Photo Credit: Nemes Laszlo
The following is a summary of “Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib,” published in the September 2024 issue of Hematology by Woyach et al.
Chronic lymphocytic leukemia (CLL) often progresses during Bruton Tyrosine Kinase (BTK) inhibitor treatments, typically due to new mutations in the B-cell receptor pathway.
The study aimed to track clonal evolution in patients with relapsed or refractory CLL progressing on acalabrutinib or ibrutinib.
They collected peripheral blood samples from patients in the ELEVATE-RR trial (NCT02477696; median of 2 prior therapies) and analyzed paired baseline and progression samples from 47 patients treated with acalabrutinib (excluding 1 Richter) and 30 patients treated with ibrutinib (excluding 6 Richter) after a median follow-up of 41 months.
The results showed that at progression, new BTK mutations were found in 66% of patients treated with acalabrutinib (n=31) and 37% of patients treated with ibrutinib (n=11), with median variant allele fractions (VAF) of 16.1% versus 15.6%. The most common BTK mutation was C481S in both groups. Patients treated with Acalabrutinib also had T474I (9 patients, 8 co-occurring with C481) and 1 E41V mutation, while patients treated with ibrutinib had L528W and A428D mutations in 1 patient. About 53% of both treatment groups had preexisting TP53 mutations. New TP53 mutations emerged in 13% of patients treated with acalabrutinib and 7% while treated with ibrutinib (median VAF 6.0% versus 37.3%). New TP53/BTK commutations developed in 6 patients treated with acalabrutinib and 1 receiving ibrutinib. New PLCG2 mutations appeared in 6% of acalabrutinib (n=3) and 20% of ibrutinib (n=6), with 5 patients (1 acalabrutinib treated, 4 ibrutinib treated) having both BTK and PLCG2 mutations. Mutation patterns and frequencies differed between the two treatments.
Investigators concluded that while BTK C481 mutations are common with both acalabrutinib and ibrutinib, the types and frequencies of mutations vary, indicating different resistance mechanisms for each treatment in patients with CLL
