Treatment of Diamond-Blackfan anemia with recombinant human interleukin- 3 [see comments]

Abstract

This report describes the response of eighteen Diamond-Blackfan anemia (DBA) patients to recombinant human interleukin-3 (rhIL-3). rhIL-3 was administered subcutaneously once daily on an escalating dose schedule (0.5 to 10 micrograms/kg/d). The rhIL-3 dose was escalated every 21 days until erythroid response was attained, grade III or IV nonhematologic toxicity was observed, or the maximum rhIL-3 dose was reached. Four patients experienced clinically significant erythroid responses. Two of the responders were steroid-dependent and transfusion- independent, while two were steroid-independent and transfusion- dependent. Baseline clinical or laboratory parameters, in particular in vitro bone marrow erythroid progenitor assays, were not useful in predicting rhIL-3 response. rhIL-3 administered at 5 to 10 micrograms/kg/d was associated with an increase in total white blood cell count, secondary to increases in neutrophils, eosinophils, and lymphocytes. Patients experienced a dose-dependent elevation in absolute eosinophils across the entire dose range. Two of the responding patients remain on maintenance rhIL-3, without diminution of effect at 244 and 370 + days. rhIL-3 was discontinued in the other two responders, because of the development of deep venous thrombi.

Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference

“…These drugs appear to be largely ineffective and there is currently no evidence that any of these has a major role in the management of DBA (Geller et al, 1975;Dunbar et al, 1991;Fiorillo et al, 1991;Niemeyer et al, 1991;Gomez-Almaguer & Gonzalez-Llano, 1992;Sumimoto et al, 1992;Bejaoui et al, 1993;Gillio et al, 1993aGillio et al, , 1993bBastion et al, 1994;Brown et al, 1994;Olivieri et al, 1994;Ozsoylu, 1994;Ball et al, 1995;Bernini et al, 1995;Buchanan, 2001;Alter, 2003). Specific patients may respond to cyclosporine (Fiorillo et al, 1991;Niemeyer et al, 1991) Interleukin-3 100 10% (Dunbar et al, 1991;Gillio et al, 1993aGillio et al, , 1993bBastion et al, 1994;Olivieri et al, 1994;Ball et al, 1995) Cyclosporine ± prednisone 20 (with steroids) 10 (CSA alone) 50% all transient 2 sustained response (Totterman et al, 1984;Williams et al, 1987;Seip & Zanussi, 1988;Leonard et al, 1989;Splain & Berman, 1992;Monteserin et al, 1993;Alessandri et al, 2000;Bobey et al, 2003) Largely ineffective (Geller et al, 1975;Sumimoto et al, 1992;Bejaoui et al, 1993;Brown et al, 1994) and anectodal communications *Data taken from Alter (2003). ATG, antithymocyte globulin; PIXY...…”

Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference

“…These drugs appear to be largely ineffective and there is currently no evidence that any of these has a major role in the management of DBA (Geller et al, 1975;Dunbar et al, 1991;Fiorillo et al, 1991;Niemeyer et al, 1991;Gomez-Almaguer & Gonzalez-Llano, 1992;Sumimoto et al, 1992;Bejaoui et al, 1993;Gillio et al, 1993aGillio et al, , 1993bBastion et al, 1994;Brown et al, 1994;Olivieri et al, 1994;Ozsoylu, 1994;Ball et al, 1995;Bernini et al, 1995;Buchanan, 2001;Alter, 2003). Specific patients may respond to cyclosporine (Fiorillo et al, 1991;Niemeyer et al, 1991) Interleukin-3 100 10% (Dunbar et al, 1991;Gillio et al, 1993aGillio et al, , 1993bBastion et al, 1994;Olivieri et al, 1994;Ball et al, 1995) Cyclosporine ± prednisone 20 (with steroids) 10 (CSA alone) 50% all transient 2 sustained response (Totterman et al, 1984;Williams et al, 1987;Seip & Zanussi, 1988;Leonard et al, 1989;Splain & Berman, 1992;Monteserin et al, 1993;Alessandri et al, 2000;Bobey et al, 2003) Largely ineffective (Geller et al, 1975;Sumimoto et al, 1992;Bejaoui et al, 1993;Brown et al, 1994) and anectodal communications *Data taken from Alter (2003). ATG, antithymocyte globulin; PIXY...…”

How I manage children with Diamond‐Blackfan anaemia

“…As metoclopramide has no serious side effects, it can be considered in patients that are refractory to low doses of GC. Treatment with recombinant Interleukin 3 (IL3), a stimulator of erythropoiesis at the stem cell level, has been studied very extensively in DBA in the past, but was eventually discarded due to conflicting results and undesired side effects, such as deep venous thrombosis and hypereosinophilia (Gillio et al, 1993;Olivieri et al, 1994;Ball et al, 1995).…”

Progress towards Mechanism-Based Treatment for Diamond-Blackfan Anemia

“…Clinical trials evaluating IL-3 as a DBA therapy demonstrated good response in some patients [ 54 – 57 ]. While it was relatively well tolerated in the majority of patients, one study reported cases of deep venous thrombosis [ 56 ]. A recent consensus conference concluded that the number of patients responding to IL-3 treatment remains too small to consider it a satisfactory option for first-line treatment [ 4 ].…”

Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference

“…These drugs appear to be largely ineffective and there is currently no evidence that any of these has a major role in the management of DBA (Geller et al, 1975;Dunbar et al, 1991;Fiorillo et al, 1991;Niemeyer et al, 1991;Gomez-Almaguer & Gonzalez-Llano, 1992;Sumimoto et al, 1992;Bejaoui et al, 1993;Gillio et al, 1993aGillio et al, , 1993bBastion et al, 1994;Brown et al, 1994;Olivieri et al, 1994;Ozsoylu, 1994;Ball et al, 1995;Bernini et al, 1995;Buchanan, 2001;Alter, 2003). Specific patients may respond to cyclosporine (Fiorillo et al, 1991;Niemeyer et al, 1991) Interleukin-3 100 10% (Dunbar et al, 1991;Gillio et al, 1993aGillio et al, , 1993bBastion et al, 1994;Olivieri et al, 1994;Ball et al, 1995) Cyclosporine ± prednisone 20 (with steroids) 10 (CSA alone) 50% all transient 2 sustained response (Totterman et al, 1984;Williams et al, 1987;Seip & Zanussi, 1988;Leonard et al, 1989;Splain & Berman, 1992;Monteserin et al, 1993;Alessandri et al, 2000;Bobey et al, 2003) Largely ineffective (Geller et al, 1975;Sumimoto et al, 1992;Bejaoui et al, 1993;Brown et al, 1994) and anectodal communications *Data taken from Alter (2003). ATG, antithymocyte globulin; PIXY...…”

How I manage children with Diamond‐Blackfan anaemia

“…As metoclopramide has no serious side effects, it can be considered in patients that are refractory to low doses of GC. Treatment with recombinant Interleukin 3 (IL3), a stimulator of erythropoiesis at the stem cell level, has been studied very extensively in DBA in the past, but was eventually discarded due to conflicting results and undesired side effects, such as deep venous thrombosis and hypereosinophilia (Gillio et al, 1993;Olivieri et al, 1994;Ball et al, 1995).…”

Progress towards Mechanism-Based Treatment for Diamond-Blackfan Anemia

“…Clinical trials evaluating IL-3 as a DBA therapy demonstrated good response in some patients [ 54 – 57 ]. While it was relatively well tolerated in the majority of patients, one study reported cases of deep venous thrombosis [ 56 ]. A recent consensus conference concluded that the number of patients responding to IL-3 treatment remains too small to consider it a satisfactory option for first-line treatment [ 4 ].…”

Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference

“…These drugs appear to be largely ineffective and there is currently no evidence that any of these has a major role in the management of DBA (Geller et al, 1975;Dunbar et al, 1991;Fiorillo et al, 1991;Niemeyer et al, 1991;Gomez-Almaguer & Gonzalez-Llano, 1992;Sumimoto et al, 1992;Bejaoui et al, 1993;Gillio et al, 1993aGillio et al, , 1993bBastion et al, 1994;Brown et al, 1994;Olivieri et al, 1994;Ozsoylu, 1994;Ball et al, 1995;Bernini et al, 1995;Buchanan, 2001;Alter, 2003). Specific patients may respond to cyclosporine (Fiorillo et al, 1991;Niemeyer et al, 1991) Interleukin-3 100 10% (Dunbar et al, 1991;Gillio et al, 1993aGillio et al, , 1993bBastion et al, 1994;Olivieri et al, 1994;Ball et al, 1995) Cyclosporine ± prednisone 20 (with steroids) 10 (CSA alone) 50% all transient 2 sustained response (Totterman et al, 1984;Williams et al, 1987;Seip & Zanussi, 1988;Leonard et al, 1989;Splain & Berman, 1992;Monteserin et al, 1993;Alessandri et al, 2000;Bobey et al, 2003) Largely ineffective (Geller et al, 1975;Sumimoto et al, 1992;Bejaoui et al, 1993;Brown et al, 1994) and anectodal communications *Data taken from Alter (2003). ATG, antithymocyte globulin; PIXY...…”

How I manage children with Diamond‐Blackfan anaemia

“…As metoclopramide has no serious side effects, it can be considered in patients that are refractory to low doses of GC. Treatment with recombinant Interleukin 3 (IL3), a stimulator of erythropoiesis at the stem cell level, has been studied very extensively in DBA in the past, but was eventually discarded due to conflicting results and undesired side effects, such as deep venous thrombosis and hypereosinophilia (Gillio et al, 1993;Olivieri et al, 1994;Ball et al, 1995).…”

Progress towards Mechanism-Based Treatment for Diamond-Blackfan Anemia

“…Clinical trials evaluating IL-3 as a DBA therapy demonstrated good response in some patients [ 54 – 57 ]. While it was relatively well tolerated in the majority of patients, one study reported cases of deep venous thrombosis [ 56 ]. A recent consensus conference concluded that the number of patients responding to IL-3 treatment remains too small to consider it a satisfactory option for first-line treatment [ 4 ].…”