title: Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens.
abstract: BACKGROUND
  Ibrutinib is active in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). In patients treated with ibrutinib for R/R CLL, del(17p), identified by interphase fluorescence in situ hybridization (FISH), is associated with inferior progression-free survival despite equivalent initial response rates. Del(17p) is frequently associated with a complex metaphase karyotype (CKT); the prognostic significance of CKT in ibrutinib-treated patients has not been reported.
  
  
  METHODS
  This study reviewed 88 patients treated for R/R CLL at The University of Texas MD Anderson Cancer Center with investigational ibrutinib-based regimens from 2010 to 2013. Pretreatment FISH and lipopolysaccharide-stimulated metaphase cytogenetic analysis were performed on bone marrow.
  
  
  RESULTS
  An adequate pretreatment metaphase karyotype was available for 56 of the 88 patients. The karyotype was complex in 21 of the 56 cases; 17 of the 21 had del(17p) according to FISH. The overall response rate, including partial remission with persistent lymphocytosis, was 94%; 18% had complete responses. In a multivariate analysis (MVA), only CKT was significantly associated with event-free survival (EFS; hazard ratio [HR], 6.6 [95% CI 1.7-25.6]; P = .006). Fludarabine-refractory CLL (HR, 6.9 [95% CI 1.8-27.1], P = .005) and CKT (HR 5.9 [95% CI 1.6-22.2], P = .008) were independently associated with inferior overall survival (OS) in MVA. Del(17p) by FISH was not significantly associated with EFS or OS in MVA.
  
  
  CONCLUSIONS
  CKT is a powerful predictor of outcomes for ibrutinib-treated patients with R/R CLL and may be a stronger predictor of biological behavior than del(17p) by FISH. Because of their relatively poor outcomes, patients with CKT are ideal candidates for studies of consolidative treatment strategies or novel treatment combinations.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: Department of Leukemia, University of California, Irvine, California.
authors.forename: Susan M
authors.initials: SM
authors.lastname: O'Brien
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Francesco
authors.initials: F
authors.lastname: Stingo
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Smith
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nitin
authors.initials: N
authors.lastname: Jain
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
mesh_terms: D059786:Abnormal Karyotype; D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics; D010880:Piperidines; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine
keywords: chronic lymphocytic leukemia (CLL); complex karyotype; del(17p); ibrutinib; relapsed and refractory