Major prognostic value of complex karyotype in addition to TP53 and IGHV mutational status in first‐line chronic lymphocytic leukemia

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Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder of remarkable heterogeneity as demonstrated by cytogenetics and molecular analyses. Complex karyotype (CK), TP53 deletions and/or mutations (TP53 disruption), IGVH mutational status, and, more recently, recurrent somatic mutations have been identified as prognostic markers in CLL. On a cohort of 110 patients with CLL treated with first-line fludarabin, cyclophosphamide, and rituximab treatment compared with 33 untreated (watch and wait) patients with CLL, we report more frequent complex karyotypes (34 vs 15%; P=.05), unmutated IGHV (70 vs 21%; P<.0001), ATM deletion (25 vs 6%, P=.02), and NOTCH mutation (3 vs 17%, P=.04). Among treated patients, 39 relapsed during the follow-up period. These patients were characterized before treatment by a higher incidence of trisomy 12 (38 vs 11%, P<.001) and TP53 disruption (31 vs 4%, P=.0002). A significantly shorter 5-year overall survival was found for treated patients with CK (72.4 vs 85.8%; P=.007), unmutated IGHV (70 vs 100%; P=.04), or TP53 disruption (55.7 vs 82.7%; P<.0001). Three risk groups were defined based on the status of TP53 disruption or unmutated IGVH, which differed significantly in terms of 5-year overall survival. Moreover, the presence of CK impacted pejoratively 5-year overall survival and progression-free survival in all these 3 groups. Conventional karyotyping therefore appears to be of value, CK being an additional factor, undetectable in classical FISH, in patients with CLL at the stage when therapy becomes required.