ELEVATE-RR Trial Identifies BTK Mutations in Patients With CLL Receiving Acalabrutinib, Ibrutinib

While more patients with chronic lymphocytic leukemia (CLL) receiving acalabrutinib acquired Bruton’s tyrosine kinase (BTK) mutations than those receiving ibrutinib, they did not fare worse than patients without BTK mutations, according to a study published in Blood.

The mutational analysis, led by Jennifer Woyach, MD, of the Ohio State University, utilized peripheral blood samples from patients with relapsed or refractory CLL in the ELEVATE-RR trial. DNA was extracted from enriched CD19+ cells and assessed using the 50-gene AmpliSeq next-generation sequencing assay. Patients who experienced disease progression while receiving acalabrutinib or ibrutinib were included in the analysis.

No BTK mutations were observed at screening in either treatment group. At a median follow-up of 41 months, emergent BTK mutations were observed in 31 (66%) patients treated with acalabrutinib, compared with 11 (37%) of those treated with ibrutinib. In both treatment groups, time to progression was “significantly longer” in patients with a BTK mutation versus those without (P=.03).

C481S was the most common mutation in both groups. T474I (co-occurring with C481 in eight patients) and E41V occurred with acalabrutinib, but not with ibrutinib. L528W and A428D co-mutations presented in one patient treated with ibrutinib.

At screening, 25 (43.2%) patients on acalabrutinib had TP53 mutations, compared with 16 (53.3%) of those on ibrutinib. With treatment, emergent TP53 mutations occurred in 13% of patients on acalabrutinib and 7% on ibrutinib. The median variant allele frequency (VAF) was 6.0% for acalabrutinib and 37.3% for ibrutinib. TP53 and BTK co-mutations emerged in six patients treated with acalabrutinib and one patient treated with ibrutinib.

PLCG2 mutations, however, emerged in fewer patients treated with acalabrutinib than ibrutinib (three [6%] vs six [20%], respectively). BTK and PLCG2 co-mutations emerged in one acalabrutinib-treated patient and four of those treated with ibrutinib.

“While common BTK C481 mutations were observed with both treatments, patterns of mutation and co-mutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I, E41V) and ibrutinib (L528W, A428D) in this patient population,” Dr. Woyach and colleagues concluded.

Reference

Woyach JA, Jones D, Jurczak W, et al. Mutational profile of previously treated chronic lymphocytic leukemia patients progressing on acalabrutinib or ibrutinib. Blood. 2024. doi:10.1182/blood.2023023659