Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Patients with double-refractory disease, which is resistant to both BTK and BCL2 inhibitors, have worse outcomes than patients who have been treated with both drugs but have not developed resistance (double-exposed).
Who Performed the Research and Where Was it Presented:
Dr. Inhye Ahn from Dana-Farber Cancer Institute and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2024.
Background:
Targeted therapies, which target specific proteins that control the growth and survival of cancer cells, have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Currently, there are two main classes of targeted therapies that are used to treat CLL / SLL: Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) and B-cell lymphoma 2 (BCL2) inhibitors (venetoclax). As BTK inhibitors and BCL2 inhibitors have become more commonly used over the last decade, there are more patients who have been treated with both types of drugs. Over time, patients can become “double-refractory,” meaning that they develop resistance to the drugs while on active treatment. Other patients are ”double-exposed,” meaning that they have been treated with both drugs, but stopped for reasons other than progressive disease, such as intolerable side effects or reaching the end of a planned treatment course. For this study, researchers looked at outcomes for patients with CLL who were either double-refractory or double-exposed.
Methods and Participants:
This was a retrospective study using data from the Dana-Farber Cancer Institute database.
Results:
- From a database of over 1000 patients with CLL, researchers were able to identify 30 double-refractory patients and 65 double-exposed patients.
- The double-refractory group had a higher proportion of patients with high-risk features including unmutated IGHV, TP53 mutations or deletions, and BTK mutations.
- Median overall survival from time of CLL diagnosis was 12 years for double-refractory patients and 21 years for double-exposed patients.
- With a median follow-up of 15 years, deaths occurred in 63% of the double-refractory group and 25% of the double-exposed group.
- The leading cause of death was progressive disease (42%) in the double-refractory group, while in the double-exposed group it was infections (25%).
- Patients developed double-refractory disease at a median of 7 years after their first therapy.
- Once double-refractory disease developed, the median overall survival was 2 years.
Conclusions:
Double-refractory CLL is very different from double-exposed CLL, with patients with double-refractory disease having worse outcomes. Patients with double-refractory CLL are more likely to have high-risk features, and they had a median survival of 2.2 years after developing double-refractory disease. This was achieved even with the use of cellular therapies, such as CAR-T or allogeneic stem cell (bone marrow) transplants, or the reversibly binding BTKi, pirtobrutinib. Patients with double-exposed CLL had better survival outcomes, and they responded well to subsequent lines of therapy. While double-refractory CLL is a challenging condition to treat, patients should remain hopeful and consider participating in clinical trials, as promising agents are being developed, including BTK degraders.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Characteristics and Outcomes of Patients with Double Refractory (DR) or Double Exposed (DE) CLL
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