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Resistance Mutations in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib

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Authored by Dr. Brian Koffman

The Bottom Line:

Mutations at BTK C481 are the most common mutations seen in pooled trial data of chronic lymphocytic leukemia (CLL) patients on ibrutinib, leading to resistance and progressive disease (PD). Other resistance mutations include ones seen in PLCƔ2, which are much rarer (<5%), and BTK mutations affecting the L528 location that develops in < 1% of patients on ibrutinib. That compared to ∼54% reported with zanubrutinib. Understanding these mutations and how well different BTKi do with each can help us guide the choice of BTKi and appropriate sequencing of therapies.

Who Performed the Research and Where Was it Presented:

The research paper titled Bruton’s Tyrosine Kinase and Phospholipase C-Gamma 2 Mutational Profiles in Pooled Analysis of Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib was presented by Inhye E. Ahn, MD, Assistant Professor, Dana-Farber Cancer Institute at the International Workshop on CLL (iwCLL) 2023 Conference held in Boston, MA.


Most CLL patients treated with ibrutinib do well with durable remissions. It drastically improved outcomes and prolonged survival. It works by blocking signaling from the B-cell receptor (BCR) on the cell surface by inhibiting BTK. Since CLL cells are “addicted” to BCR signaling, blocking it leads to excellent disease control. However, over time, mutations are acquired that may confer resistance and lead to PD. Resistance to BTK inhibitors is often due to changes in the BTK binding site where the inhibitor attaches to block the pathway, most commonly at C481. This prevents all the approved irreversible or covalently binding BTKi (ibrutinib, acalabrutinib, and zanubrutinib) from binding, so they can no longer inhibit BTK. Another way the cancer escapes control is by the downstream activation of the pathway by a gain of function mutation in phospholipase C-Ɣ2 (PLCƔ2) genes that turn on the signaling again. This is much rarer. BTK C481 mutation is by far the most common mutation found in BTK inhibitor-resistant CLL. New non-C481 BTK mutations have recently been discovered, including BTK L528W, which has been reported in patients treated with ibrutinib, zanubrutinib, and pirtobrutinib. BTK L528W was reported in 54% and 4% of patients treated with zanubrutinib and ibrutinib, respectively, and is associated with resistance to pirtobrutinib, a reversible or non-covalent BTK inhibitor that usually works well in patients with BTK C481 mutations. This research pools data to look at all the various resistance mutations that develop while patients are on ibrutinib.

Participants and Methods:

Blood samples were collected across six clinical trials evaluating ibrutinib. 419 CLL patients were studied.


  • There were 247 previously untreated and 172 relapsed or refractory (R/R) patients.
    • The median age was 69 years.
    • 46% had unmutated IGHV.
    • 39% had deletion 17p and/or TP53 mutation.
  • At the median follow-up of 43.7 months, 132 patients progressed or died, including 69 PD events in R/R CLL and 22 PD events in treatment-naive CLL.
  • 17% of patients develop some BTK mutation.
  • More than half with the mutation were not progressing when their blood was sampled.
  • BTK mutations were over 8-fold higher among patients with R/R CLL (35%) than those with previously untreated CLL (4%).
  • Similarly, PLCƔ2 mutations were more frequently found in R/R CLL (14%) than previously untreated CLL (6%).
  • In vitro (test tube) data concerning effective doses shows that:
    • Pirtobrutinib does very well with mutated C481, which has been proven out of the clinic.
    • The three irreversible BTKI do not do well at killing cells with C481.
    • Ibrutinib has the most potent cell-killing activity againstT474I.
    • Acalabrutinib has the most potent cell-killing activity against L528W.
    • Pirtobrutinib and zanubrutinib do not do well in vitro with mutated L528W.

Types of Mutations

  • The most frequently detected mutations affected BTK C481, which included C481S (16% of all evaluable patients), C481Y (3%), and C481R (2%).
  • BTK T474I and L528W were rare, found in only 0.7% (2 previously untreated and 1 R/R CLL) and 0.5% (2 previously untreated CLL), respectively.
  • Sixty-four (15%) patients had mutations exclusively at the BTK C481 locus.
  • Five (1%) patients had co-occurring BTK C481 and non-C481 mutations.
  • Two (< 1%) patients had non-C481 mutations only.
  • Two patients with BTK L528W had co-occurring BTK C481 mutations and achieved partial response to ibrutinib before PD (duration of response: 20 and 60 months, respectively.


Our understanding of all the mechanisms of resistance to BTKi, including ibrutinib, is incomplete. Some CLL patients progress, and we don’t know why. We can’t find any mutations that explain why the drug is no longer working. Some have resistance mutations but don’t progress, at least for some time. However, this research advances our knowledge about some common and rare resistance mechanisms in play. This study and more like it can help guide choices of BTKi when therapies are likely to stop working and the best drug sequencing for each patient. More data are needed to confirm these findings and to look for the other reasons these great drugs often eventually fail CLL patients. There is much work left to be done. While CLL patients live longer and better lives, most therapies eventually stop working. This research advances our understanding as to why this happens.

Watch my monologue on this research:

Resistance Mutations from Ibrutinib in Chronic Lymphocytic Leukemia (CLL)

Stay strong; we are all in this together.

Brian Koffman MDCM (retired), MS Ed
Executive Vice President and Chief Medical Officer
CLL Society