Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours

Abstract

Summary Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression.Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 fig/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed.Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x ), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhlL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin, etoposide and ifosfamide. Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 pg/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated.In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent.

Clinical Toxicity of Cytokines Used As Haemopoietic Growth Factors

“…Mild to severe skin rash or urticaria were also sometimes observed, [178,179,[180][181][182][183][184][185][186] but responded to corticosteroid and systemic antihistamine drugs.l I 84] Although in vitro and in vivo studies have shown that IL-3 increased histamine release and enhanced the formation of basophils and eosinophils, the mechanism of IL-3-induced urticaria is not well understood. Indeed, no clear relationship between histamine level, eosinophil and basophil counts has been established in patients with cutaneous reactions.l178,183-1851 In addition, recurrence after IL-3 readministration is not always observed.…”

“…IL-3 stimulates the proliferation and differentiation of multi potent haemopoietic stem cells and committed progenitor cells of the granulocyte, macrophage, eosinophil, basophil, erythroid, megakaryocyte and mast celllineages.lI69-17IJ Increases in bone marrow cellularity and peripheral multilineage haemopoietic effects following IL-3 administration have been confirmed in early clinical trialsl172-176J and in healthy volunteers.l 177J IL-3 used in humans is produced by recombinant DNA technology using yeast or E. coli systems and is currently under clinical investigation, with dosages usually ranging from 0.5 to 15 Ilg/kg/day via subcutaneous injection. Several phase 1111 trials have been performed, primarily in patients with chemotherapy-induced myeIotoxicity, [178][179][180][181][182][183][184] myelodysplastic syndrome or aplastic anaemia,l173-175, 185, 186J c Five patients also chose to discontinue therapy because of uncomfortable fever and chills. Diamond-Blackfan anaemia [187,188] and in the setting of autologous bone marrow transplantation [189] or peripheral stem cell harvesting.l 1691…”

Interleukin-3

“…Subcutaneous interleukin-3 (5 )lg/kg/day for 10 days) also reduced the duration of neutropenia and thrombocytopenia following high-dose chemotherapy with carboplatin (800 mg/m 2 ) in 15 patients with recurrent ovarian cancer compared with untreated control cycles (table III). [97] The mean duration of grade IV neutropenia ($; 0.5 x 10 9 neutrophils/L) was 3 versus 9 days, © Adis International Limited. All rights reserved.…”

“…Dercksen et al [97] Gerhartz et al [98] Gianni et al [65] Recurrent ovarian cancer (15) Extensively pretreated resistant aggressive lymphomas (25) Previously untreated breast cancer (22) High-dose carboplatin stay. rGM-CSF and rG-CSF have been the most extensively investigated factors in clinical trials to date.l 88 ,89] While both factors shorten the duration and severity of neutropenia, they do not affect thrombocytopenia, which may subsequently become dose-limiting.…”

“…These were generally mild and resolved at the end of treatment. There have been isolated reports of ur-ticariaP6] hypotension, paraesthesias and deep vein thrombosis [97,130] during interleukin-3 therapy, and thrombocytopenia, which resolved upon cessation of therapy, developed in 2 of 9 patients with myelodysplastic syndromesJl18]…”