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Therapy-Related Myeloid Leukemias Are Observed in Patients With Chronic Lymphocytic Leukemia After Treatment With Fludarabine and Chlorambucil: Results of an Intergroup Study, Cancer and Leukemia Group B 9011

From the Veterans Affairs Medical Center, Minneapolis, MN; Long Island Jewish Medical Center, New Hyde Park, and North Shore University Hospital, Manhasset, NY; Cancer and Leukemia Group B Statistical Center, Durham, NC; University of New Mexico Health Sciences Center, Albuquerque, NM; Fred Hutchinson Cancer Research Center, Seattle, WA; The Case Western Reserve University School of Medicine, Cleveland, OH; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; University of Chicago Medical Center, Chicago, IL; and Wayne State University School of Medicine, Detroit, MI.

Address reprint requests to Vicki A. Morrison, MD, Sections of Hematology/Oncology and Infectious Disease, 111E, Veterans Affairs Medical Center, One Veterans Dr, Minneapolis, MN 55417; email: morri002{at}tc.umn.edu

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin’s lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication.

PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML.

RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P = .007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months).

CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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