BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia

Abstract

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or 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 a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. 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.

Fig 1.

Cumulative incidence of ibrutinib discontinuation for transformation or chronic lymphocytic leukemia (CLL) progression. Discontinuation as a result of Richter transformation tended to occur early in ibrutinib therapy, with few transformations after 2 years. In contrast, CLL progression occurred later, with rare progressions occurring before 1 year. Other events, which include infection, other toxicity, comorbidities, and patient or physician choice, tended to occur at a fairly steady rate for the first 3 years and then plateau.

Fig 2.

Survival after ibrutinib discontinuation. Patients with disease progression while on treatment with ibrutinib were observed from the time of ibrutinib discontinuation until death. Patients who discontinued therapy as a result of transformation had a median survival of 3.9 months, and patients who discontinued therapy as a result of progressive chronic lymphocytic leukemia (CLL) had a median survival of 22.7 months.

Fig 3.

Ibrutinib resistance mutations can be detected before clinical relapse. For 20 patients with a detectable mutation in BTK or PLCG2 at time of relapse, samples before relapse were analyzed retrospectively to determine the interval of time between mutation detection and clinical relapse. An initial clone could be detected at an estimated median of 9.3 months before relapse. UPN, unique patient number.

Fig 4.

Sequential monitoring of BTK mutation levels. BTK/PLCG2 sequencing was performed every 3 months using the clinical-grade sequencing assay. In the eight patients with BTK^C481S detected at greater than 1% variant allelic frequency (VAF) who had not experienced clinical relapse, VAF did increase in all patients.