CLL/SLL|DLBCL

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

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:

 

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%)

N (range or %)

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:

Reference:
  1. Sun C. Progression on ibrutinib in patients with somatic mutations in the BCR and NF-kB pathways. XVII International Workshop on Chronic Lymphocytic Leukemia; 2017 May 12–15; New York, USA.