Treatment of Diamond‐Blackfan anaemia with haematopoietic growth factors, granulocyte‐macrophage colony stimulating factor and interleukin 3: sustained remissions following IL‐3

Abstract

We have treated six transfusion-dependent, steroid-unresponsive, Diamond-Blackfan anaemia (DBA) patients with the recombinant human growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), administered sequentially with an interim rest period. GM-CSF was given at a dose of 500 micrograms/m2/d subcutaneously for 6 weeks. Three patients increased their absolute reticulocyte counts 1.5-35-fold (mean 20.8-fold) and into the normal range, but only one showed a reduction in transfusion requirements. Between 4 and 25 weeks after discontinuation of GM-CSF, these six patients were treated with recombinant human IL-3, at doses of 60 or 125 micrograms/m2/d subcutaneously for 4-6 weeks. Three increased their absolute reticulocyte counts from 2- to 28-fold (mean 10.6-fold) and two required fewer transfusions. One of these two patients has remained transfusion independent for over a year since completion of IL-3 therapy, and the second patient required infrequent transfusions for 9 months and then became transfusion independent for the subsequent 5 months. The sustained clinical remissions seen in two of the six patients after IL-3 therapy is very encouraging and further studies in a larger cohort of DBA patients with IL-3 alone or in combination with GM-CSF or other growth factors should be carried out.

Clinical and laboratory evidence for a trilineage haematopoietic defect in patients with refractory Diamond–Blackfan anaemia

“…Of the 28 patients, eight (29%) had initially achieved a complete remission (CR) and had needed neither corticosteroids nor transfusion for 2±6 years until relapse; four (14%) were partial responders with minimal transfusion requirements on steroids who later relapsed; and 16 (57%) had never responded to steroids. Most patients had received other therapies either previously or during the course of this study, including cyclosporine and prednisone (n 10) (Leonard et al, 1989), antithymocyte globulin and/or gamma globulins (n 3), GM-CSF (n 6) or IL-3 (n 22) (Dunbar et al, 1991). These treatments were unsuccessful with the following exceptions: one patient (patient 19) responded to cyclosporine and prednisone and has remained in CR for over 9 years; one patient (patient 6) treated with IL-3 for 1 month at age 7 years remains in a sustained CR, now for more than 7 years; two others (patients 15 and 1) had transient responses to IL-3 for 6 months and 30 months respectively (Dunbar et al, 1991).…”

“…Most patients had received other therapies either previously or during the course of this study, including cyclosporine and prednisone (n 10) (Leonard et al, 1989), antithymocyte globulin and/or gamma globulins (n 3), GM-CSF (n 6) or IL-3 (n 22) (Dunbar et al, 1991). These treatments were unsuccessful with the following exceptions: one patient (patient 19) responded to cyclosporine and prednisone and has remained in CR for over 9 years; one patient (patient 6) treated with IL-3 for 1 month at age 7 years remains in a sustained CR, now for more than 7 years; two others (patients 15 and 1) had transient responses to IL-3 for 6 months and 30 months respectively (Dunbar et al, 1991). Neutrophil counts rose in all patients during GM-CSF or IL-3 therapy, and marrow cellularity increased as a result of myeloid hyperplasia.…”

Two-phase culture in Diamond Blackfan anemia: localization of erythroid defect

“…[1][2][3][4][5] Sustained remissions have occasionally been reported in response to interleukin-3 (IL-3). 6,7 Recently, clinical responses to prolactin or metoclopramide have been described, but only after prolonged administration. 8 Remissions, whether spontaneous or treatment induced, are usually associated with a residual erythropoietic defect shown by persistent mild anemia and macrocytosis, [1][2][3] with increased erythrocyte adenosine deaminase (eADA) activity.…”

Sequential interleukin 3 and granulocyte-macrophage–colony stimulating factor therapy in patients with bone marrow failure with long-term follow-up of responses

“…42 In clinical trials, IL-3 has induced sustained remission in patients with Diamond-Blackfan anemia, 43,44 albeit rarely. This molecule induces only modest hematopoietic effects in a minority of patients with bone marrow failure.…”