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

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy with diverse clinical outcomes, with some patients never requiring oncological intervention. Additionally, the recent development of B-cell pathway inhibitors and a BH3 mimetic have changed treatment paradigms and outcomes (Edelmann & Gribben, 2017). However, as all therapies have associated risks and costs, treatment initiation and choice should be based on individual risk assessment. In additional to clinical assessment of disease burden, many laboratory evaluations are available to help prognosticate disease course and to direct disease treatment. Most commonly, in CLL, interphase fluorescence in-situ hybridization (FISH) analysis is utilized for this purpose. FISH analysis can reproducibly identify patients who harbour deletion of chromosome 17p (del 17p) and it is these individuals who typically have the most aggressive natural history and poor response to conventional chemoimmunotherapy (Van Dyke et al, 2016). However, we and others have found mutational status of the immunoglobulin heavy chain variable (IGHV) region to be stable over time and more predictive of clinical outcome than interphase FISH analysis (Gladstone et al, 2011, 2012; Osman et al, 2017; Sandoval-Sus et al, 2018) in CLL. In a final step of the lymphocyte maturation process, through a T-cell dependent manner in the lymph node germinal centre after antigen stimulation, point mutations are created in IGHV, which thereby results in highly antigen-specific immunoglobulin production. CLL patients whose IGH expresses a mutated variable region often have a more indolent clinical course. According to the most common paradigm, a 2% or greater deviation in IGHV sequence in the CLL cells relative to the IGHV germline sequence defines the CLL clone as mutated. In this issue of the British Journal of Haematology, Jain et al (2017) 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. Their results establish that the PFS and OS for CLL patients treated with FCR can be stratified by IGHV mutation percentage with those with the highest mutation rates enjoying the best outcomes. However, do these finding better help guide physician and patient treatment choice? Potentially not: they confirm that about half of untreated CLL patients meet the current <2% threshold for an unmutated IGHV sequence, which already questions the use of FCR in the current dichotomous unmutated/mutated IGHV classification (Guo et al, 2016) Likewise, while this data demonstrates better clinical outcomes for those who harbour the highest IGHV mutation percentage, the data does not support limiting FCR usage to only this limited population. Moreover, while the assay in the authors' laboratory is well-described, the variety of other clinical laboratory assays for somatic hypermutation (different primer pairs, analytic algorithms, and acceptance criteria) mandates that these findings be replicated under other conditions. Importantly, as each of the subjects in this cohort received therapy, it remains unknown whether these results reflect the natural history of CLL or if these survival results can only be applied to patients treated with FCR. It remains to be determined whether IGHV mutational percentage can be utilized as a determining factor of whether therapy needs to be initiated. Additionally, as discussed by the authors, this survival data cannot be extrapolated to patients treated with novel therapies. And, as patients who harbour del(17p) have poor outcomes with conventional chemoimmunotherapy, such as FCR, the lack of correlative CLL FISH data with these IGHV mutational results limits the impact of this data on determining treatment choice. Finally, the mechanism underlying differential survival according to this biomarker remains to be elucidated. However, these data do support the need for a more comprehensive risk assessment tool which incorporates objective findings, basic laboratory findings, genetics and IGHV mutation percentage, to better define those patient populations that may safely delay therapy and the correct therapy for those who need it.