Effects of glycosylated recombinant human granulocyte colony-stimulating factor after high-dose cytarabine-based induction chemotherapy for adult acute myeloid leukaemia

Abstract

The Australian Leukaemia Study Group (ALSG) investigated whether G-CSF would accelerate haemopoietic recovery after induction treatment for acute myeloid leukaemia (AML) intensified with high-dose cytarabine, and therefore improve response rates and survival. Patients were randomised to receive lenograstim (glycosylated recombinant human G-CSF) 5 g per kg body weight subcutaneously daily from day 8 after starting chemotherapy, or no cytokine, following chemotherapy with cytarabine 3 g/m 2 every 12 h on days 1, 3, 5, and 7, together with idarubicin 9 or 12 mg/m 2 on days 1, 2, and 3, plus etoposide 75 mg/m 2 on days 1 to 7 inclusive. Patients had untreated AML, and were aged 16 to 60 years. Overall, 54 evaluable patients were randomised to receive lenograstim and 58 to no cytokine. Patients in the lenograstim arm had a significantly shorter duration of neutropenia Ͻ0.5 × 10 9 /l compared to patients in the no cytokine arm (median 18 vs 22 days; P = 0.0005), and also shorter duration of total leucopenia Ͻ1.0 × 10 9 /l (17 vs 19 days; P = 0.0002), as well as a reduction in duration of treatment with therapeutic intravenous antibiotics (20 vs 24 days; P = 0.015) and a trend to reduced number of days with fever Ͼ38.0°C (9 vs 12 days; P = 0.18). There were no differences between the two groups in platelet recovery, red cell or platelet transfusions, or non-haematological toxicities. For patients achieving CR after their first induction course, a reduction in the time to the start of the next course of therapy was observed in the lenograstim arm, from a median of 40.5 days to a median of 36 days (P = 0.082). The overall complete response rates to chemotherapy were similar, 81% in the lenograstim arm vs 75% for the no cytokine arm (P = 0.5), and there was no significant difference in the survival durations. We conclude that the granulopoietic stimulating effect of G-CSF is observed after induction therapy for AML intensified by highdose cytarabine, resulting in an improvement in a number of clinically important parameters with no major adverse effects. Leukemia (2001Leukemia ( ) 15, 1331Leukemia ( -1338

Role of cytokines in the treatment of acute leukemias: a review

“…For example, in a study by the Australian Leukemia Study Group (ALSG), glycosylated G-CSF was administered after the completion of high-dose cytarabine-containing chemotherapy, and a reduction in the duration of neutropenia of 4 days (P ¼ 0.0005) in patients who received the cytokine was reported. 17 This is of a similar magnitude to other studies employing standard-dose cytarabine. [12][13][14][15][16]21,23 Other problems with the direct comparison of these studies include the frequency of monitoring of the blood counts in the different studies, different age ranges of the study populations (Table 1), lack of uniformity in time of initiation and duration of growth factor support, differing outcome of the placebo groups, Abbreviations: CSF, colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF: granulocyte colony-stimulating factor; A, after chemotherapy; B, before chemotherapy; D, during chemotherapy.…”

“…[12][13][14][15][16][17][18][19][20][21] Owing to the lack of comparative trials, there are no indications that one cytokine may be superior to the other in this regard. Similarly, the theoretical concern of an adverse effect on platelet recovery does not appear to be relevant.…”

“…3 Such limited shortening of the duration of neutropenia has not been accompanied by a reduction in the incidence of documented, severe and fatal infections. 12,15,20 Furthermore, in the majority of these studies, the complete remission (CR) rate, 12,[15][16][17][18][19] disease-free survival (DFS), [15][16][17][18]20 and overall survival (OS) 12,[14][15][16][17][18] are not affected by growth factor therapy. Some of these studies have demonstrated an increase in the CR rate, 13,14 and even the OS, when using growth factor therapy.…”

“…15,17,18,20 An analysis of the study from Southwest Oncology Group (SWOG) did not demonstrate a reduction in the overall cost of supportive care despite the beneficial effect of G-CSF on the duration of neutropenia and infections. 15,25 However, according to a report from the study by the Eastern Co-operative Oncology Group (ECOG), the use of GM-CSF was associated with cost savings in addition to a survival benefit and a reduction in duration of neutropenia and severity of infections.…”

A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia

“…Despite reported high complete remission (CR) rates and improvements in LFS with highdose cytarabine (HiDAC) in induction chemotherapy, these regimens have been associated with substantial rates of severe gastrointestinal toxicity, increasing the risk of early death, limiting its applicability to younger patients and negating the potential long-term OS benefit of increased dose intensity of chemotherapy (van der Jagt et al, 2012). In the AML M7 clinical trial conducted by the Australasian Leukaemia and Lymphoma Group (ALLG), which used cytarabine 3 g/m 2 twice daily on days 1, 3, 5 and 7, idarubicin 9 or 12 mg/m 2 /d on days 1-3 and etoposide 75 mg/m 2 /d on days 1-7, the incidences of grades 3 and 4 oral mucositis were 21% and 24%, grades 3 and 4 diarrhoea 30% and 38%, and World Health Organization (WHO) gastrointestinal toxicity grades 3 and 4 were 7% and 14%, for patients randomized to receive recombinant granulocyte colony-stimulating factor (G-CSF; lenograstim) or placebo, respectively (Bradstock et al, 2001(Bradstock et al, , 2005. Recombinant human keratinocyte growth factor (KGF; palifermin) is a truncated recombinant protein with biological activity similar to the native molecule, a member of the fibroblast growth factor family with keratinocyte growth stimulatory properties (Rubin et al, 1989).…”