IGHV Mutation Status Does Not Add Prognostic Information In The Background Of Mutations In TP53 and SF3B1, and Deletions Of 17p and 11q, Which Are Independent Adverse Prognostic Parameters In CLL

In CLL, the IGHV mutation status is an established prognostic marker. However, associations between the IGHV mutation status and other genetic markers have been reported. Based on genome sequencing data, novel recurrent mutations have been identified in CLL and first data on their prognostic impact is also available.

In this study we addressed the following questions in a large cohort of 934 CLL patients: 1. Associations of IGHV mutation status with cytogenetic and molecular genetic markers 2. Age dependency of IGHV mutation status, cytogenetic and molecular mutations 3. Impact on survival.

In total, in 934 CLL patients the IGHV mutation status was determined. Median age was 66.8 years (range: 29.6 - 90.5 years). Further, all patients were analyzed by DNA sequencing for mutations in TP53, SF3B1, MYD88, XPO1, NOTCH1 and FBXW7 and by FISH for TP53 deletion status as well as for del(13q), del(11q) and +12.

In the entire cohort 550/934 (58.9%) patients showed a mutated and 384 (41.1%) an unmutated IGHV status. Molecular mutations were observed in the following frequencies: NOTCH1: 12.6%, SF3B1: 11.9%, TP53: 9.2%, XPO1: 4.0%, FBXW7: 2.6%, and MYD88: 1.7%. Patients showed deletions 13q in 58.7% (13q as the sole abnormality in 45.5%), trisomy 12 in 15.6%, 11q in 12.1%, and 17p in 5.8%, respectively. The following genetic aberrations were more frequent in CLL with unmutated vs mutated IGHV status: TP53mut (14.8% vs 5.3%), SF3B1mut (19.0% vs 6.9%), XPO1mut (9.1% vs 0.4%), NOTCH1mut (24.2% vs 4.5%), del(17p) (10.7% vs 2.4%), del(11q) (24.2% vs 3.6%), +12 (21.4% vs 11.6%) (for all p<0.001). In contrast, del(13q) (45.8% vs 67.6%), del(13q) sole (26.3% vs 58.9%) (for all p<0.001), and MYD88mut (0.3% vs 2.7%, p=0.004) were less frequent in CLL with unmutated IGHV status. No association between age and IGHV status was observed. With respect to all other analyzed markers only the frequency of TP53mut and del(17p) increased significantly with age. In univariate analysis the following parameters were significantly associated with shorter overall survival (OS): IGHV unmutated (HR: 2.0), age (≤70 vs >70 yrs: HR:3.4), TP53mut (HR: 3.8), SF3B1mut (HR: 2.3), del(17p) (HR: 6.2), del(11q) (HR: 2.3) (for all p<0.001), and NOTCH1mut (HR: 1.5, p=0.05), while del(13q) sole was associated with longer OS (HR: 0.6; p=0.003). In multivariate analysis the following parameters were independently associated with shorter OS: age (≤70 vs >70 yrs: HR: 3.1; p<0.001), TP53mut (HR: 2.0; p=0.018), SF3B1mut (HR: 2.1; p=0.001), del(17p) (HR: 3.6, p<0.001), del(11q) (HR: 2.1; p=0.005), while IGHV mutation status surprisingly did not show an independent impact on OS. Next we separated the cohort according to the number of adverse prognostic markers TP53mut, SF3B1mut, del(11q), and del(17p) (group A: 0 marker (n=658), group B: 1 marker (n=197), group C: 2 or more markers with alterations (n=78)). Kaplan-Meier-analysis revealed a 5 yrs OS of 89.5% in group A, of 71.3% in group B and of 37.4% in group C (for all comparisons p<0.001). Neither within groups A, B nor within group C did the IGHV mutation status have an impact on OS. On the other hand, OS at 5 yrs differed significantly according to the group within patients with either mutated IGHV or unmutated IGHV status (mutated IGHV status: group A (n=467) 90.6%, group B (n=67) 73.7% and group C (n=16) 47.2%; A vs B: p=0.031; B vs C: p=0.022; unmutated IGHV status: group A (n=191) 86.8%, group B (n=130) 69.6% and group C (n=62) 35.8%; A vs B: p=0.006; B vs C: p<0.001). Interestingly, a significant association between a higher number of adverse prognostic markers and age was observed (p=0.019). Further we performed multivariate analysis with the number of adverse prognostic factors (TP53mut, SF3B1mut, del(11q), del(17p): 0 markers to 4 markers positive) and age per decade. Both parameters were independently associated with OS (HR: 2.3 per adverse marker positive and HR: 1.7 per decade, for both p<0.001).

1. Several adverse prognostic markers (TP53mut, SF3B1mut, NOTCH1, del(17p), del(11q)) were associated with an unmutated IGHV status. 2. However, in the background of the genetic markers TP53mut, SF3B1mut, del(11q), or del(17p) IGHV status lost its independent prognostic impact. 3. An accumulation of adverse prognostic markers worsens prognosis in CLL.

Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Jeromin:MLL Munich Leukemia Laboratory: Employment. Weissmann:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.