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

Abstract

BACKGROUNDInterleukin‐3 (IL‐3) and granulocyte‐macrophage–colony stimulating factor (GM‐CSF) have synergistic, hematopoietic growth‐promoting activity in preclinical studies. Because of the paucity of effective therapies for patients with chronic bone marrow failure states, the authors studied the biologic activity of sequential IL‐3/GM‐CSF in such patients.METHODSIL‐3 was given subcutaneously for 5 days (at escalating doses of 0.15 μg/kg, 0.3 μg/kg, 0.6 μg/kg, 1.2 μg/kg, 2.5 μg/kg, 5.0 μg/kg, 10.0 μg/kg, or 15.0 μg/kg per day), and GM‐CSF for was given subcutaneously for 9 days (at a dose of 5 μg/kg per day; Phase I 3 + 3 design) followed by 14 days of rest (total, 2 courses), then maintenance therapy.RESULTSThe majority of 38 evaluable patients had aplastic anemia or myelodysplastic syndrome. Most patients (79%) had neutrophil responses. Ten patients (26%), all of whom were treated with IL‐3 doses ≥ 1.2 μg/kg per day, had platelet responses, with a median increase of 132 × 109/L (range, 41–180 × 109/L) over baseline in responders. Six patients (16%) had trilineage recovery, which could be durable (the longest ongoing at 6.5 years after therapy completion). The most common toxicities were low‐grade fever, headache, and fatigue. The maximum tolerated doses were IL‐3 at 10 μg/kg per day and GM‐CSF at 5 μg/kg per day.CONCLUSIONSSequential IL‐3/GM‐CSF effectively raised blood counts in some patients with bone marrow failure at doses that were tolerated well. These results indicate that early‐acting growth factors can induce durable, multilineage responses in a subset of individuals with bone marrow failure. Cancer 2003. © 2003 American Cancer Society.

Delayed GM‐CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages

“…This may suggest that repetitive administrations and/or higher doses of GM-CSF could have a more pronounced beneficial effect. We chose the 2 g of GM-CSF (8 -10 g/kg) dose because it is close to the subcutaneous doses (5 g/kg) used in humans for agranulocytosis (27)(28) and to intraperitoneal doses used to study hormonal GM-CSF effects in rodents (29). After daily administrations of such doses, adverse effects such as fever, myalgia, malaise, or rash occur in 20 -30% of patients but remain moderate (30), whereas higher doses are often associated with severe adverse effects (30).…”

The incidence and impact of thrombocytopenia in myelodysplastic syndromes

“…54 In 2 additional studies, active bleeding was reported in 18% to 23% of all patients at baseline, irrespective of platelet count. 55,56 In studies of a variety of treatments for MDS, rates of moderate-to-severe hemorrhage of 18%, 57 gastrointestinal hemorrhage of 6% to 7%, 58,59 and intracranial hemorrhage of 3% to 5% 42,60 have been observed. In patients with AML and MDS who were receiving combination salvage chemotherapy, 15% of patients had a mild-to-moderate hemorrhage, and 4% of patients had a severe hemorrhage.…”

How we treat lower-risk myelodysplastic syndromes

“…95,96 Growth factors nonspecific of the platelet lineage, including interleukin (IL)3, IL6, and IL11, have been used with some success, but they also produce side effects. 95,97,98 In exceptional cases, a peripheral mechanism of platelet destruction may predominate in MDS, as evidenced by platelet lifespan studies, with a possible success of splenectomy in our experience. 99 Because TPO itself is immunogenic, leading to thrombocytopenia, TPO receptor agonists including romiplostim and eltrombopag have been designed to treat thrombocytopenias of different origins.…”