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BTK and PLCG2 mutations could potentially identify early post-ibrutinib CLL relapse

Feb 23, 2017

In February, Jennifer Woyach from the Ohio State University, Columbus, Ohio, and colleagues published in the Journal of Clinical Oncology the results of a part-retrospective study of R/R CLL patients into the natural history of post-ibrutinib relapse. The study included data from four sequential clinical trials (NCT01105247, NCT01217749, NCT01589302, and NCT01578707) with a median follow-up of 3.4 years.

Key Highlights:

  • Included 308 pts from four prior studies treated with ibrutinib (monotherapy 237 pts, and 71 pts with additional ofatumumab); 40% pts had del(17)p, 27% del(11)q
  • Remained on therapy = 44%
  • Discontinued = 51% (52.5% due to disease progression, 24% due to AEs)
  • Of the 75 pts who discontinued due to AEs, 31 had infections and 21 died due to infections
  • Median time to ibrutinib discontinuation = 98 days
  • Age (≤ 65 years), del(17)p status, and complex karyotype presence ( > 3 abnormalities) independently associated with risk of disease progression
  • Ion Torrent deep sequencing results, 46 relapsing pts with samples at relapse:
    • BTK C481 mutation in 31 pts
    • PLCG2 mutation at ‘hotspots’ in 3 pts
    • Both BTK C481 and PLCG2 mutations in 6 pts
    • Overall, 40 pts (87%) had PLCG2 and/or BTK mutations
  • 112 pts enrolled in BTK and PLCG2 mutation monitoring scheme
    • Entire coding region analysis performed every three months
    • BTK C481S detected in 8 pts before clinical relapse
    • BTK C481S detected in another 8 pts of which 4 pts have increasing lymph node size
    • No signs of progression in pts without BTK C481S at greater than 1% allelic frequency
  • BTK or PLCG2 mutational clones were detected prior to clinical relapse at an estimated median of 9.3 months (95% CI, 7.7–11.7 months)

In conclusion, the authors state that due to the increase in ibrutinib treatment, and therefore ibrutinib resistant disease in CLL, biomarkers that can predict or identify early relapse are an important tool. The authors state that data presented here indicate that BTK and PLCG2 mutations could be useful biomarkers in spotting early post-ibrutinib CLL relapse.


Purpose. Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods. Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results. With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion. Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.

  1. Woyach J. et al. BTK C481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. Journal of Clinical Oncology. 2017 Feb 13. DOI: 1200/JCO.2016.70.2282. [Epub ahead of print 2017 Feb 13].