Failure of recombinant human interleukin-3 therapy to induce erythropoiesis
in patients with refractory Diamond-Blackfan anemia [see comments]
NF Olivieri, SA Feig, L Valentino, AM Berriman, R Shore and MH Freedman
Hospital for Sick Children, Toronto, Ontario, Canada.
In two previous studies, we observed that recombinant human interleukin- 3
(IL-3) induced an increase in marrow burst-forming unit-erythroid- derived
colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To
determine whether a similar erythropoietic response could be induced in
vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two
preparations of IL-3. All patients had absent absolute reticulocyte counts
and markedly reduced to absent recognizable bone marrow erythroid elements;
patients with circulating reticulocytes in the previous 12 months were
excluded from study. All patients except 1 had failed steroid therapy and
had been transfusion-dependent since infancy; 1 patient was maintained on
high-dose prednisone at the time of enrollment. On the first arm of the
study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously
using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided
dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral
ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped
prematurely because of adverse side effects. In the other 9 evaluable
cases, reticulocytes increased transiently in 1 patient from 0 to 65 x
10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion
dependency persisted. One transient peak in absolute reticulocyte count was
noted in 6 other patients, but no erythroid response was observed after
completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was
then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients
without effect, and treatment was stopped. In 2 patients, a second
preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was
initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was
coadministered with ferrous sulphate. No erythroid response was observed in
either patient, and in one of the two, alternate-day subcutaneous
recombinant erythropoietin at 300 U/kg was administered for 3 weeks in
combination with daily IL-3 at 10 micrograms/kg, but no increased
erythropoiesis was seen. Significant increases in white blood cell and
eosinophil counts during administration of both preparations of IL-3 were
observed in all patients. These data show that the response of DBA patients
to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro
studies. The absence of a corrective effect of IL-3 in these patients with
DBA indicates that a deficiency of the cytokine is not central in the
pathogenesis of the disorder.
Volume 83,
Issue 9,
pp. 2444-2450,
05/01/1994
Copyright © 1994 by The American Society of Hematology
