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The second session at this year’s iwCLL was titled “Role of Non-Leukemic Cells and the Microenvironment in CLL Development”, and was jointly chaired by Silvia Deaglio (University of Turin, Torino, Italy) and Christopher Pepper (Cardiff University, Wales, UK).
A talk titled “Progression on ibrutinib in patients with somatic mutations in the BCR and NF-kB pathways” was given during this session by Clare Sun from the National Institutes of Health, Bethesda, Maryland.
The presentation began with a summary slide detailing resistance mechanisms to ibrutinib:
Following this, a phase II trial was outlined assessing ibrutinib in patients with CLL or SLL who require treatment and are older than 65 years, have del(17p), or have TP53 mutation (NCT01500733):
Clare Sun then asked two key questions: are there mutations in the BCR and NF-kB pathways at baseline? Can such mutations predict clinical outcome during ibrutinib treatment?
Upon whole exome sequencing of patients on ibrutinib monotherapy:
N (range or %) |
||
|
Current study |
Entire cohort |
---|---|---|
Patients |
45 |
84 |
Age |
66 (33–85) |
67 (33–85) |
Male |
27 (60%) |
49 (58%) |
Rai stage III/IV |
28 (62%) |
59 (70%) |
Del(17p) |
25 (56%) |
52 (62%) |
Previously treated |
19 (42%) |
32 (38%) |
In total, 23 somatic mutations in BCR and/or members of the NF-kB pathway were identified in 17 patients: 17 missense mutations (13 “damaging”; PolyPhen-2), 4 frameshift indels, and 2 splice site mutations.
Association with baseline features:
Prognostic factor |
BCR and/or NF-kB pathway mutations |
P value |
|
---|---|---|---|
No |
Yes |
||
Del(17p)/mutated TP53 |
67.9% |
58.8% |
0.7 |
U-IGHV |
60.7% |
58.8% |
1.0 |
R/R CLL |
35.7% |
52.9% |
0.4 |
Clare Sun then moved the talk on to discuss oncogenic CARD11 mutations in ABC-DLBCL, which is dependent on NF-kB activations via BCR and MYD88 signaling pathways. Ibrutinib results in better ORR in ABC- than GCB-DLBCL. However, no response occurred in ABC-DLBCL patients with mutations in TNFAIP3 or CARD11 (Wilson et al. 2015).
The presentation was concluded with a succinct summary slide:
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