title: CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multicenter analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as an overall (OS) and treatment-free survival (TFS) predictor.
  
  
  METHODS
  A training/validation strategy was chosen to find the optimal CD49d cutoff. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLLs; Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry-based prognosticators (eg, CD38, ZAP-70) was ranked by recursive partitioning.
  
  
  RESULTS
  Patients with ≥ 30% of neoplastic cells expressing CD49d were considered CD49d+. Decrease in OS at 5 and 10 years among CD49d+ patients was 7% and 23% (decrease in TFS, 26% and 25%, respectively). Pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR, 2.0) in a Cox model adjusted for clinical and biologic prognosticators. Hierarchic trees including all patients or restricted to those with early-stage disease or those age ≤ 65 years always selected CD49d as the most important flow cytometry-based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patient subsets with poorer outcome independent of CD38 and ZAP-70.
  
  
  CONCLUSIONS
  In this analysis of approximately 3,000 patients, CD49d emerged as the strongest flow cytometry-based predictor of OS and TFS in CLL.
authors: Pietro Bulian, Antonella Zucchetto, and Valter Gattei, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico, Aviano; Lilla Cro and Luca Baldini, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico and Università degli Studi, Milan; Gianluca Gaidano and Davide Rossi, Amedeo Avogadro University of Eastern Piedmont, Novara; Giovanni Del Poeta, Tor Vergata University, S. Eugenio Hospital, Rome, Italy; Tait D. Shanafelt, Mayo Research Center, Rochester, NY; Chris Fegan and Chris Pepper, Institute of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom; Holger Nückel, University of Duisburg-Essen, Essen, Germany; and Antonina V. Kurtova, Alessandra Ferrajoli, and Jan A. Burger, University of Texas MD Anderson Cancer Center, Houston, TX.
authors: Pietro
authors: P
authors: Bulian
authors: Tait D
authors: TD
authors: Shanafelt
authors: Chris
authors: C
authors: Fegan
authors: Antonella
authors: A
authors: Zucchetto
authors: Lilla
authors: L
authors: Cro
authors: Holger
authors: H
authors: Nückel
authors: Luca
authors: L
authors: Baldini
authors: Antonina V
authors: AV
authors: Kurtova
authors: Alessandra
authors: A
authors: Ferrajoli
authors: Jan A
authors: JA
authors: Burger
authors: Gianluca
authors: G
authors: Gaidano
authors: Giovanni
authors: G
authors: Del Poeta
authors: Chris
authors: C
authors: Pepper
authors: Davide
authors: D
authors: Rossi
authors: Valter
authors: V
authors: Gattei
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018572:Disease-Free Survival; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000401:mortality*; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D039441:Integrin alpha4; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D051997:ADP-ribosyl Cyclase 1