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Efficacy and possible adverse effects of the oral iron chelator 1,2-
dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major [see comments]
FN al-Refaie, B Wonke, AV Hoffbrand, DG Wickens, P Nortey and GJ Kontoghiorghes
Department of Haematology, Royal Free Hospital School of Medicine, London,
UK.
Eleven patients with beta thalassemia major were entered into the trial of
the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Their ages ranged
from 17 to 26 years (mean +/- SD, 22.3 +/- 2.7). Six were male and five
were female. L1 was administered at an initial daily dose of 42.5 to 60
mg/kg as a single dose. After 4 weeks, the dose was increased to 85 to 119
(102 +/- 10.7) mg/kg for 191 to 352 days divided into either two or four
doses daily, except for one patient who developed agranulocytosis after 11
weeks and was taken off the trial. Initial serum ferritin values in the
remaining 10 patients ranged between 1,000 and 9,580 (5,549 +/- 3,333)
micrograms/L and at end of the trial their mean serum ferritin was
significantly lower (4,126 +/- 2,278; P less than .05 using the paired
t-test). Urinary iron excretion at a daily dose of 85 to 119 mg/kg
administered as two divided doses ranged between 0.14 and 0.82 (0.44 +/-
0.26) mg/kg/24 h. In three patients, the four doses per day schedule caused
substantially more iron excretion than the same total dose divided into
two. During the course of the trial, several possible adverse effects have
been encountered. One patient (female, aged 20) developed agranulocytosis
11 weeks after starting treatment and 6 weeks after beginning treatment
with a daily dose of 105 mg/kg. This patient's neutrophil count recovered
spontaneously 7 weeks after the discontinuation of L1. A decrease in serum
zinc levels to subnormal levels was observed in four patients with symptoms
of dry skin, with an itchy scaly rash in two that was associated with low
serum zinc levels that responded to zinc therapy. Urinary zinc levels
ranged from 4.7 to 23.4 (13 +/- 5.5) mumol/24 h and were above 9 mumol/24 h
(upper limit of normal) in eight patients. Mild nausea occurred in three
patients and transient diarrhea in a fourth. Mild musculoskeletal symptoms
occurred in three patients but settled without discontinuation of L1
therapy in two and with temporary discontinuation of L1 in the third. A
transient increase in serum aspartate transaminase was also noted in five
patients, but serum aspartate transaminase levels subsequently decreased in
all of them. No cardiovascular, neurologic, renal, or retinal toxicities
were demonstrable. These results confirm that L1 is an effective oral iron
chelator. Further clinical trials are needed to determine the incidence and
severity of adverse effects.
Volume 80,
Issue 3,
pp. 593-599,
08/01/1992
Copyright © 1992 by The American Society of Hematology
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