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F. Diop et al.
are addicted to the non-canonical NF-κB pathway, and that BIRC3-mutated CLL are resistant to fludarabine both in vitro and in patients. It still remains to be clarified
whether NF-κB activation is the only molecular pathway that causes chemo-refractoriness in BIRC3-mutated CLL or whether other mechanisms are also involved.24-29
Table 1. Clinical data of FCR-treated chronic lymphocytic leukemia patients according to BIRC3 mutational status.
Characteristics
Male Female
Binet A
Binet B-C IGHV mutated
IGHV unmutated 17p deletion
No 17p deletion
11q deletion No 11q deletion
13q deletion
No 13q deletion Trisomy 12
No trisomy 12
Median follow-up (years)
Median PFS (years) PFS % (7 years) Median OS (years) OS % (7 years)
Total
N=287
N=287
N=280
N=274
N=273
N=273
N=272
Number of patients (%)
BIRC3 mutated patients (%) 5 (55.6%)
4 (44.4)
1 (11.1%)
8 (88.9%)
0 (0%) 9 (100%)
0 (0%)
9 (100%)
5 (55.6%) 4 (44.4)
3 (33.3%)
6 (66.6%) 4 (44.4%)
5 (55.6%)
BIRC3 wildtype patients (%) 193 (69.4%)
85 (30.6%)
32 (11.5%)
246 (88.5%)
100 (36.0%) 171 (61.5%)
13 (4.7%)
252 (90.6%)
42 (15.1%) 222 (79.9%)
108 (38.8%)
156 (56.1%) 46 (16.5%)
217 (78.1%)
198 (69.0%) 89 (31.0%)
33 (11.5%)
254 (88.5%)
100 (35.7%) 180 (64.3%)
13 (4.7%)
261 (95.3%)
47 (17.2%) 226 (82.8%)
111 (40.7%)
162 (50.3%) 50 (18.4%)
222 (81.6%) 6.8
4.6 31.0% 11.7 75.5%
PFS: progression-free survival; OS: overall survival; IGHV: immunoglobulin heavy variable gene.
Figure 5. Mutational profile of the FCR-treated cohort. Case-level mutational profiles of 287 patients treated with FCR (fludarabine, cyclophosphamide, rituximab). Each column represents one tumor sample, each row represents one gene. The fraction of tumors with mutations in each gene is plotted on the right. The number and type of mutations in each patient are plotted above the heatmap. Mutations are highlighted in red. IGHV mutational status, 17p deletion and 11q deletion are plotted at the bottom of the heatmap.
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