Effect of Priming with Granulocyte Colony-Stimulating Factor on the Outcome of Chemotherapy for Acute Myeloid Leukemia
Bob Löwenberg, M.D., Wim van Putten, M.Sc., Matthias Theobald, M.D., Jurg Gmür, M.D., Leo Verdonck, M.D., Pieter Sonneveld, M.D., Martin Fey, M.D., Harry Schouten, M.D., Georgine de Greef, M.D., Augustin Ferrant, M.D., Tibor Kovacsovics, M.D., Alois Gratwohl, M.D., Simon Daenen, M.D., Peter Huijgens, M.D., Marc Boogaerts, M.D., for the Dutch–Belgian Hemato-Oncology (HOVON) Cooperative Group and the Swiss Group for Clinical Cancer Research
Background Sensitization of leukemic cells with hematopoieticgrowth factors may enhance the cytotoxicity of chemotherapyin acute myeloid leukemia (AML).
Methods In a multicenter randomized trial, we assigned patients(age range, 18 to 60 years) with newly diagnosed AML to receivecytarabine plus idarubicin (cycle 1) and cytarabine plus amsacrin(cycle 2) with granulocyte colony-stimulating factor (G-CSF)(321 patients) or without G-CSF (319). G-CSF was given concurrentlywith chemotherapy only. Idarubicin and amsacrin were given atthe end of a cycle to allow the cell-cycle-dependent cytotoxicityof cytarabine in the context of G-CSF to have a greater effect.The effect of G-CSF on disease-free survival was assessed inall patients and in cytogenetically distinct prognostic subgroups.
Results After induction chemotherapy, the rates of responsewere not significantly different in the two groups. After amedian follow-up of 55 months, patients in complete remissionafter induction chemotherapy plus G-CSF had a higher rate ofdisease-free survival than patients who did not receive G-CSF(42 percent vs. 33 percent at four years, P=0.02), owing toa reduced probability of relapse (relative risk, 0.77; 95 percentconfidence interval, 0.61 to 0.99; P=0.04). G-CSF did not significantlyimprove overall survival (P=0.16). Although G-CSF did not improvethe outcome in the subgroup with an unfavorable prognosis, the72 percent of patients with standard-risk AML benefited fromG-CSF therapy (overall survival at four years, 45 percent, ascompared with 35 percent in the group that did not receive G-CSF[relative risk of death, 0.75; 95 percent confidence interval,0.59 to 0.95; P=0.02]; disease-free survival, 45 percent vs.33 percent [relative risk, 0.70]; 95 percent confidence interval,0.55 to 0.90; P=0.006).
Conclusions Sensitization of leukemic cells with growth factorsis a clinically applicable means of enhancing the efficacy ofchemotherapy in patients with AML.
Source Information
From the Department of Hematology (B.L., P.S., G.G.) and the HOVON Data Center and Department of Statistics (W.P.), Erasmus University Medical Center, Rotterdam, the Netherlands; the Department of Hematology and Oncology, Johannes Gutenberg–University Hospital, Mainz, Germany (M.T.); Onkozentrum, Hirslanden Klinik Im Park, Zurich, Switzerland (J.G.); the Department of Hematology, University Medical Center, Utrecht, the Netherlands (L.V.); the Institute of Medical Oncology, University and Inselspital, Berne, Switzerland (M.F.); the Department of Internal Oncology and Hematology, University Hospital, Maastricht, the Netherlands (H.S.); the Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium (A.F.); the Division of Hematology, University Hospital, Lausanne, Switzerland (T.K.); the Division of Hematology, Kantonsspital, Basel, Switzerland (A.G.); the Department of Hematology, University Hospital, Groningen, the Netherlands (S.D.); the Department of Hematology, Free University Medical Center, Amsterdam (P.H.); and the Department of Hematology, Hospital Gasthuisberg, Leuven, Belgium (M.B.).
Address reprint requests to Dr. Löwenberg at Erasmus University Medical Center, Department of Hematology, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands, or at b.lowenberg{at}erasmusmc.nl.
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