Pirtobrutinib Recovers BTK Inhibition in Relapsed or Refractory CLL

By Patrick Daly - Last Updated: August 7, 2023

Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who fail a covalent Bruton’s tyrosine kinase (BTK) inhibitor treatment are in need of new treatment options. Pirtobrutinib is a novel, highly selective, noncovalent BTK inhibitor developed to treat this population. Anthony Mato, MD, and colleagues conducted a phase I-II trial on pirtobrutinib in patients with relapsed or refractory B-cell cancers.

The study, published in the New England Journal of Medicine, analyzed the safety of pirtobrutinib in all participants and the efficacy in participants who previously received a BTK inhibitor therapy. According to Dr. Mato, pirtobrutinib demonstrated clinical efficacy in patients with heavily pretreated CLL or SLL who experienced treatment failure on a covalent BTK inhibitor. The most common adverse events (AEs) were infections, bleeding, and neutropenia.

BTK Inhibitor Effective for Relapsed or Refractory CLL

The study enrolled 317 patients with CLL or SLL, of whom 247 had previously received a BTK inhibitor. Among the 247, the median number of previous lines of therapy was three (range, 1-11 lines), and 100 (40.5%) participants had also previously received a B-cell lymphoma 2 inhibitor such as venetoclax.

Reportedly, pirtobrutinib achieved an overall response rate of 73.3% (95% CI, 67.3-78.7) in patients with relapsed or refractory CLL or SLL who previously failed a BTK inhibitor. The study’s authors noted the overall rate increased to 82.2% (95% CI, 76.8-86.7) when partial responses with lymphocytosis were included. Additionally, the median progression-free survival was 19.6 months (95% CI, 16.9-22.1).

Among all 317 patients who received pirtobrutinib, infections occurred in 71.0%, bleeding in 42.6%, and neutropenia in 32.5%. At a median treatment duration of 16.5 months (range, 0.2-39.9 months), researchers stated AEs typically associated with BTK inhibitors were relatively infrequent, including hypertension in 14.2% of participants, atrial fibrillation or flutter in 3.8%, and major hemorrhage in 2.2%. In total, nine (2.8%) of 317 patients discontinued treatment due to a pirtobrutinib-related AE.

Dr. Mato and colleagues concluded that pirtobrutinib showed promising efficacy among patients with heavily pretreated CLL or SLL who had previously received a covalent BTK inhibitor.


Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696 

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