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N. Giménez et al.
92% (95 CI: 76-100%) for patients with subclonal muta- tions, 70% (95 CI: 42-98%) for patients with clonal muta- tions, and 51% (95% CI: 42-60%; P≤0.001) for those without mutations. The adverse effect of mutations in genes of the RAS-BRAF-MAPK-ERK pathway was observed independently of the mutated gene (Online Supplementary Figure S2). Overall, patients with mutations in the RAS-BRAF-MAPK-ERK pathway had a worse TTFT than that of patients without mutations (P<0.001) (Figure 2A). However, when other adverse mutations (TP53, ATM or BIRC3)26,27 were taken into account, patients with muta- tions in both the RAS-BRAF-MAPK-ERK pathway and in TP53, ATM or BIRC3 (n=6, 1%) had the shortest 5-year TTFT (100%) followed by patients with mutations in TP53, ATM or BIRC3 [n=64,15%; 5-year TTFT of 83% (CI 95%: 71-95%)], patients with mutations only in the RAS- BRAF-MAPK-ERK pathway [n=16, 4%; 5-year TTFT of 75% (CI 95%: 54-96%)], and patients without mutations [n=337, 79%; 5-year TTFT of 44% (CI 95%: 34-54%)]
(P≤0.001) (Figure 2B). In the subgroup of patients with Binet A or B CLL with U-IGHV, those patients with adverse gene mutations concomitantly with mutations in RAS-BRAF-MAPK-ERK pathway genes (n=6, 4%) again had a worse 5-year TTFT (all treated) than patients with only mutations in TP53, ATM or BIRC3 (n=45, 30%; 5- year TTFT: 87%, CI 95%: 77-97%), patients with only mutations in RAS-BRAF-MAPK-ERK pathway genes (n=13, 8%; 5-year TTFT: 85%, CI 95%: 65-100%), and patients without mutations in these genes (n=88, 56%; 5- year TTFT: 71%, CI: 95%: 60-82%) (P=0.001) (Figure 2C). A multivariate analysis including IGHV status, mutations in RAS-BRAF-MAPK-ERK pathway genes, and mutations in TP53, ATM or BIRC3 in a final model with 418 patients showed an independent impact on TTFT for IGHV status [hazard risk (HR) 3.4 (95% CI: 2.5-4.8), P<0.001], muta- tions in the RAS-BRAF-MAPK-ERK pathway [HR 1.8 (95% CI: 1.1- 3), P=0.016] and adverse mutations [HR 2.0 (95% CI: 1.5-2.8), P<0.001].
Table 3. Main clinical and biological characteristics of patients according to the presence or absence of mutations in genes of the RAS-BRAF- MAPK-ERK pathway in the subgroup with unmutated IGHV chronic lymphocytic leukemia.
Parameter
Gender
Age (years), median (range) Binet stage
Rai stage
Lymphocytes count (x109/L), median (range) Absolute CLL cells count (x109/L), median (range) Hemoglobin (g/L), median (range)
Platelets (x109/L), median (range)
B2 microglobulin
Lactate dehydrogenase
CD49d
CD38
ZAP-70
Genetics
Driver mutations
NOTCH1
SF3B1
TP53
BIRC3
ATM
Treated
5-year TTFT (95% CI) 5-year OS (95% CI) 5-year t-DLBCL
Category
Male (%)
A B C
0 I-II III-IV
UNV UNV >30% >30% ≥20%
P-value 16 (76%) ns
61 (44-78)ns
18/20 (90%)
1/20 (5%) ns 1/20 (5%)
11/20 (55%)
8/20 (40%) ns
1/20 (5%)
12 (1-26) ns 7 (0.7-83) ns
149 (125-159) ns 163 (99-315) ns 7/15 (47%) ns
Unmutated (n=145)
94 (65%)
61 (18-93)
105/142 (74%) 32/142 (22%) 5/142 (4%)
67/141 (47%) 66/141 (47%) 8/141 (6%)
10.7 (1-106)
8 (0.8-114)
140 (45-166)
210 (49-470)
57/128 (45%)
15/137 (11%)
42/89 (47%)
61/136 (45%)
77/1131 (59%)
38/102 (37%) 22/102 (22%) 21/102 (20%) 5/102 (5%)
96/145 (66%) 43/145 (30%) 21/145 (15%) 9/134 (7%) 30/145 (21%) 38/145 (26%) 108/145 (75%) 78% (68-88) 70% (60-80) 9% (5-13)
Mutated (n=21)
6/16 (37%)
8/11 (73%) ns
10/19 (53%) ns 13/18(72%) ns 1/10 (10%) ns
0.011
del(13q)(q14.3) Trisomy 12 del(11q)(q22.3) del(17p)(p13.1)
6/10 (60%)
0/10 (9%) ns
1/10 (10%) ns 14/21(67%) ns 5/21 (24%) ns
1/21 (5%) ns 2/20 (10%) ns 2/21 (12%) ns 3/21 (14%) ns
0.015
≥3 Mutated Mutated Disrupted Disrupted Disrupted
A&B
U-IGHV
All
20/21 (95%) 90% (76-100) 84% (64-100)
0.048 0.025 0.020
12% (0-26) ns
TTFT: time to first treatment; OS: overall survival; 95% CI: 95% confidence interval; t-DLBCL: transformation into diffuse large B-cell lymphoma (Richter syndrome); ns: not sig- nificant: UNV: above normal value: 95% CI: 95% confidence interval; U-IGHV: unmutated IGHV genes
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