Page 112 - 2020_11-Haematologica-web

S. Jaramillo et al.
Table 1. Baseline characteristics early stage chronic lymphocytic leukemia (CLL) according to subset assignment.
Target analysis population, n (%)
Age at study entry (years) median (range) Gender, n (%) male
ECOG performance status median (range)
CLL-IPI risk group, n (%) Low
Intermediate High
Very high
Leukocyte count (x 109/L)
median (range)
Serum thymidine kinase c(U/L) median (range)
Serum β2-microglobulin(MG/L) median (range)
Deletion 11Q by FISH, n (%) Deletion 17P by FISH, n (%) Trisomy 12 by FISH, n (%) Deletion 13Q by FISH, n (%) NOTCH1 MUTATED, n (%) SF3B1 MUTATED, n (%)
Richter syndrome status, n (%)
Subset #1
8 (1.35%)
64 (56-70) 6 (75.0)
0 (0-0)
8
0 (0.0)
6 (75.0)
2 (25.0)
0 (0.0) 36.9 (19.2-128.7) 13.0 (3.5-109.0) 2.3 (1.6-6.7) 3 (37.5)
0 (0.0)
1 (12.5)
3 (37.5)
2 (25.0)
2 (25.0)
0
Subset #2
16 (2.7%)
62 (45-75) 6 (37.5) 0 (0-1) 15
9 (60.0) 6 (40.0) 0 (0.0) 0 (0.0) 23.9 (4.7-94.4) 8.9 (2.9-23.9) 2.8 (1.1-4.4) 1 (6.7) 0 (0.0) 0 (0.0) 9 (60.0) 1 (6.7) 8 (53.3)
0
Subset #4
8 (1.35%)
58 (41-72) 4 (50.0) 0 (0-0)
Subset #8
2 (0.337%)
61 (56-66) 1 (50.0) 0 (0-0)
u-IGHV
174 (29.39%)
60 (37-75) 114 (65.5) 0 (0-1)
m-IGHV
384 (64.86%)
60 (32-75) 233 (60.7) 0 (0-2)
All
592
60 (32-75) 364 (61.5) 0 (0-2)
8 2 160 371 564
8 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 21.3 (4.7-94.4) 3.8 (2.0-6.5) 1.5 (1.0-3.4) 0 (0.0) 0 (0.0) 1 (12.5) 2 (25.0) 0 (0.0) 0 (0.0)
0
0 (0.0) 2 (100.0) 0 (0.0) 0 (0.0) 10.7 (8.9-12.4) 8.6 (6.5-10.6) 1.8 (1.3-2.3) 0 (0.0) 0 (0.0) 2 (100.0) 1 (50.0) 1 (50.0) 0 (0.0)
0
0 (0.0) 130 (81.3) 26 (16.3) 4 (2.5) 23.3 (4.6-184.0) 7.3 (2.0-56.0) 2.0 (0.2-9.4) 32 (19.6) 7 (4.3) 33 (20.0) 87 (52.4) 10 (6.6) 17 (11.3) 4 (2.3)
347 (93.5) 16 (4.3) 7 (1.9)
1 (0.3) 20.4 (6.3-184.2) 5.1 (1.1-80.0) 1.7 (0.4-8.9) 5 (1.3)
8 (2.1) 20 (5.3) 250 (67.2) 4 (1.1) 11 (3.1) 5 (1.3)
364 (64.5) 160 (28.4) 35 (6.2) 5 (0.9) 21.2 (4.6-184.2) 5.7 (1.1-109.0) 1.8 (0.2-9.4) 39 (6.9) 15 (2.7) 51 (9.1) 295 (52.4) 18 (3.4) 38 (7.1) 9 (1.5)
n: number of cases; u: unmutated; m: mutated; IGHV: non-subset immunoglobulin heavy variable; ECOG: Eastern Cooperative Oncology Group; IPI: International Prognostic Index;FISH: fluorescence in situ hybridization.
expressing the IGHV3-21 gene. Among those, 16 cases (2.7%) belonged to subset #2, of which 6 cases (1%) were u-subset #2 and 10 cases (1.7%) were m-subset #2. The remaining 13 cases (2.2%) carried heterogeneous (non- subset) BcR IG (IGHV3-21). Of these, 3 (0.5%) were u- IGHV3-21 and 10 (1.7%) were m-IGHV3-21 (Online Supplementary Table S1).
For patients requiring front-line treatment from the CLL8, CLL10 and CLL11 trials or advanced stage cohort, immunogenetic data were available in 1,861 cases (86.2%), of which 39 (2.1%) were assigned to subset #1, 61 (3.3%) to subset #2, 11 (0.6%) to subset #4, and 16 (0.9%) to subset #8. The remaining 1,734 cases did not belong to these subsets; 1,088 (58.4%) were U-CLL and 646 (34.7%) cases were M-CLL. For the second analysis, we identified 126 cases (6.8%) expressing IGHV3-21 BcR IG. Of these, 61 (3.3%) were assigned to subset #2, 18 (1.0%) were u-subset #2, and 43 (2.3 %) m-subset #2, while 65 (3.5%) cases belonged to the group expressing heterogeneous IGHV3-21. Of these, 35 (1.9%) were u-IGHV3-21 and 30 (1.6%) were m-IGHV3-21 (Online Supplementary Table S2).
Association of subsets with clinical and biological characteristics
Clinical and biological characteristics in the early stage CLL cohort according to subset assignment and IGHV mutational status are listed in Table 1. Despite the size of the overall cohort, small case numbers in patient sub- groups precluded valid statistical assessment, but a pattern similar to that observed in the advanced stage cohort (see below) was seen. Subset #1 showed a high frequency of
del(11q) and NOTCH1 mutations, subset #2 had a lower rate of male patients and a high frequency of SF3B1 muta- tions, and subset #4 were younger at study entry. Both cases of subset #8 had trisomy 12 and intermediate risk according to CLL-IPI, and neither of them displayed a Richter transformation. In the second analysis, when we compared m-subset #2 with m-IGHV3-21 and m-IGHV, we found an imbalance of SF3B1 mutations (P<0.001) and a higher presence of del(11q) (P=0.014).
The clinical and biological characteristics of the advanced stage cohort according to BcR IG stereotype and IGHV SHM status are listed in Table 2. Subset #1 together with subset #8 showed higher frequencies of NOTCH1 mutations and del(11q). Subset #2 demonstrated an enrichment for SF3B1 mutations. As in the early stage cohort, subset #4 were younger at diagnosis. Finally, sub- set #8 showed a higher frequency of Richter transforma- tion. In the second analysis, we observed a higher preva- lence of del(13q) in u-subset #2 (88.9%) compared to the u-IGHV3-21 (46.9%) and u-IGHV patients (45.1%, P=0.001). A higher frequency of SF3B1 mutations was also seen in subset #2 patients independently of the IGHV SHM status (u-subset #2, 41.7 % and m-subset #2, 46.7%, respectively). M-subset #2 showed a higher prevalence of del(11q) compared to m-IGHV3-21 and m-IGHV (32.5% vs. 13.3% vs. 5.5%, respectively).
Association between stereotyped subsets and clinical outcomes
After a median observation time of 97.8 (range, 2.5- 166.9) months (ms) of the early stage cohort, there were 246, 362 and 106 events for TTFT, PFS, and OS, respec-
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