A randomized study of granulocyte colony-stimulating factor applied during and after chemotherapy in patients with poor risk myelodysplastic syndromes: a report from the HOVON Cooperative Group

Abstract

The purpose of this study was to determine the safety and efficacy of filgrastim as an adjunct to induction and consolidation chemotherapy in poor risk patients with myelodysplastic syndrome (MDS). Filgrastim was given both during and after chemotherapy with the objective to accelerate hematopoietic repopulation and enhance the efficacy of chemotherapy. In a prospective randomized multicentre phase II trial, a total of 64 patients with poor risk primary MDS were randomized to receive either granulocyte colony-stimulating factor (G-CSF, filgrastim, AMGEN, Breda, The Netherlands) 5 g/kg/day subcutaneously or no G-CSF in addition to daunomycin (30 mg/m 2 /days 1, 2 and 3 intravenous bolus) and cytarabine (200 mg/m 2 days 1-7, continuous infusion). The overall complete response rate was 63%: 73% for patients receiving filgrastim as compared to 52% in the standard arm (P = 0.08). Overall survival at 2 years was estimated at 29% for patients assigned to the filgrastim arm and 16% for control patients (P = 0.22). The median time for recovery of granulocytes towards 1.0 × 10 9 /l post-chemotherapy was 23 days in the filgrastim-treated patients vs 35 days in the standard arm (P = 0.015). There were no differences in time of platelet recovery, length of hospital stay, duration of antibiotic use or infectious complications between the two treatment groups. However the earlier recovery of neutrophils in the filgrastim group was associated with a reduced interval of 9 days between the induction and consolidation cycle. In patients with poor risk MDS the use of filgrastim during and after induction therapy results in a significantly reduced neutrophil recovery time. Further study may be warranted to see if the apparent trend of the improved response to chemotherapy in combination with filgrastim can be confirmed in greater number of patients and to assess the effect of the addition of filgrastim on survival.

Granulocyte–macrophage colony-stimulating factor (GM-CSF) priming with successive concomitant low-dose Ara-C for elderly patients with secondary/refractory acute myeloid leukemia or advanced myelodysplastic syndrome

“…In this setting they have been associated with trends toward improved response rates and survival which were not statistically significant. 17,25 There is less published experience with growth factor priming before and during attenuated dosing regimens for AML or MDS. Furthermore, compared with lowdose cytarabine, intensive chemotherapy does not prolong survival in elderly AML patients due to an increased early death rate.…”

“…Response criteria were similar to those of other investigators. 17,20 Complete response (CR) was defined as achievement of all the following: reduction of bone marrow blasts and peripheral blasts to less than 5% and 1%, respectively; sustained neutrophil count Ͼ1000/mm 3 for at least 4 weeks; sustained platelet count Ͼ100 000/mm 3 for at least 4 weeks; reduction by Ͼ50% of red blood cell (RBC) transfusion requirements over a period of 4 weeks. Partial response (PR) was defined as achievement of any one of the following: a sustained (4 weeks) increase of neutrophils of at least 100% or more than 1000/mm 3 in patients with pretreatment ANC of less than 1000/mm 3 , a sustained increase in platelet count of at least 100% or more than 50 000/mm 3 in patients with pretreatment platelet count of less than 100 000/mm 3 , or a reduction of the bone marrow blasts by 50%.…”

“…15,16 Complete response (CR) rates and diseasefree survival (DFS) rates have increased in some studies using growth factor priming. 5,15,17 However, no trials have shown improved overall survival with growth factor priming for intensive induction chemotherapy. Much less is known about the utility of priming strategies when used with low-dose regimens, which may best suit elderly, high-risk patients.…”

Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine

“…1 To optimize results of standard chemotherapy, the use of G-CSF or GM-CSF concurrently with induction chemotherapy has been studied in several randomized trials. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] The primary intent of these studies has been to sensitize the leukemic cells to the cytotoxic effects of the chemotherapeutic agents. 16 In vitro studies with AML cells had demonstrated that priming with granulocytic hematopoietic growth factors, such as GM-CSF, G-CSF, and IL-3, may critically modulate cell cycle kinetics of AML blasts and render them more susceptible to the cytotoxicity of chemotherapy, especially of the cell cycle specific compound cytarabine.…”

“…17,18 A number of studies have addressed this concept in AML patients. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] All these reports show that stimulation of leukemia or prolonged cytopenias resulting from sensitization of normal progenitor cells do not appear as major problems.…”