iwCLL 2017 | Progression on ibrutinib in patients with somatic mutations in the BCR and NF-kB pathways 

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):

• Overall, 84 patients enrolled
• Ibrutinib 420mg one daily until disease progression or intolerable side effects
• PFS at 36 months = 83.6%
• Higher risk of progression found in patients with del(17p)/mutated TP53, Rai stage III/IV, and R/R CLL
• Targeted sequencing found mutations in BTK and/or PLCG2 in 9/13 (69%) patients
• Mutations identified up to 15.4 months before clinical progression, but not at treatment initiation

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: