New Data from ALPINE Trial May Guide Salvage Therapy Decisions in Relapsed CLL

Two-year follow-up data from the ALPINE trial support the use of non-covalent Bruton tyrosine kinase inhibitors (ncBTKis) as a salvage therapy option for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) following treatment with zanubrutinib or ibrutinib.

Results published in Blood Advances showed that a short duration of covalent BTKi therapy and early disease progression were associated with a low incidence of BTK and PLCG2 mutations, warranting closer evaluation of treatment with ncBTKis, such as pirtobrutinib.

Jennifer R. Brown, MD, of the Dana-Farber Cancer Institute, and colleagues collected matched baseline and peripheral blood samples from 52 evaluable patients who progressed on zanubrutinib (n=24) or ibrutinib (n=28) at a median follow-up of 25.7 months.

BTK/PLCG2 Mutations

While no BTK mutations were observed at baseline, five patients treated with zanubrutinib and three patients treated with ibrutinib acquired BTK mutations at disease progression. The median number of acquired mutations was three for patients treated with zanubrutinib and one for patients treated with ibrutinib.

The cancer cell fraction (CCF) of acquired BTK mutations, estimated by dividing the variant allele frequency (VAF) by absolute lymphocyte count/white blood cell count, was 5.31% for zanubrutinib-treated patients and 1.84% for ibrutinib-treated patients.

Most of the single-nucleotide variants in BTK (77.8%) occurred at position C481 and were more common in patients treated with zanubrutinib (n=11/14) versus ibrutinib (n=3/4). Three patients who progressed on zanubrutinib had non-C481 mutations, including L528W (n=2; CCF=9.58% and 17.6%) and A428D (n=1; CCF=37.03%).

Of the two patients on ibrutinib who acquired PLCG2 mutations at disease progression, one had concurrent BTK and PLCG2 mutations. No PLCG2 mutations were found in patients treated with zanubrutinib.

Driver Mutations

Most patients (48/52; 92.3%) had at least one driver mutation at baseline, including NOTCH1 (n=21), TP53 (n=19), BRAF (n=10), SF3B1 (n=8), and ATM (n=8). Patients had a median of three driver mutations.

At disease progression, one patient treated with zanubrutinib acquired TP53 and XPO1 mutations, while five patients treated with ibrutinib acquired TP53 (n=1), SETD2 (n=1), SF3B1 (n=1), or ASXL1 (n=2) mutations.

While baseline driver gene mutations were not associated with the development of BTK mutations, patients with two or more baseline driver gene mutations were more likely to acquire BTK mutations at disease progression compared to patients with fewer than two mutations.

“Among patients with relatively early relapse on ibrutinib or zanubrutinib, the known resistance mutations in BTK and PLCG2 are relatively uncommon (17%),” Dr. Brown told Blood Cancers Today. “At present, the mechanisms of resistance that affect these patients are relatively poorly understood. We are working to try to better understand predictors of early relapse because these patients may particularly benefit from combination therapy.”

Reference

Brown JR, et al. Blood Adv. 2025;9(8):1918-1926. doi:10.1182/bloodadvances.2024014206