title: 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.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Section of Hematology/Oncology, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. morri002@tc.umn.edu
authors.forename: Vicki A
authors.initials: VA
authors.lastname: Morrison
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.forename: Bercedis L
authors.initials: BL
authors.lastname: Peterson
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Laurence
authors.initials: L
authors.lastname: Elias
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: John D
authors.initials: JD
authors.lastname: Hines
authors.forename: Lois
authors.initials: L
authors.lastname: Shepherd
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Charles A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D002699:Chlorambucil / Q000008:administration & dosage / Q000009:adverse effects; D002869:Chromosome Aberrations; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D007951:Leukemia, Myeloid / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000473:pathology; D012074:Remission Induction; D012189:Retrospective Studies; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D002699:Chlorambucil; D014740:Vidarabine; C024352:fludarabine