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

Research output: Contribution to journalArticle

Abstract

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 (US)
Pages (from-to)33-40
Number of pages8
JournalBritish Journal of Haematology
Volume180
Issue number1
DOIs
StatePublished - Jan 2018
Externally publishedYes

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B-Cell Chronic Lymphocytic Leukemia
Cyclophosphamide
Mutation
Survival
Immunoglobulin Heavy Chain Genes
Proportional Hazards Models
Multivariate Analysis
fludarabine
Rituximab

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

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

In: British Journal of Haematology, Vol. 180, No. 1, 01.2018, p. 33-40.

Research output: Contribution to journalArticle

Jain, P, Nogueras González, GM, Kanagal-Shamanna, R, Rozovski, U, Sarwari, N, Tam, C, Wierda, WG, Thompson, PA, Jain, N, Luthra, R, Quesada, A, Sanchez-Petitto, G, Ferrajoli, A, Burger, J, Kantarjian, H, Cortes, J, O'Brien, S, Keating, MJ & Estrov, Z 2018, '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', British Journal of Haematology, vol. 180, no. 1, pp. 33-40. https://doi.org/10.1111/bjh.15018
Jain, Preetesh ; Nogueras González, Graciela M. ; Kanagal-Shamanna, Rashmi ; Rozovski, Uri ; Sarwari, Nawid ; Tam, Constantine ; Wierda, William G. ; Thompson, Philip A. ; Jain, Nitin ; Luthra, Rajyalakshmi ; Quesada, Andres ; Sanchez-Petitto, Gabriela ; Ferrajoli, Alessandra ; Burger, Jan ; Kantarjian, Hagop ; Cortes, Jorge ; O'Brien, Susan ; Keating, Michael J. ; Estrov, Zeev. / 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. In: British Journal of Haematology. 2018 ; Vol. 180, No. 1. pp. 33-40.
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abstract = "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.",
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AU - Jain, Preetesh

AU - Nogueras González, Graciela M.

AU - Kanagal-Shamanna, Rashmi

AU - Rozovski, Uri

AU - Sarwari, Nawid

AU - Tam, Constantine

AU - Wierda, William G.

AU - Thompson, Philip A.

AU - Jain, Nitin

AU - Luthra, Rajyalakshmi

AU - Quesada, Andres

AU - Sanchez-Petitto, Gabriela

AU - Ferrajoli, Alessandra

AU - Burger, Jan

AU - Kantarjian, Hagop

AU - Cortes, Jorge

AU - O'Brien, Susan

AU - Keating, Michael J.

AU - Estrov, Zeev

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N2 - 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.

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