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

Abstract

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 ¼ 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.

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

“…Ventricular arrhythmias, conduction disorders and hypertension, have also been observed (Salem et al, 2019) and in mice, the inducibility of atrial and ventricular arrhythmia increases after ibrutinib intake (Tuomi et al, 2018). While this needs further investigation, there is evidence that the risk to develop cardiovascular AEs increases over time (Archibald et al, 2020) and during a 7-year follow-up of ibrutinib therapy, hypertension was sustained (Byrd et al, 2020a).…”

How We Manage Patients With Chronic Lymphocytic Leukemia During the SARS‐CoV‐2 Pandemic

“…However, if ibrutinib is discontinued because of an adverse event while CLL is in remission, the disease may continue being under control for a prolonged period of time before an alternative therapy is required. 46 , 50 , 88 – 90 …”

The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer

“…In addition, ibrutinib has also been shown to have potential effects against autoimmune arthritis (Akinleye et al, 2013). Some patients have had reported relapse during ibrutinib therapy, which was based on an acquired resistance to this drug, based in most cases of cytogenetic abnormalities (Byrd et al, 2020). Functional studies indicate that the C481S mutation in BTK is the reason for resistance to ibrutinib by preventing irreversible drug binding (Woyach et al, 2014).…”