title: Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy.
abstract: OBJECTIVE
  Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig V(H) mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy.
  
  
  METHODS
  We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712.
  
  
  RESULTS
  Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig V(H) mutational status to classify risk, there was no association between complete response rate with either unmutated Ig V(H) mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig V(H) unmutated patients as compared with the Ig V(H) mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk.
  
  
  CONCLUSIONS
  These data demonstrate that high-risk CLL patients characterized by Ig V(H) unmutated (> or = 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig V(H) mutational status and interphase cytogenetics on treatment outcome.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. john.byrd@osumc.edu
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Bercedis L
authors.initials: BL
authors.lastname: Peterson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.forename: Ben
authors.initials: B
authors.lastname: Lampson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002880:Chromosomes, Human, Pair 11; D002886:Chromosomes, Human, Pair 17; D017322:Clinical Trials, Phase II as Topic; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D017353:Gene Deletion; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D000069283:Rituximab; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; D014740:Vidarabine; C024352:fludarabine