Alan R. Cohen

Safety profile of the oral iron chelator deferiprone: a multicentre study.

In previous trials, the orally active iron chelator deferiprone (L1) has been associated with sporadic agranulocytosis, milder forms of neutropenia and other side‐effects. To determine the incidence of these events, we performed a multicentre prospective study of the chelator. Blood counts were performed weekly, and confirmed neutropenia mandated discontinuation of therapy. Among 187 patients with thalassaemia major, the incidence of agranulocytosis (neutrophils < 0.5 × 109/l) was 0.6/100 patient–years, and the incidence of milder forms of neutropenia (neutrophils 0.5–1.5 × 109/l) was 5.4/100 patient–years. All cases of neutropenia resolved after interruption of therapy. Neutropenia occurred predominantly in non‐splenectomized patients. Nausea and/or vomiting occurred early in therapy, was usually transient and caused discontinuation of deferiprone in three patients. Mild to moderate joint pain and/or swelling did not require permanent cessation of deferiprone and occurred more commonly in patients with higher ferritin levels. Mean alanine transaminase (ALT) levels rose during therapy. Increased ALT levels were generally transient and occurred more commonly in patients with hepatitis C. Persistent changes in immunological studies were infrequent, although sporadic abnormalities occurred commonly. Mean zinc levels decreased during therapy. Ferritin levels did not change in the overall group but decreased in those patients with baseline levels > 2500 μg/l. This study characterized the safety profile of deferiprone, and, under the specific conditions of monitoring, demonstrated that agranulocytosis is less common than previously predicted.

International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers.

To examine the reproducibility of the single breathhold T2* technique from different scanners, after installation of standard methodology in five international centers.

Depletion of excessive liver iron stores with desferrioxamine

TO determine the therapeutic effect of long‐term, intensive iron chelation therapy, we studied liver iron content and histology in four children with thalassaemia major during 52‐83 months of intensive therapy with desferrioxamine. The initial biopsies obtained prior to or within 21 months after beginning chelation therapy had Grade IV iron staining, with heavy iron deposition present in parenchymal and reticuloendothelial cells. Subsequent biopsies, obtained when serum ferritin levels had fallen to 71‐246 μg/1, contained Grade 0 or Grade I stainable iron. Little or no iron was present in parenchymal or reticuloendothelial cells. The liver iron concentration, measured by magnetic susceptibility, returned to normal or nearly normal levels. Hepatic fibrosis did not progress during treatment with desferrioxamine. These findings demonstrate that intensive and sustained chelation therapy with desferrioxamine will remove excessive liver iron and preserve hepatocellular structure.

Rapid removal of excessive iron with daily, high-dose intravenous chelation therapy

We investigated the value of high-dose intravenous iron chelation therapy with deferoxamine as an alternative to conventional subcutaneous therapy in eight patients receiving regular transfusions who had massive iron stores, including two with clinical heart disease. Six to twelve grams of deferoxamine was infused daily for 12 hours over 12 to 25 months through externalized central venous catheters or implanted reservoirs. Serum ferritin levels decreased by 56% to 99%. Liver iron concentrations, measured by magnetic susceptibility in two patients, were 1234 and 2438 micrograms/gm wet weight (22.1 and 43.6 mumol/gm wet weight) after treatment for 17 and 25 months, respectively. A patient with congestive heart failure and a patient with severe ventricular dysrhythmias no longer required cardiac medication after 12 to 24 months of chelation therapy. Three episodes of bacteremia and three episodes of cellulitis accounted for a catheter-related infection rate of 0.14 per 100 patient-days. The catheter removal rate was 0.20 per 100 patient-days. No patient experienced serious visual, auditory, or other toxicities. We conclude that in some patients receiving regular erythrocyte transfusions, high-dose intravenous chelation therapy with deferoxamine is superior to conventional subcutaneous treatment.

Neurologic events after partial exchange transfusion for priapism in sickle cell disease

We describe six boys with homozygous sickle cell disease, aged 7 to 13 years, in whom acute, severe neurologic abnormalities developed 1 to 11 days after partial exchange transfusion was performed to treat priapism that was unresponsive to more conservative therapy. Hemoglobin levels were 10.5 to 13.4 gm/dl (mean 12.1 gm/dl), and hemoglobin S levels were 18% to 33% (mean 27%) before the onset of neurologic complications. Severe headache was the initial finding in five patients, four of whom had increased intracranial pressure and three of whom required tracheal intubation and hyperventilation. Four patients had seizures; three had focal neurologic deficits for more than 24 hours. Cerebral arteriography demonstrated vascular abnormalities, including irregularity, stenosis, and complete occlusion of vessels. Patients treated with regular erythrocyte transfusions had no recurrence of neurologic signs or symptoms when hemoglobin S levels were kept at 30% to 50%. The occurrence of serious neurologic complications after partial exchange transfusion in patients with homozygous sickle cell disease from three centers indicates the possibility of a causal relationship between the events. Early and thorough investigation of neurologic symptoms, especially severe headache, is warranted in this clinical setting.

Evaluation of iron overload by single voxel MRS measurement of liver T2

To overcome the difficulty of poor signal‐to‐noise ratio of magnetic resonance imaging (MRI) in evaluating heavy iron overload by using a single voxel magnetic resonance spectroscopy (MRS) technique.

Self-reported diagnostic and management strategies in childhood idiopathic thrombocytopenic purpura: results of a survey of practicing pediatric hematology/oncology specialists.

PURPOSE To assess current physician self-reported practices regarding initial management of childhood idiopathic thrombocytopenic purpura (ITP) and to determine physician self-reported willingness to participate in randomized clinical trials comparing different initial management strategies. PATIENTS AND METHODS A questionnaire was mailed in November 1997 to all 720 members of the American Society of Pediatric Hematology/Oncology asking how they would diagnose and manage ITP in children 18 months, 5 years, and 15 years of age who were experiencing either dry purpura (cutaneous hemorrhage only) or wet purpura (active mucous membrane hemorrhage). Specific questions dealt with bone marrow aspiration, hospital admittance, treatment strategy, and specific doses of corticosteroids and intravenous immunoglobulin. RESULTS The response rate to the questionnaire was 57%. Most respondents indicated they usually perform a bone marrow aspirate when corticosteroids are to be prescribed and administer drug therapy to patients with newly diagnosed ITP with wet or dry purpura. Only 16% of respondents would administer no drug therapy to a child with dry purpura. Intravenous immunoglobulin (IVIG) was preferred to steroids, with anti-D immunoglobulin prescribed less frequently. Hospital admittance often was used for patients with dry purpura and usually recommended for patients with wet purpura. Most respondents expressed willingness to randomize patients with dry purpura to IVIG versus no therapy and those with wet purpura to IVIG versus prednisone as part of a randomized controlled clinical trial. CONCLUSIONS The self-reported care of the patient with ITP was influenced by the severity of presentation (dry versus wet purpura). Most physicians reported they would administer specific drug treatment in both scenarios. This survey illustrates the diverse diagnostic and management strategies currently used in childhood ITP. Because no one therapeutic approach is predominant and a scientific basis for decision making in childhood ITP has not been developed, future randomized trials are warranted. On the basis of these survey results, such trials are desired by most pediatric hematology/oncology specialists.

Vision and hearing during deferoxamine therapy

To determine the frequency of eye and auditory complications and their relationship to drug dosage and iron stores in patients receiving deferoxamine, we studied 52 regularly transfused patients who received deferoxamine by subcutaneous or intravenous infusion in doses from 26 to 136 mg/kg/day, and whose serum ferritin levels of 185 to 17,775 micrograms/L reflected a wide range of iron stores. Forty-nine patients (94%) had no evidence of drug-induced visual or auditory abnormalities. Symptomatic loss of vision and hearing developed in one patient; both problems improved when chelation therapy was stopped. Of the 51 symptom-free patients, one had a mild degree of macular stippling and one had a mild, bilateral, high-frequency sensorineural hearing loss. Eye and ear abnormalities in the symptom-free patients did not progress despite continuation or resumption of chelation therapy at the same dosage. Patients with ophthalmologic and audiologic abnormalities did not receive higher doses of deferoxamine and did not have lower serum ferritin levels than patients without such abnormalities. These findings demonstrate that eye and ear abnormalities during chelation therapy with deferoxamine may not occur uniformly at as high a frequency as previously reported, even in patients who receive large doses of the chelating agent or who have only modest amounts of excessive iron.

Scurvy and altered iron stores in thalassemia major.

SCURVY is a rare disorder in the United States because of the wide availability of fresh fruits and vegetables and the frequent supplementation of common packaged foods with vitamin C. Although vit...

Risks of immunodeficiency, AIDS, and death related to purity of factor VIII concentrate

In HIV-infected subjects with haemophilia, CD4 counts seem to fall more slowly in those on high-purity factor VIII (FVIII) than on intermediate-purity product. We evaluated whether risks for AIDS or death were associated with either product among 411 HIV-infected individuals. The relative hazard of AIDS was slightly elevated for both current (1.34) [corrected] and cumulative (1.01 per month) use of high-purity products (neither significant). The corresponding hazards for death were 1.49 and 1.03 (neither significant). Thus we found no evidence that high-purity FVIII concentrates retard the development of AIDS.