BTK, PLCG2 Mutations Presage CLL Relapse on Ibrutinib

The emergence of ibrutinib-resistant chronic lymphocytic leukemia (CLL) can be detected prior to clinical relapse, according to an analysis of patients from four ibrutinib trials, published in the Journal of Clinical Oncology.

“Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance,” reported co-lead study author Jennifer A. Woyach, MD, of The Ohio State University in Columbus, Ohio, and colleagues. “We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.”

Clinical resistance was “preceded by a prolonged period of asymptomatic clonal expansion, which suggests the ability to pre-emptively target these cells with alternative therapies in the context of a clinical trial before the patient becomes acutely ill with refractory disease,” they explained.

Ibrutinib is an irreversible inhibitor of the Tec-family Bruton tyrosine kinase (BTK); it has “transformed” the treatment of CLL, the researchers noted, yielding durable remissions for most patients. However, some patients suffer relapse and CLL progression. Both the BTK and PLCG2 gene mutations have been identified in the team’s prior research as candidate driver mutations in relapse.

To evaluate the role of BTK and PLCG2 mutations in CLL relapse, the study authors analyzed data from 308 patients who participated in four sequential phase II and phase III clinical ibrutinib trials at The Ohio State University Comprehensive Cancer Center in Columbus, Ohio. Time to ibrutinib discontinuation was analyzed with multivariate models that included age, prior therapies (more than 3 prior lines of treatment), complex karyotype, and the presence of MYC aberrations.

At a median follow-up of 3.4 years, the overall 4-year progression rate was 19%. The hazard ratio (HR) for transformation was 5.0 (95% CI, 1.51–16.52; P = .008) for patients with complex karyotype and 2.15 (95% CI, 1.0–4.7; P = .051) for MYC abnormality. Complex karyotype, the presence of del(17)(p13.1) on FISH analysis, and age over 65 years each correlated significantly with discontinuation due to progressive CLL.

“Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression,” the researchers reported. “Among patients who relapse, acquired mutations of BTK and PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse.”

Of the 46 patients with progressive CLL for whom samples were available for deep sequencing, 40 had BTK mutations, PLCG2 mutations, or both at relapse. Thirty-one patients had BTK C481 mutation only, six patients had both BTK and PLCG2 mutations, and three patients had PLCG2 mutations only.

For 20 patients whose CLL relapsed and for whom serial archived samples had been obtained prior to relapse, retrospective deep sequencing of malignant specimens for BTK and PLCG2 confirmed that CLL progression on ibrutinib is indeed associated with acquired mutations at these loci, and that these mutations are present before clinical relapse, the authors reported.

Noting that patients who relapse while taking ibrutinib frequently experience rapid disease progression, the researchers monitored mutations for the coding regions of BLK and PLCG2 for a cohort of 112 patients.

“To date, eight of those patients have experienced clinical relapse, and all eight patients had BTK^C481S mutations with expansion of the clone before relapse,” the authors reported. “BTK^C481S mutations of greater than 1% allelic frequency were detected in an additional eight patients. All but one patient who discontinued therapy and went to hospice without clinical relapse had increasing circulating CLL cells in the peripheral blood by flow cytometry, and all have had expansion of the resistant clones.” Half of the eight have experienced increased lymph node diameter on CT scan, but have not yet met the criteria for clinical relapse, the authors noted.