A randomized placebo-controlled phase III study of granulocyte- macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490)

Abstract

The treatment of adult patients greater than 55 to 70 years of age with acute myelogenous leukemia (AML) is associated with a treatment-related mortality of approximately 25%. This prospective, double-blind randomized study was designed to see if the use of granulocyte- macrophage colony stimulating factor (GM-CSF; yeast-derived) could shorten the period of neutropenia and to determine any effect this would have on therapy-related morbidity and mortality. A total of 124 patients entered this study. Induction consisted of standard daunorubicin and cytarabine. A day-10 bone marrow was examined; if this was aplastic without leukemia, patients received blinded placebo or GM- CSF from day 11 until neutrophil recovery. Patients who entered complete remission received the identical study medication (blinded GM- CSF or placebo) in consolidation that they had received during induction. The overall complete remission rate was 52%; 60% for the GM- CSF arm and 44% for the placebo arm (P = .08). Median times to neutrophil recovery were significantly shortened on the GM-CSF arm. The overall treatment-related toxicity from start of GM-CSF/placebo was reduced on the GM-CSF arm (P = .049). Similarly, the infectious toxicity was significantly reduced on the GM-CSF arm (P = .015). The median survival for all patients was 10.6 months in the GM-CSF group and 4.8 months in the placebo arm (P = .048). It appears that GM-CSF is safe and efficacious for adult patients greater than 55 to 70 years of age with AML; its major impact is in reducing the duration of neutropenia and therapy-related mortality and morbidity. This may result in a better response rate.

Granulocyte‐macrophage colony‐stimulating factor to increase efficacy of mitoxantrone, etoposide and cytarabine in previously untreated elderly patients with acute myeloid leukaemia: a Swedish multicentre randomized trial

“…We found a small but significant reduction of the time to neutrophil recovery for the GM-CSF-treated patients, which is in accordance with previous studies with GM-CSF (Rowe et al, 1995), as well as granulocyte colony-stimulating factor (G-CSF) (Heil et al, 1997;Bennet et al, 2001) but, even for our growth factor-treated patients, this period was comparably long (median 17 d), despite initiating GM-CSF treatment 1 d before the start of induction treatment. This probably mirrors a weaker proliferative capacity of the normal haematopoietic stem cells in these older patients (Stone et al, 1995;Leith et al, 1997).…”

“…The reason for this might be due to a selection bias as only patients considered fit for intensive treatment were included in our study, which excluded those patients with severe organ dysfunction or concomitant severe diseases. Despite the very high mean age of our patients, the 12% that were long-term survivors in our study is comparable with previously published results of studies using similar treatments in elderly patients (Shepherd et al, 1993;Rowe et al, 1995;Andersson et al, 2002). An interesting finding was that patients older than the median age of 77 years did not have a worse outcome than the younger patients, nor did the older patients have a significantly higher treatment-related mortality.…”

“…Finally, only 12% of the patients died within the first 30 d. This is a lower number of toxic deaths than reported in other studies that treated elderly patients 5-10 years younger than the patients in our study (Rowe et al, 1995;Stone et al, 1995;Kalaycio & Andresen, 2001). The reason for this might be due to a selection bias as only patients considered fit for intensive treatment were included in our study, which excluded those patients with severe organ dysfunction or concomitant severe diseases.…”

Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte‐macrophage–colony stimulating factor (GM‐CSF) alternating with methotrexate and cytarabine plus rituximab and GM‐CSF in patients with Richter syndrome or fludarabine‐refractory chronic lymphocytic leukemia

“…49,50 GM-CSF has been approved in the U.S. as an adjunct therapy to improve the survival of elderly patients undergoing induction therapy for acute myeloid leukemia: The supportive data for this indication were based on an Eastern Cooperative Oncology Group randomized, double-blind, placebocontrolled study in which the apparent main benefit in patients who received GM-CSF was a reduction in overall and lethal, systemic fungal infections. 51 This survival benefit has not been confirmed in other studies of this issue. 52,53 In this study, Grade 4 neutropenia occurred in all cycles of therapy, and only eight pa-tients (16%) received the full six cycles of therapy intended on protocol.…”

Modulation of antitumor immune responses by hematopoietic cytokines

“…78 By contrast, in an earlier report of a trial in patients with AML, chemotherapy followed by consolidation treatment that included GM-CSF resulted in improved remission rates, fewer treatment-related toxicities, and improved survival. 79…”