Brown and colleagues reported final results from a phase 1b study of ibrutinib combined with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).¹ The primary objective of the study was to evaluate the safety and tolerance of ibrutinib in combination with BR in patients with relapsed or refractory CLL. The secondary objective was to assess the efficacy of this combination.

The study enrolled 30 patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) who had a median of 2 previous therapies. The patients received up to 6 cycles of BR with a continuous fixed daily dose of ibrutinib. Ibrutinib dosing continued past 6 cycles until disease progression or other reason for discontinuation of treatment.¹

The patients’ median age was 62 years and most patients were male. Approximately half of the enrolled patients had advanced stage III/IV disease; 23% and 43% of patients tested positive for deletion 17p and deletion 11q, respectively. Furthermore, bulky disease was present in 53% of patients.¹

The observed safety profile for this combination therapy was generally consistent with the safety profile of BR and ibrutinib monotherapy. The most frequently reported treatment-emergent adverse events (AEs) were diarrhea, nausea, fatigue, neutropenia, and upper respiratory tract infection. The most frequently reported treatment-emergent AEs grade 3 or higher were neutropenia, rash, fatigue, thrombocytopenia, febrile neutropenia, and cellulitis.¹

Overall, patients completed a median of 6 cycles of BR with no treatment discontinuations due to AEs and no deaths within 30 days after their last dose. The initial transient treatment-related lymphocytosis, reported in 78% of patients treated with ibrutinib monotherapy,² occurred less frequently (27%) in patients treated with ibrutinib plus BR.¹  

At the study’s completion in November 2012, 70% of patients who were still receiving ibrutinib monotherapy after finishing BR treatment, enrolled in a long-term extension study to continue therapy with ibrutinib.  Overall, 9 patients (30%) had discontinued the study treatment, 5 of whom proceeded to stem cell transplantation and 4 of whom experienced disease progression.¹

After a median treatment duration of 16 months, the overall response rate (ORR) was 93%, including 5 patients who achieved complete response and 3 patients who achieved nodular partial remission; one additional patient achieved partial response with lymphocytosis. Responses appeared independent of high-risk features. The estimated 12-month progression-free survival was 90%.¹

Brown and colleagues concluded that ibrutinib administered in combination with BR was tolerable and highly active in patients with relapsed or refractory CLL/SLL. The high ORR and a good tolerability profile compare favorably with historical controls. This combination is currently under further global investigation in a phase 3 trial.¹

References

1. Brown JR, Barrientos JC, Barr PM, et al. Ibrutinib in combination with bendamustine and rituximab is active and tolerable in patients with relapsed/refractory CLL/SLL: final results of a phase 1b study. Blood. 2013;122(21). Abstract 525.
2. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.