The absolute percent deviation of IGHV mutation rather than a 98% cut-off predicts survival of chronic lymphocytic leukaemia patients treated with fludarabine, cyclophosphamide and rituximab

Preetesh Jain, Graciela M. Nogueras González, Rashmi Kanagal-Shamanna, Uri Rozovski, Nawid Sarwari, Constantine Tam, William G. Wierda, Philip A. Thompson, Nitin Jain, Rajyalakshmi Luthra, Andres Quesada, Gabriela Sanchez-Petitto, Alessandra Ferrajoli, Jan Burger, Hagop Kantarjian, Jorge Cortes, Susan O'Brien, Michael J. Keating, Zeev Estrov

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The degree of somatic hypermutation, determined as percent deviation of immunoglobulin heavy chain gene variable region sequence from the germline (IGHV%), is an important prognostic factor in chronic lymphocytic leukaemia (CLL). Currently, a cut-off of 2% deviation or 98% sequence identity to germline in IGHV sequence is routinely used to dichotomize CLL patients into mutated and unmutated groups. Because dissimilar IGHV% cut-offs of 1–5% were identified in different studies, we wondered whether no cut-off should be applied and IGHV% treated as a continuous variable. We analysed the significance of IGHV% in 203 CLL patients enrolled on the original frontline fludarabine, cyclophosphamide and rituximab (FCR) trial with a median of 10 years follow-up. Using the Cox Proportional Hazard model, IGHV% was identified as a continuous variable that is significantly associated with progression-free (PFS) and overall survival (OS) (P < 0·001). Furthermore, we validated this finding in 323 patients treated with FCR off-protocol and in the total cohort (n = 535). Multivariate analysis revealed a continuous trend. Higher IGHV% levels were incrementally associated with favorable PFS and OS in both FCR-treated cohorts (P < 0·001, both cohorts). Taken together, our data suggest that IGHV% is a continuous variable in CLL patients treated with FCR.

Original languageEnglish
Pages (from-to)33-40
Number of pages8
JournalBritish Journal of Haematology
Issue number1
Publication statusPublished - Jan 2018
Externally publishedYes


  • CLL
  • FCR
  • IGHV gene
  • immunoglobulin heavy chain gene

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