Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients.
[en] Treatment with erythropoietin (epo) may improve the anemia of myelodysplastic syndromes (MDS) in approximately 20% of patients. Previous studies have suggested that treatment with the combination of granulocyte colony-stimulating factor (G-CSF) and epo may increase this response rate. In the present phase II study, patients with MDS and anemia were randomized to treatment with G-CSF + epo according to one of two alternatives; arm A starting with G-CSF for 4 weeks followed by the combination for 12 weeks, and arm B starting with epo for 8 weeks followed by the combination for 10 weeks. Fifty evaluable patients (10 refractory anemia [RA], 13 refractory anemia with ring sideroblasts [RARS], and 27 refractory anemia with excess blasts [RAEB]) were included in the study, three were evaluable only for epo as monotherapy and 47 for the combined treatment. The overall response rate to G-CSF + epo was 38%, which is identical to that in our previous study. The response rates for patients with RA, RARS, and RAEB were 20%, 46%, and 37%, respectively. Response rates were identical in the two treatment groups indicating that an initial treatment with G-CSF was not neccessary for a response to the combination. Nine patients in arm B showed a response to the combined treatment, but only three of these responded to epo alone. This suggests a synergistic effect in vivo by G-CSF + epo. A long-term follow-up was made on 71 evaluable patients from both the present and the preceding Scandinavian study on G-CSF + epo. Median survival was 26 months, and the overall risk of leukemic transformation during a median follow-up of 43 months was 28%. Twenty patients entered long-term maintenance treatment and showed a median duration of response of 24 months.The international prognostic scoring system (IPSS) was effective to predict survival, leukemic transformation, and to a lesser extent, duration of response, but had no impact on primary response rates.
Disciplines :
Hematology
Author, co-author :
Hellstrom-Lindberg, E.
Ahlgren, T.
Beguin, Yves ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients.
Publication date :
1998
Journal title :
Blood
ISSN :
0006-4971
eISSN :
1528-0020
Publisher :
American Society of Hematology, Washington, United States - District of Columbia
Greenberg PL: The myelodysplastic syndromes, in Hoffman R, Benz E, Shattil S, Furie B, Cohen H (eds): Hematology: Basic Principles and Practice (ed 2). New York, NY, Churchill Livingstone, 1994, p 1098
Greenberg PL, Cox C, LeBeau M, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079, 1997
Negrin R, Haeuber D, Nagler A, Kobayashi Y, Sklar J, Donlon T, Vincent M, Greenberg P: Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor. Blood 76:36, 1990
Yoshida Y, Hirashima K, Asano S, Takaku F: A phase II trial of recombinant human granulocyte colony-stimulating factor in the myelodysplastic syndromes. Br J Haematol 78:378, 1991
Greenberg P, Taylor K, Larson R, Koeffler P, Negrin R, Saba H, Ganser A, Jakubowski A, Gabrilove J, Mufti G, Cruz J, Hammond W, Broudy V, Langley GR, Keating A, Vardiman J, Lamborn K, Brown S: Phase III randomized multicenter trial of G-CSF vs observation for myelodysplastic syndromes (MDS). Blood 82:196a, 1993 (suppl 1)
Vadhan-Raj S, Keating M, LeMaistre A, Hittelman W, McCredie K, Trujillo J. Broxmeyer H, Henney C and Gutterman J: Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N Engl J Med 317:1545, 1987
Shuster MW. Larson RA, Thompson JA, Coiffier B. Bennett JM, Israel RJ for the Shering-Plough/Sandoz MDS Study Group: Granulocyte-macrophage colony-stimulating factor (GM-CSF) for myelodysplastic syndrome (MDS): Results of a multi-center randomized controlled trial. Blood 76:318a, 1990
Shuster MW, Thompson JA, Larson RA, Dugan et al: Randomized phase II study of recombinant granulocyte-macrophage colony-stimulating factor (RGM-CSF) in patients with neutropenia secondary to myelodysplastic syndrome (MDS). Blood 86:338a, 1995
Bessho M, Jinnai I, Matsuda A, Saito M, Hirashima K: Improvement of anaemia by recombinant eryhtropoietin in patients with myelodysplastic syndromes and aplastic anaemia. Int J Cell Cloning 8:445, 1990
Hellström E, Birgegård G, Lockner D, Wide L, Helmers C, Öst Å: Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Eur J Haematol 47:355, 1991
Rose EH, Abels RI, Nelson RA, McCullough DM, Lessin L: The use of r-HUEpo in the treatment of anaemia related to myelodysplasia (MDS). Br J Haematol 89:831, 1995
Hellström Lindberg E: Efficacy of erythropoietin in the myelodysplastic syndromes. An analysis of 205 patients in 17 studies. Br J Haematol 89:67, 1995
Amano Y, Koike K, Nakahata T: Stem cell factor enhances the growth of primitive erythroid progenitors to a greater extent than interleukin 3 in patients with aplastic anemia. Br J Haematol 85:663, 1993
Backx B, Breeders L, Löwenberg B: Kit ligand improves in vitro erythropoiesis in myelodysplastic syndromes. Blood 80:1213, 1992
Negrin RS, Stein R, Doherty K, Cornwell J, Vardiman J, Krantz S, Greenberg P: Treatment of the anaemia of myelodysplastic syndromes using human granulocyte-CSF in combination with erythropoietin. Blood 82:737, 1993
Hellström-Lindberg E, Birgegård G, Carlsson M, Carneskog J, Dahl IM, Dybedal I, Grimfors G, Merk K, Tangen JM, Winqvist I, Öst Å: A combination of granulocyte-colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes. Leuk Lymphoma 11:221, 1993
Negrin RS, Stein R, Doherty K, Cornwell J, Vardiman J. Krantz S, Greenberg P: Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: Evidence for in vivo synergy. Blood 87:4076, 1996
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR. Sultan C, The French-American-British (FAB) Group: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189, 1982
Wide L, Bengtsson C, Birgegård G: Circadian rythm of human serum erythropoietin. Br J Haematol 51:189, 1989
Beguin Y, Clemons G, Pootrakul P, Fillet G: Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin. Blood 81:1067, 1993
Hellström-Lindberg E, Robèrt KH, Gahrton G, Forsblom AM, Lindberg G, Kock Y, Öst Å: A predictive model for the clinical response to low dose ara-C: A study of 102 patients with myelodysplastic syndromes or acute leukemia. Br J Haematol 81:503, 1992
Miller KB, Kyungman K, Morrison FS, Winter JN, Bennett JM, Neiman RS, Head DR, Cassileth PA. O'Connell MJ: The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: A phase-III intergroup study. Ann Hematol 65:162, 1992
Ganser A, Maurer A, Contzen C, Seipelt G, Ottmann OG, Schadeck-Gressel C, Kolbe K, Haas R, Zander C, Reutzel R, Hoelzer D: Improved multilineage response of hematopoiesis in patients with myelodysplastic syndromes to a combination therapy with all-transretinoic acid, granulocyte colony-stimulating factor, erythropoietin and alpha-tocopherol. Ann Hematol 72:237, 1996
Imamura M, Kobayashi M, Kobayashi S, Yoshida K, Mikuni C, Ishikawa Y, Matsumoto S, Sakamaki S, Niitsu Y, Hinoda Y, Yachi A, Kudoh T, Chiba S, Kasai M, Oka T, Okuno A, Maekawa T, Sakurada K, Miyazaki T: Failure of combination therapy with granulocyte colony-stimulating factor and erythropoietin in myelodysplastic syndromes. Ann Hematol 68:163, 1994
Musto P, Falvone A, Carotenuto M: Granulocyte colony-stimulating factor and erythropoietin for the anemia of myelodysplastic syndromes: A real improvement with respect to EPO alone? Blood 84:1687, 1994
Cazzola M, Mercuriali F, Brugnara C: Use of recombinant human erythropoietin outside the setting of uremia. Blood 89:4248, 1997
Stenke L, Wallvik J, Celsing F, Hast R: Prediction of response to treatment with human recombinant erythropoietin in myelodysplastic syndromes. Leukemia 7:1324, 1993
Hellström-Lindberg E, Negrin R, Stein R, Krantz S, Lindberg G, Vardiman J, Öst Å, Greenberg P: Erythroid response to treatment with G-CSF plus erythropoietin for the anemia of patients with myelodysplastic syndromes: Proposal for a predictive model. Br J Haematol 99:344, 1997
May SJ, Smith SA, Jacobs A, Williams A, Bailey-Wood R: The myelodysplastic syndromes: Analysis of laboratory characteristics in relation to the FAB classifiacation. Br J Haematol 59:311, 1985
Hellström-Lindberg E, Kanter-Lewensohn L, Öst Å: Morphological changes and apoptosis in bone marrow from patients treated with granulocyte-CSF and erythropoietin. Leuk Res 21:415, 1997
Bowen DT, Culligan D, Beguin Y, Kendall R, Willis N: Estimation of effective and total erythropoiesis in myelodysplasia using serum transferrin receptor and erythropoietin concentrations, with automated reticulocyte parameters. Leukemia 8:151, 1994