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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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S. S. Kadkol, A. Bruno, C. Dodge, V. Lindgren, and F. Ravandi
Comprehensive Analysis of CBF{beta}-MYH11 Fusion Transcripts in Acute Myeloid Leukemia by RT-PCR Analysis
J. Mol. Diagn., February 1, 2004; 6(1): 22 - 27.
[Abstract] [Full Text]

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Y. Ge, T. L. Jensen, M. L. Stout, R. M. Flatley, P. J. Grohar, Y. Ravindranath, L. H. Matherly, and J. W. Taub
The Role of Cytidine Deaminase and GATA1 Mutations in the Increased Cytosine Arabinoside Sensitivity of Down Syndrome Myeloblasts and Leukemia Cell Lines
Cancer Res., January 15, 2004; 64(2): 728 - 735.
[Abstract] [Full Text] [PDF]

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R. M. Stone, M. R. O'Donnell, and M. A. Sekeres
Acute Myeloid Leukemia
Hematology, January 1, 2004; 2004(1): 98 - 117.
[Abstract] [Full Text] [PDF]

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T. Buchner, W. Hiddemann, W. E. Berdel, B. Wormann, C. Schoch, C. Fonatsch, H. Loffler, T. Haferlach, W.-D. Ludwig, G. Maschmeyer, 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 or 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., December 15, 2003; 21(24): 4496 - 4504.
[Abstract] [Full Text] [PDF]

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J. Krauter, K. Gorlich, O. Ottmann, M. Lubbert, H. Dohner, W. Heit, L. Kanz, A. Ganser, and G. Heil
Prognostic Value of Minimal Residual Disease Quantification by Real-Time Reverse Transcriptase Polymerase Chain Reaction in Patients With Core Binding Factor Leukemias
J. Clin. Oncol., December 1, 2003; 21(23): 4413 - 4422.
[Abstract] [Full Text] [PDF]

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C. D. Baldus, S. M. Tanner, A. S. Ruppert, S. P. Whitman, K. J. Archer, G. Marcucci, M. A. Caligiuri, A. J. Carroll, J. W. Vardiman, B. L. Powell, et al.
BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study
Blood, September 1, 2003; 102(5): 1613 - 1618.
[Abstract] [Full Text] [PDF]

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E. Solary, B. Drenou, L. Campos, P. de Cremoux, F. Mugneret, P. Moreau, B. Lioure, A. Falkenrodt, B. Witz, M. Bernard, et al.
Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia
Blood, August 15, 2003; 102(4): 1202 - 1210.
[Abstract] [Full Text] [PDF]

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J. Delaunay, N. Vey, T. Leblanc, P. Fenaux, F. Rigal-Huguet, F. Witz, T. Lamy, A. Auvrignon, D. Blaise, A. Pigneux, et al.
Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup
Blood, July 15, 2003; 102(2): 462 - 469.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
L. M. Staudt
Molecular Diagnosis of the Hematologic Cancers
N. Engl. J. Med., May 1, 2003; 348(18): 1777 - 1785.
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D. A. Rizzieri, V. K. Ibom, J. O. Moore, C. M. DeCastro, G. L. Rosner, D. J. Adams, T. Foster, N. Payne, M. Thompson, J. J. Vredenburgh, et al.
Phase I Evaluation of Prolonged-infusion Gemcitabine with Fludarabine for Relapsed or Refractory Acute Myelogenous Leukemia
Clin. Cancer Res., February 1, 2003; 9(2): 663 - 668.
[Abstract] [Full Text] [PDF]

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T. Haferlach, C. Schoch, H. Loffler, W. Gassmann, W. Kern, S. Schnittger, C. Fonatsch, W.-D. Ludwig, C. Wuchter, B. Schlegelberger, et al.
Morphologic Dysplasia in De Novo Acute Myeloid Leukemia (AML) Is Related to Unfavorable Cytogenetics but Has No Independent Prognostic Relevance Under the Conditions of Intensive Induction Therapy: Results of a Multiparameter Analysis From the German AML Cooperative Group Studies
J. Clin. Oncol., January 15, 2003; 21(2): 256 - 265.
[Abstract] [Full Text] [PDF]

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J. C. Byrd, B. L. Peterson, V. A. Morrison, K. Park, R. Jacobson, E. Hoke, J. W. Vardiman, K. Rai, C. A. Schiffer, and R. A. Larson
Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712)
Blood, January 1, 2003; 101(1): 6 - 14.
[Abstract] [Full Text] [PDF]

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K. Neben, C. Giesecke, S. Schweizer, A. D. Ho, and A. Kramer
Centrosome aberrations in acute myeloid leukemia are correlated with cytogenetic risk profile
Blood, January 1, 2003; 101(1): 289 - 291.
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J. C. Byrd, K. Mrozek, R. K. Dodge, A. J. Carroll, C. G. Edwards, D. C. Arthur, M. J. Pettenati, S. R. Patil, K. W. Rao, M. S. Watson, et al.
Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)
Blood, December 15, 2002; 100(13): 4325 - 4336.
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S. Frohling, R. F. Schlenk, J. Breitruck, A. Benner, S. Kreitmeier, K. Tobis, H. Dohner, and K. Dohner
Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm
Blood, December 15, 2002; 100(13): 4372 - 4380.
[Abstract] [Full Text] [PDF]

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A. Viardot, P. Moller, J. Hogel, K. Werner, G. Mechtersheimer, A. D. Ho, G. Ott, T. F.E. Barth, R. Siebert, S. Gesk, et al.
Clinicopathologic Correlations of Genomic Gains and Losses in Follicular Lymphoma
J. Clin. Oncol., December 1, 2002; 20(23): 4523 - 4530.
[Abstract] [Full Text] [PDF]

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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.
[Abstract] [Full Text] [PDF]

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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.
[Abstract] [Full Text] [PDF]

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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.
[Abstract] [Full Text] [PDF]

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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.
[Abstract] [Full Text] [PDF]

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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.
[Abstract] [Full Text] [PDF]

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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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J. E. Rubnitz, S. C. Raimondi, X. Tong, D. K. Srivastava, B. I. Razzouk, S. A. Shurtleff, J. R. Downing, C.-H. Pui, R. C. Ribeiro, and F. G. Behm
Favorable Impact of the t(9;11) in Childhood Acute Myeloid Leukemia
J. Clin. Oncol., May 1, 2002; 20(9): 2302 - 2309.
[Abstract] [Full Text] [PDF]

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D. A. Rizzieri, A. J. Bass, G. L. Rosner, J. P. Gockerman, C. M. DeCastro, W. P. Petros, D. J. Adams, M. J. Laughlin, P. Davis, T. Foster, et al.
Phase I Evaluation of Prolonged-Infusion Gemcitabine With Mitoxantrone for Relapsed or Refractory Acute Leukemia
J. Clin. Oncol., February 1, 2002; 20(3): 674 - 679.
[Abstract] [Full Text] [PDF]

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J. F. San Miguel, M. B. Vidriales, C. Lopez-Berges, J. Diaz-Mediavilla, N. Gutierrez, C. Canizo, F. Ramos, M. J. Calmuntia, J. J. Perez, M. Gonzalez, et al.
Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification
Blood, September 15, 2001; 98(6): 1746 - 1751.
[Abstract] [Full Text] [PDF]

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R. M. Stone, D. T. Berg, S. L. George, R. K. Dodge, P. A. Paciucci, P. P. Schulman, E. J. Lee, J. O. Moore, B. L. Powell, M. R. Baer, et al.
Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine
Blood, August 1, 2001; 98(3): 548 - 553.
[Abstract] [Full Text] [PDF]

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R. A. Krance, C. A. Hurwitz, D. R. Head, S. C. Raimondi, F. G. Behm, K. R. Crews, D. K. Srivastava, H. Mahmoud, W. M. Roberts, X. Tong, et al.
Experience With 2-Chlorodeoxyadenosine in Previously Untreated Children With Newly Diagnosed Acute Myeloid Leukemia and Myelodysplastic Diseases
J. Clin. Oncol., June 1, 2001; 19(11): 2804 - 2811.
[Abstract] [Full Text] [PDF]

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K. Mrozek, T. W. Prior, C. Edwards, G. Marcucci, A. J. Carroll, P. J. Snyder, P. R.K. Koduru, K. S. Theil, M. J. Pettenati, K. J. Archer, et al.
Comparison of Cytogenetic and Molecular Genetic Detection of t(8;21) and inv(16) in a Prospective Series of Adults With De Novo Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
J. Clin. Oncol., May 1, 2001; 19(9): 2482 - 2492.
[Abstract] [Full Text] [PDF]

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M. L. Slovak, K. J. Kopecky, P. A. Cassileth, D. H. Harrington, K. S. Theil, A. Mohamed, E. Paietta, C. L. Willman, D. R. Head, J. M. Rowe, et al.
Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study
Blood, December 15, 2000; 96(13): 4075 - 4083.
[Abstract] [Full Text] [PDF]

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E. H. Estey
How I treat older patients with AML
Blood, September 1, 2000; 96(5): 1670 - 1673.
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D. D. Ross, J. E. Karp, T. T. Chen, and L. A. Doyle
Expression of breast cancer resistance protein in blast cells from patients with acute leukemia
Blood, July 1, 2000; 96(1): 365 - 368.
[Abstract] [Full Text] [PDF]

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J. C. Byrd, R. K. Dodge, A. Carroll, M. R. Baer, C. Edwards, J. Stamberg, M. Qumsiyeh, J. O. Moore, R. J. Mayer, F. Davey, et al.
Patients With t(8;21)(q22;q22) and Acute Myeloid Leukemia Have Superior Failure-Free and Overall Survival When Repetitive Cycles of High-Dose Cytarabine Are Administered
J. Clin. Oncol., December 1, 1999; 17(12): 3767 - 3775.
[Abstract] [Full Text] [PDF]

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T. Buchner, W. Hiddemann, B. Wormann, H. Loffler, W. Gassmann, T. Haferlach, C. Fonatsch, D. Haase, C. Schoch, D. Hossfeld, et al.
Double Induction Strategy for Acute Myeloid Leukemia: The Effect of High-Dose Cytarabine With Mitoxantrone Instead of Standard-Dose Cytarabine With Daunorubicin and 6-Thioguanine: A Randomized Trial by the German AML Cooperative Group
Blood, June 15, 1999; 93(12): 4116 - 4124.
[Abstract] [Full Text] [PDF]


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