Smart Patients Get Smart Care™

The World’s Leading Authority for Chronic Lymphocytic Leukemia Patients

New England Journal of Medicine February 24, 2022: Mechanism of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors (BTKi)

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.


Covalent BTKi treatments such as ibrutinib and acalabrutinib have transformed the treatment of  B-cell cancers such as chronic lymphocytic leukemia/small lymphocytic leukemia (CLL / SLL).   BTKi’s irreversibly (covalently) attach to the Bruton Tyrosine Kinase (BTK) receptor site on CLL / SLL cells called C481S.

However, mutations at this binding site can render current covalent BTK inhibitors (BTKi’s) ineffective treatments. On the other hand, noncovalent reversible BTKi’s like pirtobrutinib can outsmart this C481S mutation and remain effective. Unfortunately, like in the game of cat and mouse, cancer cells can develop other mutations to counter Pirtobrutinib, so continuous research is needed to outsmart these mutations.

In this study published in the New England Journal of Medicine in February 2022, a large group of researchers performed genetic testing in patients before treatment and in patients that relapsed or failed treatment with the noncovalent BTKi,  Pirtobrutinib.   These tests allowed the researchers to discover many other genetic mutations in CLL / SLL cells. 


  • Covalent BTKi’s like acalabrutinib attach permanently to site C481S on BTK in CLL / SLL cells and thus successfully block the B-cell receptor (BCR), leading to the death of cancerous B-cells. 
  • However, the BTK site C418S on CLL / SLL cells can adapt or mutate, preventing binding of the irreversible BTK inhibitors and thus rendering covalent BTKi’s ineffective therapies.
  • Noncovalent BTKi’s, like pirtobrutinib, attach temporarily and can outsmart the C481 mutation, thereby retaining effectiveness in treating CLL / SLL. However, even this new therapy can fail due to different genetic mutations.
  • The BRUIN phase 1-2 study used a pirtobrutinib to treat CLL / SLL patients that had relapsed or failed to respond to either a covalent BTKi or at least 2 other types of therapy.
  • In the current study, 55 CLL / SLL patients were selected from the phase 1-2 BRUIN study. They all underwent pre-treatment genomic studies before starting on pirtobrutinib. Of these, 9 patients relapsed and had, repeat genomic testing.
  • The repeat testing in the relapsed CLL / SLL patients uncovered other mutations (V416L, A428D, M437R, T47RI, and L528W)  at sites on the kinase portion of BTK. These mutations rendered both noncovalent and some covalent BTKi’s ineffective.
  • Another mutation of a BTK substrate, phospholipase C gamma 2 (PLCy2), was also identified. This is a downstream mutation that leads to diminished reliance of CLL / SLL cells on BTK. This, in turn, limits the effectiveness of BTKi’s.
  • The next step in the cat and mouse game between CLL / SLL mutations and various therapies is identifying new medications to outsmart the newly identified mutations.


Although covalent BTKi’s like ibrutinib and acalabrutinib have revolutionized the treatment of CLL / SLL, mutations of the B cancer cells render these therapies ineffective in some cases.   Other medications, such as the noncovalent BTKi,  pirtobrutinib, can be successful in many patients that failed prior treatments.   However, because of other mutations, it is not an invincible therapy.   The next step will be to develop newer treatments to outsmart the mutations for patients that relapse or fail older treatments.

SMART PATIENTS GET SMART CARE™. Be sure to ask your doctor about available, newer, more promising therapies or consider entering a clinical trial.

Stay Strong. We are all in this together.

Michael Green MD and CLL patient

To review the abstract and a short video explanation from the New England Journal of Medicine article, please see Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors. The full article is behind a paywall.

To learn more about pirtobrutinib, see:

EHA 2021 Top Pick #5: Pirtobrutinib (LOXO-305), A Next Generation, Highly Selective, Noncovalent BTK Inhibitor in Previously Treated CLL / SLL: Results From the Phase I/II BRUIN Study