Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, (MDCM )retired, MSEd
The Bottom Line:
Measurable residual disease (MRD)-guided therapy is a powerful tool for tailoring CLL treatment to the individual patient. MRD-guided ibrutinib–venetoclax significantly improved outcomes for previously untreated patients with CLL compared with ibrutinib or chemoimmunotherapy.
Who Performed the Research and Where Was it Presented:
Dr. Talha Munir from Leeds Teaching Hospitals NHS Trust and St. James’s University Hospital, along with colleagues, published the results in the New England Journal of Medicine in 2023. Dr. Munir also presented updated results at the European Hematology Association (EHA) annual meeting 2025.
Background:
When patients receive treatment for any type of cancer, one of the key outcomes is their response to treatment. For chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), response to treatment can be assessed by looking at a combination of clinical factors, including lab values (ie, white blood cell counts), lymph node size, spleen size, and liver size. These are the measures healthcare providers usually look at to determine whether patients have responded to treatment, and patients are categorized as having a complete response or a partial response based on the extent of change in these markers. However, even though patients may have a clinical response, there still may be CLL cells present in their bodies.
MRD is a much more sensitive way of determining the level of response / remission in patients with CLL / SLL. This is a test that quantifies how many CLL cells are present in the blood or bone marrow, and it can detect CLL cells at extremely low levels (as low as 1 in 10,000 [1 x 10-4] or 1 in a million cells [1 x 10-6] depending on the type of test). If patients have undetectable measurable residual disease (uMRD), it means that the number of CLL cells in their body is less than what can be measured by the test, which indicates a deep remission. Reaching uMRD status is associated with longer progression-free survival. While continuous therapies like BTK inhibitors usually do not produce uMRD, fixed-duration combination therapies that combine BTK inhibitors with BCL2 inhibitors have been successful in helping patients get to uMRD. Researchers are interested in whether MRD testing can be used to guide the duration of therapy, and Dr. Munir and colleagues have been testing this question in the FLAIR trial.
Methods and Participants:
The FLAIR trial is a phase 3 adaptive clinical trial for patients with previously untreated CLL. Patients were randomly assigned to one of three treatments:
- FCR chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab)
- Ibrutinib
- Ibrutinib + venetoclax
The duration of ibrutinib-ventoclax treatment was guided by the time it took patients to reach uMRD, with treatment time being double the time to uMRD. So if a patient were MRD-negative at one year, they would receive an additional year of therapy for a total of two years of treatment. If a patient were MRD-negative at two years, they would receive four years of treatment in total. The maximum duration of therapy patients could receive was six years.
Results:
- A total of 786 patients were randomized to FCR (n=263), ibrutinib (n=263), and ibrutinib-venetoclax (n=260).
- Ibrutinib-venetoclax provided superior progression-free survival (97% vs. 77% at 3 years) and overall survival (98% vs 93% at 3 years) compared with FCR.
- Interestingly, patients with unmutated IgHV status (which historically has had a worse prognosis) actually responded better to ibrutinib-venetoclax and reached uMRD more quickly than patients with mutated IgHV status.
- Combining ibrutinib with venetoclax did not result in any new unexpected safety signals, and side effects were typical of what is usually expected with the two drugs.
- Updated results from EHA 2025 show that with a median of 5 years of follow-up, ibrutinib-venetoclax provides significantly better progression-free survival and overall survival compared with ibrutinib.
- The 5-year estimated progression-free survival rates were 94% for ibrutinib-venetoclax, 81% for ibrutinib, and 62% for FCR.
- The 5-year estimated overall survival rates were 96% for ibrutinib-venetoclax, 91% for ibrutinib, and 88% for FCR.
Conclusions:
MRD-guided ibrutinib-venetoclax significantly improved outcomes for previously untreated patients with CLL compared with ibrutinib or FCR. Because there is a lot of variability in how individual patients respond to treatments, MRD-guided therapy is a powerful tool for tailoring treatment to individuals. Currently, MRD testing is mainly used in clinical trials and academic research centers. There are still regulatory issues to be resolved before it can transition to wider use in community practices. However, thus far, it could be beneficial for guiding CLL treatment, especially in high-risk patients.
Links and Resources:
Watch the interview on the abstract here:
You can read the full paper here: Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease.
You can read the actual EHA abstract here: Ibrutinib Plus Venetoclax With MRD-Guided Duration Of Treatment Is Superior To Both Continuous Ibrutinib Monotherapy And FCR For Previously Untreated CLL: Report Of The Phase III UK FLAIR Study.
