A PILOT-STUDY OF CONTINUOUS-INFUSION ARA-C IN COMBINATION WITH RHG-CSF IN RELAPSED CHILDHOOD ACUTE MYELOID-LEUKEMIA

Relapse in acute myeloid leukemia (AML) following intensive chemothera py bears a bad prognosis. We treated 18 children with relapsed AML on two separate protocols that included continuous infusion (CI) of cytos ine arabinoside (ara-C) (total dose 4gr-6gr/m(2)) over 96-120 hours. I n an attempt to increase the fraction of blasts in S-phase and render them more sensitive to cell-cycle specific agents such as ara-C, 10 pa tients received 5mcg/kg rhG-CSF twice daily beginning 48 hours before and continuing through the duration of the CI ara-C (FOG #9192 study). The percentage of cells is S phase before and after G-CSF administrat ion was determined. In a second group of patients (n = 8) who received ara-C alone, endogenous concentrations of G-CSF and serial blood coun ts were measured (St Jude's R4 study), The rationale of the St Jude's R4 was to optimize the schedule of the second course of ara-C at a tim e when the patient's endogenous C-CSF concentration was increased and thus maximize the percent of cells captured in S phase. Four out of 8 patients receiving CI ara-C alone and 4 out of 10 patients receiving C I ara-C with rhG-CSF achieved a complete remission (CR) after 1 cycle of therapy. Four patients in CR underwent marrow transplantation ( all ogeneic and 2 autologous). Cell cycle analysis of blast cells cultured in vitro with or without G-CSF showed a two fold increase in the perc entage of cells in S phase (P = 0.03) whereas cells obtained from pati ents before and after G-CSF administration showed no difference in cel l cycling. Correlation between G-CSF concentrations and ANC showed a n egative association indicating that the regulatory mechanisms for G-CS F production remained intact. In our relatively small series, CI ara-C achieved a CR rate of 44% with rhG-CSF having no effect on the remiss ion rate, Although in vitro rhG-CSF increased the percentage of blasts in S phase significantly, in vivo effects were not observed, Larger s tudies with combinations sf different hematopoietic growth factors and cell-cycle active drugs are needed to evaluate the role of these cyto kines in the therapy of recurrent AML.