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Cited by 42Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentCutaneous lymphoproliferative disorders research

Pirtobrutinib: a new hope for patients with BTK inhibitor-refractory lymphoproliferative disorders

Open access
Thompson, Philip A, Tam, Constantine·2023·Blood Journal
DOI 10.1182/blood.2023020240PMC PMC10646821
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Abstract

Patients with lymphoproliferative disorders such as CLL and Mantle Cell Lymphoma (MCL) who are resistant to covalent BTK inhibitors (cBTKi), especially if also venetoclax-refractory, have an unmet therapeutic need. Pirtobrutinib, a non-covalent BTK inhibitor, achieves high response rates in cBTKi refractory patients regardless of mechanism of cBTKi resistance. This led to recent accelerated FDA approval in MCL. The toxicity profile in early studies suggests suitability for use in combination approaches. We summarize existing pre-clinical and clinical data with pirtobrutinib.

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  • In contrast to C481S, which retains the enzymatic activity of BTK, C481Y/R/F cause steric hindrance and structural clashing within the ATP binding pocket, preventing BTK Y223 autophosphorylation.

    “In contrast to C481S, which retains the enzymatic activity of BTK, C481Y/R/F cause steric hindrance and structural clashing within the ATP binding pocket, preventing BTK Y223 autophosphorylation (34, 37).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [37]

    The mechanism-of-action section reports kinase inhibition in C481S-mutated BTK, and the resistance section says many non-C481S mutants are kinase-dead and cannot autophosphorylate Y223. Table 1 lists C481Y and C481R among kinase-dead mutations. Our copy does not identify C481F or say that steric hindrance and structural clashing in the ATP pocket cause the loss of autophosphorylation. Page numbers are unavailable in our copy. (LLM, conf=0.82)

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Research works printed but not linked: 25

  1. [1]Hatashima A Karami M Shadman M Approved and emerging Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia Expert Opin Pharmacother 23 13 2022 1545 1557 35973973
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Authors
Thompson, P. A., & Tam, C.
Affiliations
  • The Royal Melbourne Hospital (AU)
  • The University of Melbourne (AU)
Corresponding author
Tam, Constantine
ORCID
Venue
Blood Journal
Publisher
American Society of Hematology
Published
2023-05-08
Volume
141
Issue
26
Pages
3137-3142
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2023020240
PMC
PMC10646821
OpenAlex
W4375852787
Cited by
42
References
6
Citations by year
2026: 4 · 2025: 23 · 2024: 14 · 2023: 1
FWCI
7.28
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Blood (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Dermatology › Cutaneous lymphoproliferative disorders research
Keywords
pirtobrutinib, BTK inhibitors, chronic lymphocytic leukemia, mantle cell lymphoma, BTK inhibitor resistance, venetoclax resistance, lymphoproliferative disorders, combination therapy, drug toxicity
MeSH terms
Antineoplastic Agents, Humans, Lymphoproliferative Disorders, Pyrazoles, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Mantle-Cell, Protein Kinase Inhibitors

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