH who have undergone phlebotomy conducted before the introduction of deferasirox reported that up to 59% would prefer an oral therapy vs. phlebotomy (7, 8). Previous studies in patients with transfusional iron overload due to sickle cell disease (SCD) or thalassemia have reported high levels of satisfaction and longer persistence with treatment with deferasirox than parenteral iron chelation therapy (14–17). The objective of this study was to determine the safety and efficacy of deferasirox in patients with HH and IOL.
545
Cancßado et al.
Phase 2 study of deferasirox in hereditary hemochromatosis
Materials and methods Study design and patients
This was an open-label, prospective, phase 2 study of deferasirox in adult patients with IOL due to HH who were refractory to or who were unable or unwilling to comply with phlebotomy. Enrolled patients were those with HH homozygous for the HFE C282Y or doubly heterozygous to C282Y/H63D gene mutations with IOL defined by transferrin saturation (TS) ≥ 45%, serum ferritin (SF) ≥ 500 ng/mL confirmed at two visits, and liver iron concentration (LIC) by magnetic resonance imaging [MRI] ≥5 mg Fe/g dw. All patients had serum creatinine within normal and estimated creatinine clearance ≥60 mL/min. All patients provided written, informed consent prior to enrollment, and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Recruitment of patients was initiated in August 2010 and was completed in January 2011. The study, however, lasted 12 months from August 2010 through July 2011. Dosing
Deferasirox, at a starting dose 10 mg/kg/d, was administered for 12 months. The dose of study drug was recalculated if there was a change (increase or decrease) in body weight of >10% from baseline at any study visit. Dose adjustments of 5 mg/kg/d were allowed after 10 wk. If SF fell to 300 ng/mL, at which point, the study drug was restarted at the same dose. If SF continued to be low after the restart of study drug, the investigator could chose to discontinue the patient from the study. Study drug reduction was implemented in the event of increased serum creatinine to ≥33% above baseline on two consecutive occasions. Study drug was discontinued if serum creatinine increased to more than the upper limit of normal (ULN), in the event of persistent rash (i.e., >1 wk or worsening), or if liver function enzymes [aspartate transaminase (AST) or alanine aminotransaminase (ALT)] increased to >39 baseline value. When study drug was restarted, doses were generally 50% of the initial dose with close monitoring. The efficacy and safety of deferasirox in patients who received it for 12 months were assessed monthly. Efficacy was determined by the evaluation of changes in TS, SF, and LIC from baseline to 12 months, specifically the time elapsed to reduce baseline values of SF by at least 50% and/ or the achievement of SF
ORIGINAL ARTICLE
Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study Rodolfo Cancßado1, Murilo R. Melo2, Roberto de Moraes Bastos3, Paulo C. J. L. Santos4, Elivira M. Guerra-Shinohara5, Carlos Chiattone1, Samir K. Ballas6 1
Department of Hematology/Oncology, Santa Casa Medical School, Sao Paulo; 2Molecular Medicine Laboratory, Santa Casa Medical School, Sao Paolo; 3Radiology Department, Santa Casa Medical School, Sao Paolo; 4Laboratory of Genetics and Molecular Cardiology, Heart Institute (InC0r), University of Sao Paolo Medical School, Sao Paolo; 5Department of Clinical Chemistry and Toxicology, Pharmaceutical Sciences School, University of Sao Paolo, Sao Paolo, Brazil; 6Cardeza Foundation for Hematological Research; Jefferson Medical College, Thomas Jefferson University Philadelphia, Philadelphia, PA, USA
Abstract This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 5 mg/ kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients. Key words iron overload; hereditary hemochromatosis; transfusional siderosis; deferasirox; chelation therapy; phlebotomy; erythrocytapheresis Correspondence Rodolfo Cancado, MD, Hematology/Oncology Department, Santa Casa Medical School, Rua Marques de Itu, 579, CEP 01221-003 Sao Paulo, SP, Brazil. Tel: +551121767255; Fax: +551121767255; e-mail: [email protected] Accepted for publication 2 February 2015
Hereditary hemochromatosis (HH) is one of the most common inherited causes of non-transfusional iron overload (IOL) (1, 2). The majority of cases are associated with mutations in the HFE gene which results in reduced hepcidin expression and up-regulation of both dietary iron absorption and mobilization (1–3). Untreated IOL may lead to hepatic cirrhosis, diabetes mellitus, hypogonadotrophic hypogonadism, arthropathy, cardiomyopathy, and increased risk of hepatocellular carcinoma (1, 3, 4). Nevertheless, early diagnosis of HH and the initiation of therapy with phlebotomy on a regular basis largely prevent the adverse consequences of iron overload (4–6). Patients with poor venous access and patients with congestive heart failure, however, may not tolerate therapeutic phlebotomy (3). In addition, compliance with phlebotomy may be variable over time as a result of
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12530
the inconvenience of frequent visits and the discomfort associated with the procedure (7–9). Erythrocytapheresis has also been reported as effective in the treatment of HH, but it was not studied in large randomized trials and is not as widely available as phlebotomy (10–13). Moreover, surveys of patients with HH who have undergone phlebotomy conducted before the introduction of deferasirox reported that up to 59% would prefer an oral therapy vs. phlebotomy (7, 8). Previous studies in patients with transfusional iron overload due to sickle cell disease (SCD) or thalassemia have reported high levels of satisfaction and longer persistence with treatment with deferasirox than parenteral iron chelation therapy (14–17). The objective of this study was to determine the safety and efficacy of deferasirox in patients with HH and IOL.
545
Cancßado et al.
Phase 2 study of deferasirox in hereditary hemochromatosis
Materials and methods Study design and patients
This was an open-label, prospective, phase 2 study of deferasirox in adult patients with IOL due to HH who were refractory to or who were unable or unwilling to comply with phlebotomy. Enrolled patients were those with HH homozygous for the HFE C282Y or doubly heterozygous to C282Y/H63D gene mutations with IOL defined by transferrin saturation (TS) ≥ 45%, serum ferritin (SF) ≥ 500 ng/mL confirmed at two visits, and liver iron concentration (LIC) by magnetic resonance imaging [MRI] ≥5 mg Fe/g dw. All patients had serum creatinine within normal and estimated creatinine clearance ≥60 mL/min. All patients provided written, informed consent prior to enrollment, and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Recruitment of patients was initiated in August 2010 and was completed in January 2011. The study, however, lasted 12 months from August 2010 through July 2011. Dosing
Deferasirox, at a starting dose 10 mg/kg/d, was administered for 12 months. The dose of study drug was recalculated if there was a change (increase or decrease) in body weight of >10% from baseline at any study visit. Dose adjustments of 5 mg/kg/d were allowed after 10 wk. If SF fell to 300 ng/mL, at which point, the study drug was restarted at the same dose. If SF continued to be low after the restart of study drug, the investigator could chose to discontinue the patient from the study. Study drug reduction was implemented in the event of increased serum creatinine to ≥33% above baseline on two consecutive occasions. Study drug was discontinued if serum creatinine increased to more than the upper limit of normal (ULN), in the event of persistent rash (i.e., >1 wk or worsening), or if liver function enzymes [aspartate transaminase (AST) or alanine aminotransaminase (ALT)] increased to >39 baseline value. When study drug was restarted, doses were generally 50% of the initial dose with close monitoring. The efficacy and safety of deferasirox in patients who received it for 12 months were assessed monthly. Efficacy was determined by the evaluation of changes in TS, SF, and LIC from baseline to 12 months, specifically the time elapsed to reduce baseline values of SF by at least 50% and/ or the achievement of SF
