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

Abstract

SummaryThe 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 < 0Á001). 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 < 0Á001, both cohorts). Taken together, our data suggest that IGHV% is a continuous variable in CLL patients treated with FCR.Keywords: CLL, FCR, IGHV gene, immunoglobulin heavy chain gene.The mutation status of the immunoglobulin heavy chain variable region gene (IGHV) is an established prognostic factor in patients with chronic lymphocytic leukaemia (CLL). Fais et al (1998) identified the presence of somatic hypermutation (SHM) in CLL cells and the prognostic significance of the percent of SHM deviation from the germline sequence (IGHV%) in patients with CLL was described the following year (Damle et al, 1999;Hamblin et al, 1999). In recent years a cut-off value of 2% deviation from the germline sequence of IGHV (i.e. 98% identity) has been commonly used in clinical practice and, according to the current dogma, CLL patients with ≥2% deviation, or otherwise ≤98% identity, are considered 'mutated' (M-CLL), whereas CLL patients with <2% IGHV% deviation or >98% identity are considered research paper ª

Immunoglobulin heavy chain variable region gene and prediction of time to first treatment in patients with chronic lymphocytic leukemia: Mutational load or mutational status? Analysis of 1003 cases

“…Recently, Jain et al 13 demonstrated in patients treated with the fludarabine, cyclophosphamide, and rituximab regimen that their subsequent course and survival was greatly influenced by the amount of mutations present in the IGHV gene segment. Thus, the higher levels of mutation corresponded to a better outcome, pointing to the potential prognostic relevance of the percentage of IGHV gene mutation as a continuous rather than a dichotomized variable.…”

“…Thus, the higher levels of mutation corresponded to a better outcome, pointing to the potential prognostic relevance of the percentage of IGHV gene mutation as a continuous rather than a dichotomized variable. 13 The particular study design adopted by Jain Table S1). …”

“…Finally, stratification methods based upon the extent of the IGHV mutation do not seem [superfluous at least] to add in determining the chance for a given patient to be treated, although it remains to be seen whether such stratification may be needed for a more accurate prognostication in special clinical situations as those reported by Jain et al 13 …”

Why Is the Immunoglobulin Heavy Chain Gene Mutation Status a Prognostic Indicator in Chronic Lymphocytic Leukemia?

“…CLL patients' survival correlated with a continuous increase of IgHV% deviation. The higher the percent deviation, the better was the treatment outcome, suggesting that IgHV% is a continuous and not a dichotomized prognostic variable [11]. Furthermore, the CLL cell gene profile is independent of the IgVH mutation status.…”

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 this issue of the British Journal of Haematology, Jain et al () tested the presumption that IGHV somatic hypermutation as a continuous variable is a better predictor of outcome than treating it as a dichotomous variable. Over 500 CLL patients treated with fludarabine, cyclophosphamide and rituximab (FCR) were followed for progression‐free (PFS) and overall survival (OS) based on their pre‐treatment IGHV percentage.…”