Resistance to Acalabrutinib in Chronic Lymphocytic Leukemia Is Mediated Predominantly by BTK Mutations

Conference Correspondent - ASH 2019 Wrap-up


Acquired resistance to ibrutinib, a first-generation Bruton tyrosine kinase (BTK) inhibitor, is most frequently mediated by a cysteine to serine mutation (C481S) in BTK. This mutation decreases binding affinity and changes binding from irreversible to reversible. Acalabrutinib is a selective, second-generation, irreversible inhibitor of BTK that is approved for use in patients with chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma. Because mechanisms of resistance to acalabrutinib were not known, researchers felt compelled to explore this issue further. Results of their analysis were presented at ASH 2019.

All patients treated at the Ohio State University and enrolled on an Institutional Review Board–approved phase 1b/2 study in CLL were included in the analysis. Beginning 12 months after acalabrutinib initiation, patients underwent deep sequencing every 3 to 6 cycles using a digital droplet polymerase chain reaction assay for BTK C481S or ion torrent sequencing for any BTK or PLCG2 mutations. At relapse, samples from each patient underwent complete BTK and PLCG2 sequencing.  

A total of 105 patients with CLL were included in this analysis: 36% were treatment-naïve, 48% had relapsed or refractory disease, and 16% were previously treated with ibrutinib but were intolerant to this therapy. The median age of patients was 62 years (range, 33-84 years), and the median number of prior therapies was 1 (range, 0-11). Most patients had CLL with high-risk features: 66% had unmutated IGHV, 24% had del(11)(q22.3), 15% had del(17)(p13.1), and 28% had a complex karyotype (≥3 abnormalities).

After a median follow-up of 47.5 months (range, 38-59 months), 30% of patients had discontinued acalabrutinib therapy; 17 for progression of disease (CLL in 16 patients, Richter’s transformation in 1 patient), and 14 for other reasons.

The cumulative incidence rate (CIR) of progression varied significantly by cohort. In the treatment-naïve and relapsed cohorts, it was 0%. In contrast, CIR of progression was 12% (95% confidence interval [CI], 2%-32%) in patients who were intolerant. By 36 months, CIR of progression was 5% (95% CI, 1%-16%) in the treatment-naïve cohort, 6% (95% CI, 2%-15%) in the relapsed/refractory cohort, and 35% (95% CI, 14%-58%) in the intolerant cohort.

In univariable analysis, higher risk for progression was associated with del(17)(p13.1) on baseline fluorescence in situ hybridization (FISH) (P <.0001), number of prior therapies (P = .009), female sex (P = .01), increased baseline lactate dehydrogenase (P = .02), and presence of Myc abnormality on baseline FISH (P = .05). Treatment status was also associated with risk for progression. Whereas treatment-naïve patients had a similar risk compared with relapsed patients, intolerant patients had a higher risk for progression (P = .02).

In multivariable analysis, del(17)(p13.1) (P = .01) and sex (P = .03) remained significantly associated with risk for progression after accounting for other variables. When considering total time of BTK inhibitor exposure, there was no statistically significant increased risk for progression for intolerant patients (P = .13). However, at 48 months of BTK inhibitor exposure, those who had only received acalabrutinib had a CIR of progression of 17% (95% CI, 8%-30%), whereas those who switched BTK inhibitors had a CIR of 36% (95% CI, 14%-59%).

All 16 patients with CLL relapse had a sample evaluated for BTK C481S at relapse; 14 had samples evaluated for full BTK and PLCG2 mutations using ion torrent deep sequencing. BTK C481 mutations were found in 11 of 16 patients (69%; C481S in 10, C481R and C481Y in 1). One patient with a C481S mutation also had a BTK T474I gatekeeper mutation, and 1 had coexisting C481R mutation. Two patients with BTK C481S mutations had coexisting PLCG2 mutations previously associated with ibrutinib resistance at <3% variant allele frequency.

Of 105 patients, 103 were screened every 3 to 6 cycles for BTK mutations. A total of 22 patients had mutations detected after a median of 32 months of acalabrutinib therapy. Treatment-naïve and relapsed patients had median time to mutation of 39 months and 33 months, respectively. For intolerant patients, median time to mutation detection was 25 months from start of acalabrutinib, and 34 months from the start of any BTK inhibitor. Median time from BTK mutation detection to clinical relapse was 12 months.

The researchers concluded that progression of CLL during acalabrutinib treatment is mediated predominantly by BTK mutations that are similar to ibrutinib. This research also suggests that monitoring for BTK resistance mutations in patients being treated with acalabrutinib offers an opportunity to intervene clinically before disease-related symptoms appear.

Woyach J, et al. ASH Abstract 504. Session 642.