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[Cancer Research 58, 4173-4179, September 15, 1998]
© 1998 American Association for Cancer Research

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Frequency of Prolonged Remission Duration after High-Dose Cytarabine Intensification in Acute Myeloid Leukemia Varies by Cytogenetic Subtype1

Clara D. Bloomfield, David Lawrence, John C. Byrd2, Andrew Carroll, Mark J. Pettenati, Ramana Tantravahi, Shivanand R. Patil, Frederick R. Davey, Deborah T. Berg, Charles A. Schiffer, Diane C. Arthur and Robert J. Mayer

The Ohio State University, Columbus, Ohio 43210 [C. D. B.]; Roswell Park Cancer Institute, Buffalo, New York 14263 [D. L.]; Walter Reed Army Medical Center, Washington, D.C. 20307 [J. C. B.]; University of Alabama at Birmingham, Birmingham, Alabama 35229 [A. C.]; Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157 [M. J. P.]; Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [R. T., D. T. B., R. J. M.]; University of Iowa, Iowa City, Iowa 52242 [S. R. P.]; State University of New York Health Science Center at Syracuse, Syracuse, New York 13210 [F. R. D.]; University of Maryland Cancer Center, Baltimore, Maryland 21201 [C. A. S.]; and University of Minnesota, Minneapolis, Minnesota 55455 [D. C. A.]

Advances in the treatment of acute myeloid leukemia (AML) have occurred with the introduction of new therapies including high-dose cytarabine and the identification of powerful prognostic factors such as cytogenetics that predict for long-term outcome. To date, the prognostic impact of cytarabine dose escalation within various cytogenetic groups of AML has not been assessed. We describe 285 newly diagnosed patients with primary AML who had adequate karyotypes and were enrolled on a prospective Cancer and Leukemia Group B cytogenetic study. All patients were randomly assigned to postremission treatment with standard-, intermediate-, or high-dose cytarabine intensification. Patients were categorized to one of three cytogenetic groups: (a) core binding factor type [(CBF); i.e., t(8;21) inv(16), t(16;16), and del(16)]; (b) normal; and (c) other abnormality karyotype. An evaluation of these patients after a median follow-up time of over 7 years was performed to determine the relationship of intensification to outcome by cytogenetic group. Patients included 57 patients with CBF AML, 140 patients with normal karyotype AML, and 88 patients with other cytogenetic abnormalities. The treatment outcome of CBF AML patients was superior, with an estimated 50% still in complete remission (CR) after 5 years as compared with 32 and 15% for patients with normal karyotype AML and other abnormality AML, respectively (P < 0.001). Univariate analysis showed the following nonkaryotype factors to predict a prolonged CR duration: (a) younger age (P < 0.008); (b) lower leukocyte count (P = 0.01); (c) the presence of Auer rods (P = 0.004); (d) a lower percentage of bone marrow blasts (P = 0.001) at the time of diagnosis, (e) and a higher postremission cytarabine dose (P < 0.001). The impact of cytarabine dose on long-term remission was most marked (P < 0.001) in the CBF AML group (after 5 years, 78% of those with a dose of 3 g/m2 were still in CR, 57% of those with a dose of 400 mg/m2 were still in CR, and 16% of those with a dose of 100 mg/m2 were still in CR) followed by normal karyotype AML (P = 0.01; after 5 years, 40% of those with a dose of 3 g/m2 were still in CR, 37% of those with a dose of 400 mg/m2 were still in CR, and 20% of those with a dose of 100 mg/m2 were still in CR). In contrast, cytarabine at all doses produced only a 21% or less chance of long-term continuous CR for patients with other cytogenetic abnormalities. A multivariate analysis of CR duration assessed the independent impact of each of these variables on cure. Significant factors entering this model in descending order of importance were cytogenetic group (CBF > normal > other abnormality; P = 0.00001), cytarabine dose (3 g/m2 > 400 mg/m2 > 100 mg/m2; P = 0.00001), logarithm of leukocyte count at the time of diagnosis (P = 0.0005), and histological subtype of AML (P = 0.005). This study demonstrates that the curative impact of cytarabine intensification varies significantly among cytogenetic groups and results in a substantial prolongation of CR among patients with CBF and normal karyotypes, but not in those with other karyotypic abnormalities. These findings support the use of pretreatment cytogenetics in risk stratification of postremission AML therapy.

1 Supported by National Cancer Institute Grants 31946, 16058, and 26806 and by the Coleman Leukemia Research Fund. C. D. B. was supported by Grants CA31946 and CA77658. D. L. was supported by Grant CA59518. J. C. B. was supported by Grant CA26806. A. C. was supported by Grant CA47545. M. J. P. was supported by Grant CA03927. R. T. and R. J. M. were supported by Grant CA32291. S. R. P. was supported by Grant CA47642. F. R. D. was supported by Grant CA21060. C. A. S. was supported by Grant CA31983. D. C. A. was supported by Grant CA16450. This work was presented in part at the Plenary Session of the December 1994 meeting of the American Society of Hematology.

2 To whom requests for reprints should be addressed, at Hematology-Oncology Service, Ward 78, Walter Reed Army Medical Center, Washington, D.C. 20307. Phone: (202) 782-5746; Fax: (202) 782-3256.

Received 4/ 9/98. Accepted 7/17/98.




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Clinicopathologic Correlations of Genomic Gains and Losses in Follicular Lymphoma
J. Clin. Oncol., December 1, 2002; 20(23): 4523 - 4530.
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Proc. Natl. Acad. Sci. USAHome page
K. Barseguian, B. Lutterbach, S. W. Hiebert, J. Nickerson, J. B. Lian, J. L. Stein, A. J. van Wijnen, and G. S. Stein
Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins
PNAS, November 26, 2002; 99(24): 15434 - 15439.
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CA Cancer J ClinHome page
R. M. Stone
The Difficult Problem of Acute Myeloid Leukemia in the Older Adult
CA Cancer J Clin, November 1, 2002; 52(6): 363 - 371.
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BloodHome page
R. Powles, B. Sirohi, J. Treleaven, S. Kulkarni, D. Tait, S. Singhal, and J. Mehta
The role of posttransplantation maintenance chemotherapy in improving the outcome of autotransplantation in adult acute lymphoblastic leukemia
Blood, August 13, 2002; 100(5): 1641 - 1647.
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K. Dohner, K. Tobis, R. Ulrich, S. Frohling, A. Benner, R. F. Schlenk, and H. Dohner
Prognostic Significance of Partial Tandem Duplications of the MLL Gene in Adult Patients 16 to 60 Years Old With Acute Myeloid Leukemia and Normal Cytogenetics: A Study of the Acute Myeloid Leukemia Study Group Ulm
J. Clin. Oncol., August 1, 2002; 20(15): 3254 - 3261.
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JCOHome page
S. Frohling, S. Skelin, C. Liebisch, C. Scholl, R. F. Schlenk, H. Dohner, and K. Dohner
Comparison of Cytogenetic and Molecular Cytogenetic Detection of Chromosome Abnormalities in 240 Consecutive Adult Patients With Acute Myeloid Leukemia
J. Clin. Oncol., May 15, 2002; 20(10): 2480 - 2485.
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BloodHome page
S. Nguyen, T. Leblanc, P. Fenaux, F. Witz, D. Blaise, A. Pigneux, X. Thomas, F. Rigal-Huguet, B. Lioure, A. Auvrignon, et al.
A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup
Blood, May 15, 2002; 99(10): 3517 - 3523.
[Abstract] [Full Text] [PDF]

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