Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition

Thomas E. Lew, Victor S. Lin, Edward R. Cliff, Piers Blombery, Ella R. Thompson, Sasanka M. Handunnetti, David A. Westerman, Bryone J. Kuss, Constantine S. Tam, David C.S. Huang, John F. Seymour, Andrew W. Roberts, Mary Ann Anderson

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)
55 Downloads (Pure)


Covalent Bruton tyrosine kinase inhibitors (BTKi’s) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n512; BTKi, then venetoclax, n 5 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.

Original languageEnglish
Pages (from-to)4054-4058
Number of pages5
JournalBlood Advances
Issue number20
Publication statusPublished - 26 Oct 2021


  • Bruton tyrosine kinase inhibitors
  • BTKi’s
  • B-cell lymphoma 2
  • BCL2
  • Chronic Lymphocytic Leukemia (CLL)
  • Patient outcomes


Dive into the research topics of 'Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition'. Together they form a unique fingerprint.

Cite this