Evaluation of the Oral Iron Chelator 1,2-Dimethyl-3-hydroxypyrid-4-one (Ll) in Iron-Loaded Patients" NANCY F. OLIVIERI,b,c~d,eDOUGLAS M. TEMPLETON! GIDEON KOREN:',g DEREK CHUNG: AND CHRISTINE HERMANNF MELVIN H. ROBERT A. McCLELLAND~ Divisions of hHaematology-Oncology and gClinical Pharmacology and "Department of Paediatrics The Hospital for Sick Children Toronto, Ontario, Canada M5G 1x8 and Departments of fClinica1 Biochemistry and Chemistry University of Toronto Toronto, Canada M5G 1LS Despite the problems associated with its chronic administration to patients with Cooley's anemia, parenteral deferoxamine (DFO) remains the mainstay of iron chelation therapy.' Intensive administration of this drug is associated with serious neurotoxicity and considerable cost. However, the most problematic aspect of long-term therapy with D F O is the requirement for subcutaneous infusion using a battery-powered pump. Consequently, as early as 10 years of age, patient compliancc with subcutaneous DFO becomes erratic, and it declines further during the teenage years, at the time when transfusional iron accumulation is accelerated.* An increasing body of evidence, some of which has been presented at the mccting on which this volume is based, indicates that iron chelation, although problematic, rcduccs the morbidity and mortality associated with iron overload. Regular DFO therapy removes hepatic iron3-' and prevents hepatic fibrosis' in iron-loaded patients. Survival," and in some patients linear growth' and sexual maturation,'^" may also improvc. Reversal of iron-related cardiac dysfunction has been less convincingly demonstrated. In some patients with Cooley's anemia, clinical improvement in cardiac function and unexpectedly prolonged survival have followed intensification of DFO therapy.'."' In other patients, progressive cardiac deterioration has not been altercd."'~"It appears that the key to the preservation of organ function in transfusiondependent patients may be the prevention of accumulation of iron in body tissucs, including the heart.' The failure of many patients with Cooley's anemia to comply with subcutancous D F O therapy is a major obstacle to prevention of iron-related morbidity and UThiswork was supported by Grant No. MA-10601 from the Medical Research Council of Canada. dRecipient of a Career Scientist Award from the Ontario Ministry of Health. 'Address correspondence to Dr. Nancy F. Olivieri, Director, Hemoglobinopathy Program, Division of HematologyiOncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1x8. 369
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ANNALS NEW YORK ACADEMY OF SCIENCES
mortality." Oral chelation not only has the potential to make long-term therapy more acceptable to the patient, but it may also increase efficacy by providing a continuous supply of circulating drug.13 A safe, inexpensive, orally available chelating agent would also make therapy available to the thousands of Cooley's anemia patients worldwide for whom chelation is presently unavailable and who die of iron overload. During the last ten years, many oral chclators have been tested in rodent or primate models of iron overload. Some are discussed elsewhere in this volume; a few have been the subject of human trials.Ibl7
HYDROXYPYRIDONE CHELATORS
1,2-dimethyl-3-hydroxypyrid-4-one, or L1 in the terminology used by its first clinical investigator^,'^ '' is one of several hydroxypyridone chelators which have been evaluated in cell culture,'' animal studies,"-" and a small number of patients.'"'' Hydroxypyridones are neutral bidentate ligands with a high specificity for ferric iron. The stability constant of their iron complexes (log K, = 37) is six orders of magnitude higher than that of DFO. In animal studies, the source of chelated iron was found to be mainly hepatocellular. When L1 was administered to iron-loaded patients, it resulted in urinary iron excretion similar to that obtained by equivalent doses of parenteral DFO.I4." However, baseline fecal iron excretion was not measured in these studies, and patients in the control and treatment groups were not matched for hemoglobin levels. Since DFO has been shown previously to induce fecal iron excretion at levels of 10-16% of total iron excretion in a patient with a low hemoglobin level and of 22-52% in a different patient with a high hemoglobin level,zz the total evaluation of a new chelator necessitates careful quantification of fecal iron excretion and attention to the hemoglobin level at the time of iron excretion. Acohort of our iron-overloaded patients with Cooley's anemia do not achieve net negative iron balance with DFO, either because significant neurotoxicity limits their dose, or because of poor compliance with the regimen of subcutaneous DFO. They are thus at high risk of organ toxicity and death from iron overload. Earlier trials of L1 in iron-loaded patients in the United Kingdom have demonstrated its short-tcrm efficacy in a small number of patient^.'^.'' Accordingly, we administered L1 to patients with transfusional iron overload in whom DFO therapy was failing. The results demonstrate that in the short-term, L1 is as effective as DFO in promoting iron excretion and is well tolerated by these patients.
PATIENTS AND METHODS
Twenty-six transfusion-dependent patients with a mean age of 22 years (range, 8 4 9 years) were admitted to the hospital for supervised administration of L1. Twenty-four patients had Cooley's anemia, and two had Diamond-Blackfan anemia. Fifteen patients were poorly compliant with nightly subcutaneous DFO for at least two years (defined as
370
ANNALS NEW YORK ACADEMY OF SCIENCES
mortality." Oral chelation not only has the potential to make long-term therapy more acceptable to the patient, but it may also increase efficacy by providing a continuous supply of circulating drug.13 A safe, inexpensive, orally available chelating agent would also make therapy available to the thousands of Cooley's anemia patients worldwide for whom chelation is presently unavailable and who die of iron overload. During the last ten years, many oral chclators have been tested in rodent or primate models of iron overload. Some are discussed elsewhere in this volume; a few have been the subject of human trials.Ibl7
HYDROXYPYRIDONE CHELATORS
1,2-dimethyl-3-hydroxypyrid-4-one, or L1 in the terminology used by its first clinical investigator^,'^ '' is one of several hydroxypyridone chelators which have been evaluated in cell culture,'' animal studies,"-" and a small number of patients.'"'' Hydroxypyridones are neutral bidentate ligands with a high specificity for ferric iron. The stability constant of their iron complexes (log K, = 37) is six orders of magnitude higher than that of DFO. In animal studies, the source of chelated iron was found to be mainly hepatocellular. When L1 was administered to iron-loaded patients, it resulted in urinary iron excretion similar to that obtained by equivalent doses of parenteral DFO.I4." However, baseline fecal iron excretion was not measured in these studies, and patients in the control and treatment groups were not matched for hemoglobin levels. Since DFO has been shown previously to induce fecal iron excretion at levels of 10-16% of total iron excretion in a patient with a low hemoglobin level and of 22-52% in a different patient with a high hemoglobin level,zz the total evaluation of a new chelator necessitates careful quantification of fecal iron excretion and attention to the hemoglobin level at the time of iron excretion. Acohort of our iron-overloaded patients with Cooley's anemia do not achieve net negative iron balance with DFO, either because significant neurotoxicity limits their dose, or because of poor compliance with the regimen of subcutaneous DFO. They are thus at high risk of organ toxicity and death from iron overload. Earlier trials of L1 in iron-loaded patients in the United Kingdom have demonstrated its short-tcrm efficacy in a small number of patient^.'^.'' Accordingly, we administered L1 to patients with transfusional iron overload in whom DFO therapy was failing. The results demonstrate that in the short-term, L1 is as effective as DFO in promoting iron excretion and is well tolerated by these patients.
PATIENTS AND METHODS
Twenty-six transfusion-dependent patients with a mean age of 22 years (range, 8 4 9 years) were admitted to the hospital for supervised administration of L1. Twenty-four patients had Cooley's anemia, and two had Diamond-Blackfan anemia. Fifteen patients were poorly compliant with nightly subcutaneous DFO for at least two years (defined as
