Prognostic impact of epigenetic classification in chronic lymphocytic leukemia: The case of subset #2

Figures & data

Figure 1. Epigenetic classification and hierarchical clustering of CLL patients. (A) Distribution of IGHV germline identity levels in the 3 epigenetic subgroups. (B) Bricks plot showing the methylation level of the of 5 CpG sites in 3 epigenetic subgroups. (C) Hierarchical clustering of the samples based on the methylation pattern of the 5 CpG signature.

Table 1. Main clinico-biological characteristics of the 3 epigenetic subgroups (n = 135).

Variable	N 135	n-CLL 49	i-CLL 29	m-CLL 57	P-value
Binet Stage	127	48	27	56
A	96 (75.6%)	29	22	48	<0.01
B	25 (19.7%)	15	5	6	0.03
C	6 (4.7%)	4	0	2	ns
IGHV mutational status	135	49	29	57
Mutated	69(51%)	3	13	53	<0.001
Unmutated	54 (40%)	46	5	3	<0.001
Subset #2	12 (9%)	0	11	1	<0.001
Chromosomal aberration	131	47	27	57
no aberration	29 (22%)	10	4	15	ns
del(13q)	65 (49.6%)	13	15	37	<0.001
del(11q)	22 (16.8%)	14	8	0	<0.001
del(17p)	4 (3%)	3	0	1	ns
trisomy 12	11 (8.4%)	7	0	4	0.07
Recurrent mutations^*		47	29	57
TP53 (n = 135)	5 (3.7%)	2	1	2	ns
NOTCH1 (n = 133)	10 (7.5%)	8	1	1	<0.01
SF3B1 (n = 133)	7 (5.26%)	5	2	0	0.04
CD38 (7%)	135	49	29	57
Low	86 (63.7%)	17	17	52	<0.001
High	49 (36.3%)	32	12	5	<0.001

* number of analyzed and mutated cases are indicated, ns: not significant.

Figure 2. Kaplan-Meier survival curve analysis for overall survival (OS) and time-to-first-treatment (TTFT) in epigenetic subgroups. (A) Impact of epigenetic classification on OS in 3 epigenetic subgroups. (B) Impact of epigenetic classification on OS when sub-classifying subset #2 and non-subset #2 i-CLL. (C) Impact of epigenetic classification on TTFT in 3 epigenetic subgroups. (D) Impact of epigenetic classification on TTFT when sub-classifying subset #2 and non-subset #2 i-CLL.

Table 2. Multivariate Cox regression analysis of epigenetic classification and established molecular prognostic markers for overall survival and time-to-first-treatment in CLL.

	Overall survival (n = 131)			time-to-first-treatment (n = 123)
Variable	HR	95% CI	p-value	HR	95% CI	P-value
Age^1	1.63	1.03–2.58	0.039	0.91	0.58–1.42	0.669
Unmutated IGHV	2.15	1.08–4.27	0.029	2.66	1.04–4.92	0.039
TP53 abnormalities	3.40	1.40–8.25	0.007	2.74	1.05–7.14	0.039
NOTCH1/SF3B1 mutations	1.96	1.07–3.58	0.030	1.69	0.90–3.16	0.101
n-CLL	2.36	1.05–5.27	0.037	3.67	1.54–8.77	0.003
i-CLL	2.31	1.18–4.55	0.015	3.90	1.97–7.73	<0.001

¹ above median (63.3 y), TP53 abnormalities: [(del(17p) and/or TP53 mutations], NOTCH1 and SF3B1 mutations were grouped together due to their low frequency in the present series, HR: Hazard ratio, CI: Confidence interval. All listed parameters were included in the multivariate analysis.