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ASH 2022: Dr. Talha Munir on How IgHV Mutation Status in Chronic Lymphocytic Leukemia (CLL) Affects Response to Taking Ibrutinib in Combination with Venetoclax

In science and medicine, information is constantly changing and may become out-of-date as new data emerge.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.

The Bottom Line:

In this study, patients with the unmutated IgHV gene responded better when taking a combination of ibrutinib + venetoclax than patients with mutated IgHV, and were more likely to achieve undetectable measurable residual disease (uMRD) in the peripheral blood and bone marrow.

Who Performed the Research and Where Was it Presented:

Dr. Talha Munir from St. James’s University Hospital and colleagues presented the results at the American Society for Hematology Annual Meeting in 2022.


IgHV mutation status is one of the most important predictors of how much time will pass before the first treatment is needed in those with CLL and SLL. Those with unmutated IgHV have a form of the disease that tends to grow and progress very quickly. In addition, those with unmutated IgHV do not respond well to chemoimmunotherapy, with most relapsing within 2-3 years. Those with mutated IgHV have a more slow-growing or indolent disease and respond well to chemoimmunotherapy.

In this interview, Dr. Brian Koffman interviewed Dr. Talha Munir, a hematologist at St. James’s University Hospital in Leeds, United Kingdom. They discussed how IgHV mutational status influences the eradication of CLL / SLL in response to the combination therapy of ibrutinib + venetoclax.

Methods and Participants:

The FLAIR trial is an ongoing phase 3 clinical trial with an adaptive trial design. While it initially compared chemoimmunotherapy (FCR) against the combination of ibrutinib + rituximab, it later compared ibrutinib against the combination of ibrutinib + venetoclax. Enrolled patients had not been previously treated and received either ibrutinib alone or the combination of ibrutinib + venetoclax for up to 6 years, and the duration of therapy was defined by MRD status. Thus far, 523 patients have been randomly assigned to take either ibrutinib alone or a combination of ibrutinib + venetoclax.


  • This report is an interim analysis of the first 274 patients randomized to the study.
  • IgHV data was available for 256 patients, with 48% IgHV unmutated and 45% IgHV mutated.
  • In the ibrutinib + venetoclax arm, 80% of IgHV unmutated patients were uMRD (MRD negative) in the bone marrow within 24 months, compared with 56% of IgHV mutated patients.
  • In the peripheral blood, the uMRD rates in IgHV unmutated patients were 55% at nine months, and 83% at 24 months post-randomization.
  • For IgHV mutated patients, uMRD rates in the peripheral blood were 33% at nine months, and 64% at 24 months.
  • No new safety signals were observed.


Historically, those with unmutated IgHV have had a worse prognosis. However, that may no longer be true in this new era of targeted therapies. In this study, those unmutated IgHV responded better to the combination of ibrutinib + venetoclax than patients with mutated IgHV and were more likely to achieve uMRD in the peripheral blood and bone marrow.

Links and Resources:

Watch the interview on the abstract here:

You can read the actual ASH abstract here: Combination of Ibrutinib Plus Venetoclax with MRD-Driven Duration of Treatment Results in a Higher Rate of MRD Negativity in IGHV Unmutated Than Mutated CLL: Updated Interim Analysis of FLAIR Study

Take care of yourself first.

Ann Liu, PhD