Medically reviewed by Dr. Brian Koffman
The Bottom Line:
Acalabrutinib produced durable responses in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at higher risk of disease progression. In addition, longitudinal mutational profiling identified some genes that may contribute to acalabrutinib resistance mechanisms in CLL.
Who Performed the Research and Where Was it Presented:
Dr. Clare Sun from the National Heart, Lung, and Blood Institute (NHLBI, a part of NIH) and colleagues presented the results at the American Society for Hematology Annual Meeting 2022.
Background:
When we treat CLL / SLL, it can change and mutate through a process called clonal evolution, which can lead to the development of treatment resistance. Progressive disease is driven by clonal evolution, and it is crucial to understand why resistance develops and try to predict it so that we can hopefully prevent it in the future. For example, it is well known that mutations in Bruton tyrosine kinase (BTK) can cause resistance to BTK inhibitors such as ibrutinib. Newer therapies, such as pirtobrutinib, are trying to find ways to overcome resistance mutations.
In this video, Dr. Nicole Lamanna, a CLL specialist at Columbia University Medical Center in New York, NY, interviewed Dr. Clare Sun, an Associate Research Physician at the National Heart, Lung, and Blood Institute in Bethesda, MD. They discussed a study examining mutations that occur in CLL throughout acalabrutinib therapy.
Methods and Participants:
This was a phase 2 clinical trial of acalabrutinib in patients with relapsed/refractory CLL or treatment-naïve CLL with high-risk genomic features (deletion 17p, TP53 mutation, or NOTCH1 mutation). Patients were randomized to receive acalabrutinib as 100 mg twice daily or 200 mg once daily. Tumor samples were collected annually, and next-generation sequencing was performed to look at 600 genes commonly mutated in blood cancers.
Results:
- Forty-eight patients were enrolled in this study, which is now at 5.5 years of follow-up.
- The median progression-free survival was six years, and 35% of patients in this study developed progressive disease.
- This shows durable responses with acalabrutinib, even in a high-risk population of patients.
- Researchers looked at 25 genes that are known drivers of CLL, and nearly all patients had at least one CLL driver gene that was mutated at baseline.
- At baseline, the most commonly mutated genes were NOTCH1, ZNF292, TP53, SF3B1, ATM, and NFKBIE.
- Baseline mutations in BCOR and SPEN were observed exclusively in patients who later developed progressive disease.
- Among patients who developed progressive disease, 70% had acquired a mutation in BTK or PLCG2, which are common resistance mutations,at the time the progressive disease was identified.
- Patients who developed progressive disease without BTK or PLCG2 mutations acquired mutations in NOTCH1, ZNF292, and BIRC3 during treatment.
Conclusions:
Acalabrutinib produced durable responses in patients with CLL / SLL who are at higher risk of disease progression. In addition, longitudinal mutational profiling identified some genes that may contribute to acalabrutinib resistance mechanisms in CLL. For example, an acquired mutation in BTK or PLCG2 accounts for resistance in 7 out of 10 patients.
Links and Resources:
Watch the interview on the abstract here:
Here is where you can read the actual ASH abstract: Longitudinal Mutation Profiling in CLL Patients during Acalabrutinib Therapy and at Progression
Take care of yourself first.
Ann Liu, PhD
