BTK is an essential mediator of B-cell receptor signaling in normal and malignant B-cells. Ibrutinib (PCI-32765), an oral inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Chemoimmunotherapy (CIT) treatment approaches such as fludarabine, cyclophosphamide and rituximab have markedly improved outcomes of younger, fit patients as initial or second-line therapy. Unfortunately, fludarabine-based therapy is less well tolerated in the elderly and carries significant risk of cellular immune suppression, myelosupression, and subsequent myeloid neoplasia. Additionally, virtually all patients eventually relapse after fludarabine-based CIT, leading to the need for effective salvage regimens that induce durable remissions.
Recently, at the biennial international workshop on CLL (iwCLL), in Cologne, Germany, Dr. Richard Furman presented final results from a large (n=116 patients) multi-cohort Phase Ib/II trial of ibrutinib in treatment-naive (TN) or relapsed/refractory (RR) CLL/SLL. Patients demonstrated a high frequency of durable responses extending beyond 24 months in both TN and RR CLL/SLL including those with high-risk genomic features.
Patients who were TN (all age ≥65 years) or RR (≥ 2 prior therapies including a purine analog and with high-risk (HR) (relapsed within 2 years from combination CIT) were treated with ibrutinib at fixed doses of 420mg or 840mg daily until disease progression (PD). The study’s primary objective was to determine the safety and response rates of both dosing regimens. The overall response rates for the TN and RR patients were 84% and 88% respectively. The progression free survival (PFS) estimated at 26 months for the 85 RR patients is 74% and for the 31 TN patients is 96%. Estimated 26 month overall survival (OS) for 85 RR patients is 78% and for the 31 TN patients is 97%. Median duration of response, PFS, and OS have not been reached at the time of this analysis.
In conclusion, Ibrutinib monotherapy was found to be highly active, well tolerated, and induced durable responses in CLL patients with high-risk disease, R/R patients, and older TN patients. At present there are ongoing randomized trials comparing the safety profile of ibrutinib with other CLL therapeutic agents. Ongoing CLL trials at Weill Cornell Medical College can be found here.
New Developments in Lymphoma 