The Bottom Line:
Measurable residual disease (MRD)-guided treatment of chronic lymphocytic leukemia (CLL) with ibrutinib plus venetoclax significantly increased time in remission and improved patients’ survival chances.
Who Performed the Research and Where Was it Presented:
Dr. Peter Hillmen from the University of Leeds and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.
Background:
MRD testing measures the number of cancer cells in the blood or bone marrow. Routine testing with flow cytometry can detect one CLL / SLL cell in 10,000 cells, and some other types of testing are even more sensitive. Patients who become MRD negative (meaning no CLL / SLL cells can be detected, a.k.a. undetectable MRD) have longer remissions. CLL clinical trials have been testing MRD-guided treatment discontinuation, meaning that the length of treatment depends on how quickly patients reach undetectable MRD. These trials usually test combination therapies with two or three drugs that work through different mechanisms of action to get patients into deep remissions faster.
Methods and Participants:
FLAIR is a phase 3 clinical trial for untreated CLL. Patients were randomly assigned to one of three treatment groups:
- FCR (fludarabine, cyclophosphamide, and rituximab; a type of chemoimmunotherapy)
- Ibrutinib
- Ibrutinib plus venetoclax (I+V)
The results presented here specifically compared FCR with I+V. MRD was assessed after one year and then every six months after that. If the peripheral blood and bone marrow were MRD negative, then the duration of I+V was double the time between the start of I+V and the initial MRD negative result. For example, if it took one year for a patient to become MRD negative, they would be treated for two years.
Results:
- Between 2017 and 2021, 263 patients were randomized to FCR, and 260 were randomized to I+V.
- As of May 2023 (when the data was analyzed), the median follow-up was over 3.5 years.
- At 3 years, 23% of patients in the FCR group had progressed compared with only 3% in the I+V group, meaning progression-free survival in the I+V group was 97%.
- At 3 years, 7% of patients in the FCR group had died compared with only 2% in the I+V group, meaning overall survival in the I+V group was 98%.
- Most patients in the I+V group could stop treatment after 2 years, and 75% had stopped treatment by 4 years.
- At the time of analysis, 91% of patients in the I+V group were MRD negative in the blood with up to 5 years of follow-up.
Conclusions:
These results are very promising and clearly show that MRD-guided treatment with I+V increased time in remission and improved patients’ chances of surviving. This study is still ongoing, and patients are still being followed. Still, these results align with previous research showing that patients who achieved uMRD after fixed-duration I+V treatment continued to have excellent outcomes four years after stopping initial therapy. It remains to be seen if this type of MRD-guided approach would also work with different combination treatments.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study.
Take care of yourself first.
Ann Liu, PhD
