Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study

Abstract

Purpose: The safety and efficacy of ibrutinib, a once-daily Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was demonstrated in this phase Ib/II study. Extended follow-up up to 8 years is described, representing the longest follow-up for single-agent ibrutinib, or any BTK inhibitor, to date.

Patients and methods: Phase Ib/II PCYC-1102 (NCT01105247) and extension study PCYC-1103 (NCT01109069) included patients receiving single-agent ibrutinib in first-line or relapsed/refractory CLL/SLL.

Results: Overall response rate was 89%, with similar rates in first-line (87%; complete response, 35%) and relapsed/refractory settings (89%; 10%). Estimated 7-year progression-free survival (PFS) rates were 83% in first-line and 34% in relapsed/refractory settings. Forty-one patients had CLL progression (n = 11 with Richter's transformation). Median PFS was not reached with first-line ibrutinib. In relapsed/refractory CLL/SLL, median PFS was 52 months overall, 26 months in patients with chromosome 17p deletion, 51 months with 11q deletion, not reached with trisomy 12 or 13q deletion, and 88 months in patients without these cytogenetic abnormalities. Estimated 7-year overall survival rates were 84% in first-line and 55% in relapsed/refractory settings. Grade ≥3 adverse events (AE) in >15% of patients were hypertension (28%), pneumonia (24%), and neutropenia (18%). These grade ≥3 AEs generally declined over time, except hypertension. AEs leading to discontinuation in ≥2 patients were observed only in the relapsed/refractory setting (sepsis, diarrhea, subdural hematoma, and Richter's transformation).

Conclusions: With up to 8 years of follow-up, sustained responses and long-term tolerability of single-agent ibrutinib were observed with treatment of first-line or relapsed/refractory CLL/SLL, including high-risk CLL/SLL.

Figure 1.

PFS in patients receiving ibrutinib in the first-line and relapsed/refractory treatment settings (A) and by chromosomal abnormality in the relapsed/refractory setting (B). Cytogenetic subgroups presented in a hierarchy of CLL chromosomal abnormalities based on Döhner classification (26). Progression-free time is calculated as the number of months from first dose date of study treatment to disease progression or death or date of censoring. Patients were censored if they were not assessed as having disease progression by investigators or died at the time of analysis. Tick marks represent censored patients. In panel B, HR, 95% CI, and P value are for cytogenetic subgroups versus no abnormality subgroup.

Figure 2.

OS in patients receiving single-agent ibrutinib in the first-line and relapsed/refractory treatment settings (A) and by chromosomal abnormality for patients treated for relapsed/refractory CLL/SLL (B). Cytogenetic subgroups presented in a hierarchy of CLL chromosomal abnormalities based on Döhner classification (26). OS time is calculated as the number of months from first dose date of study treatment to death or date of censoring. Tick marks represent censored patients. In panel B, HR, 95% CI, and P value are for cytogenetic subgroups versus no abnormality subgroup.

Figure 3.

Grade ≥3 AEs by time to onset from first dose occurring in ≥5% of patients receiving ibrutinib. The dashed lines represent a 5% rate. Numbers at the end of each bar represent the percentage of patients with AE onset during that time interval.