Clinical importance of DNA methylation signatures in chronic lymphocytic leukaemia patients treated with chemo-immunotherapy

Amarasinghe, Harindra, Wojdacz, Tomasz K., Rose-Zerilli, Matthew John Jerome, Beattie, Alice, Forster, Jade, Kadalayil, Latha, Blakemore, Stuart, Parker, Helen, Larrayoz, Marta, Clifford, Ruth, Davis, Zadie, Else, Monica, Cohen, Dena, Steele, Andrew J., Rosenquist, Richard, Collins, Andrew, Pettitt, Andrew, Hillmen, Peter, Robbe, Pauline, Plass, Christopher, Schuh, Anna, Catovsky, Daniel, Oscier, David, Oakes, Christopher C. and Strefford, Jonathan C. (2017) Clinical importance of DNA methylation signatures in chronic lymphocytic leukaemia patients treated with chemo-immunotherapy. Blood, 130. (doi:10.1158/1538-7445).

Abstract

Variations in the CLL DNA methylome reflect modifications that occur during normal B cell maturation, along with IGHV mutated (M-CLL) and unmutated CLL (U-CLL), retaining an imprint of the DNA methylation signature of memory (m-CLL) and naive B cells (n-CLL), respectively, with a third intermediate epigenetic subgroup (i-CLL) (1-3). To further test the clinical utility of DNA methylation signatures, we performed the first analysis of patients entering clinical trials; we tested treatment-naive CLL patients [n=605] randomized to CLL4 (chemotherapy, CT) (4), ARCTIC and ADMIRE (both chemo-immunotherapy, CIT) (5, 6). We identified n-, i- and m-CLL in 49.3% (n=299), 32.0% (n=195) and 18.5% (n=112) of our patients, respectively. Fewer m-CLL patients were identified in our study compared to published data reflecting the progressive nature of our cohort, with 80% (n=245/305, P<0.001) of U-CLL cases exhibiting the n-CLL signature (i-CLL: 17% and m-CLL: 3%). For M-CLL cases, 9%, 50% and 41% exhibited the n-, i- and m-CLL epigenetic signature, respectively. 68% (80/117, p<0.001) of cases with del(11q), 77% (41/53, p<0.001) with trisomy 12, and 68% (38/56, p=0.03) with TP53 lesions were n-CLL. Cases with NOTCH1 (p=0.01) and SF3B1 (p=0.02) mutations were also enriched in n-CLL. Next, we investigated the impact of methylation signatures on progression-free (PFS) and overall survival (OS). In CT patients, n-, i- and m-CLL patients exhibited a median PFS of 23, 34 and 35 months, and OS of 63, 66 and 106 months, respectively. n-CLL showed significantly shorter PFS than i-CLL (HR 0.64, p<0.001) and m-CLL (HR 0.52, p<0.001), and had the shortest OS, again compared to i-CLL (HR 0.73, p=0.01) and m-CLL (HR 0.33, p<0.001). Ten-year OS differed according to epigenetic signature (P<0.001) and was reached by only 14% of n-CLL patients. Multivariate Cox proportional analysis, controlling for confounding variables (incl. clinical features, IGHV status, TP53, NOTCH1 and SF3B1) in 278 patients, showed that m-CLL was an independent prognostic factor for OS (HR 0.46, p<0.01). In 247 CIT patients, univariate analysis showed that the i- (HR:0.57, p=0.05) and m-CLL (HR:0.3, p=0.002) subgroups displayed longer PFS. In a multivariate model, including TP53 lesions and IGHV status (239 patients), the m-CLL subgroup retained independent prognostic significance (HR:0.25, p<0.001). In conclusion, we provide important evidence that DNA methylation analysis may aid in the identification of patients destined to demonstrate durable remissions when treated with these agents.

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Contributors

Author: Andrew J. Steele

Author: Jonathan C. Strefford

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