Correspondence

Priming with Granulocyte Colony-Stimulating Factor — Relation to High-Dose Cytarabine in Acute Myeloid Leukemia

N Engl J Med 2004; 350:2215-2216May 20, 2004

Article

To the Editor:

Granulocyte colony-stimulating factor (G-CSF) given concurrently with chemotherapy was recently shown to improve disease-free and overall survival in patients 18 to 60 years of age who had acute myeloid leukemia (AML) and who were considered to be in a “standard risk” prognostic category.1 This finding raised questions about whether similar effects would be found in other subgroups and with combination regimens including high-dose cytarabine.1

We therefore present data on 895 patients 16 to 83 years of age who had AML and who entered a multicenter trial between June 1999 and October 2003. The median observation time was 22 months. At entry, the patients were randomly assigned either to no G-CSF or to 150 μg of G-CSF per square meter of body-surface area per day, starting two days before each chemotherapy course and continuing until its last day. G-CSF was combined in this way in both induction courses, in the consolidation course, and in monthly maintenance courses during the first year. Induction chemotherapy was randomly assigned and consisted either of standard-dose thioguanine, cytarabine, and daunorubicin (TAD) followed by high-dose cytarabine (six doses of 3 g per square meter in patients 16 to 60 years old and 1 g per square meter in patients older than 60 years) and standard-dose mitoxantrone (HAM) or two courses of HAM. Consolidation consisted of one course of TAD, and maintenance consisted of monthly reduced courses of TAD, as in a previous trial.2 Half the younger patients were randomly assigned to high-dose chemotherapy and autologous stem-cell transplantation instead of maintenance therapy. Each randomization was balanced.

Figure 1Figure 1Cumulative Rates of Overall Survival and of Disease-free Survival among Patients with Acute Myeloid Leukemia, According to Age. shows the cumulative rates of overall survival and disease-free survival according to randomization to G-CSF or no G-CSF in the two age groups. In none of the more favorable or less favorable subgroups, as defined by cytogenetic characteristics,1,3,4 initial serum lactate dehydrogenase level, and percentage of bone marrow blasts on day 16 of therapy,2 was there a significant difference between the patients assigned to G-CSF and those assigned to no G-CSF in overall or disease-free survival. The same was true of the 685 patients with spontaneous AML and the 204 patients with AML due to cytotoxic treatment or myelodysplasia; of the patients who received one or two induction courses with cytarabine (3 g or 1 g per square meter); and of those who received maintenance therapy or autologous transplantation.

It will take another two years of observation time to confirm the results of the present trial. For the time being, physicians should be cautious in expecting benefits from priming with G-CSF in patients other than the subpopulation considered by Löwenberg et al.1

Thomas Büchner, M.D.
Wolfgang E. Berdel, M.D.
University of Münster, 48129 Münster, Germany

Wolfgang Hiddemann, M.D.
University of Munich, 81377 Munich, Germany

4 References

1. 1

   Lowenberg B, van Putten W, Theobald M, et al. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 2003;349:743-752
   Full Text | Web of Science | Medline

2. 2

   Buchner T, Hiddemann W, Berdel WE, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD versus TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol 2003;21:4496-4504
   CrossRef | Web of Science | Medline

3. 3

   Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 1998;58:4173-4179
   Web of Science | Medline

4. 4

   Burnett AK, Goldstone AH, Stevens RM, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet 1998;351:700-708
   CrossRef | Web of Science | Medline

Citing Articles (10)

Citing Articles

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   Todd L. Rosenblat, Joseph G. Jurcic. (2011) Induction and Postremission Strategies in Acute Myeloid Leukemia: State of the Art and Future Directions. Hematology/Oncology Clinics of North America 25:6, 1189-1213
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   Ronit Gurion, Yulia Belnik-Plitman, Anat Gafter-Gvili, Mical Paul, Liat Vidal, Isaac Ben-Bassat, Ofer Shpilberg, Pia Raanani, Pia Raanani. 2011. Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia. .
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   Michael Heuser, Antonia Zapf, Michael Morgan, Jürgen Krauter, Arnold Ganser. (2011) Myeloid growth factors in acute myeloid leukemia: systematic review of randomized controlled trials. Annals of Hematology 90:3, 273-281
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   Daniel A. Pollyea, Holbrook E. Kohrt, Bruno C. Medeiros. (2011) Acute myeloid leukaemia in the elderly: a review. British Journal of Haematology 152:5, 524-542
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   Yoriko Saito, Naoyuki Uchida, Satoshi Tanaka, Nahoko Suzuki, Mariko Tomizawa-Murasawa, Akiko Sone, Yuho Najima, Shinsuke Takagi, Yuki Aoki, Atsushi Wake, Shuichi Taniguchi, Leonard D Shultz, Fumihiko Ishikawa. (2010) Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nature Biotechnology
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   H. Dohner, E. H. Estey, S. Amadori, F. R. Appelbaum, T. Buchner, A. K. Burnett, H. Dombret, P. Fenaux, D. Grimwade, R. A. Larson, F. Lo-Coco, T. Naoe, D. Niederwieser, G. J. Ossenkoppele, M. A. Sanz, J. Sierra, M. S. Tallman, B. Lowenberg, C. D. Bloomfield. (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115:3, 453-474
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7. 7

   Oliver G. Ottmann, Gesine Bug, Jürgen Krauter. (2007) Current Status of Growth Factors in the Treatment of Acute Myeloid and Lymphoblastic Leukemia. Seminars in Hematology 44:3, 183-192
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8. 8

   F Ravandi. (2006) Role of cytokines in the treatment of acute leukemias: a review. Leukemia 20:4, 563-571
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10. 10

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