Ibrutinib Plus Chemoimmunotherapy Highly Effective in CLL

Jennifer R. Brown, MD, PhD

Jennifer R. Brown, MD, PhD

Treatment with the BTK inhibitor ibrutinib could enhance the efficacy of chemoimmunotherapy without increasing toxicity for patients with chronic lymphocytic leukemia (CLL), according to phase Ib findings published in the journalBloodby Jennifer R. Brown, MD, PhD, and colleagues.

In the study, daily ibrutinib at 420 mg was evaluated in combination with bendamustine and rituximab (n = 30) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles in patients with CLL treated with 1 to 3 prior regimens. However, the FCR arm of the study was closed after enrolling only 3 patients, due challenges accruing fludarabine-naive patients who had already received other treatments.

Added Toxicity Absent With Ibrutinib

"Although chemoimmunotherapy has made great strides in improving clinical response in CLL/SLL, it is likely not curative for most patients," the authors wrote. "A goal of newer agents and combination therapies is to induce a high level of durable objective response while minimizing toxicity."The primary endpoint of the phase Ib study focused on hematologic toxicity in cycle 1, defined as persistent grade ≥3 neutropenia or thrombocytopenia. Most of the adverse events observed were anticipated with bendamustine and rituximab alone, with ibrutinib adding very little toxicity.

The most frequently reported adverse events were diarrhea, nausea, fatigue, neutropenia, and upper respiratory tract infection.

In the bendamustine-rituximab arm, none of the patients experienced prolonged cytopenia in cycle 1. At cycle 2, 6.7% of patients had a grate 3 cytopenia and 6.7% had grade 4 cytopenia. Approximately 50% of patients received supportive care with a G-CSF (pegfilgrastim or filgrastim) during the study.

Response Rate Nears 100%

"The vast majority of patients (76.2%) with baseline cytopenias who were treated with bendamustine, rituximab, and ibrutinib showed a sustained hematologic improvement with a median follow-up of 15.8 months on the primary study," the authors wrote. "These findings are consistent with the lack of myelotoxicity of ibrutinib, suggesting that it is an excellent combination partner for chemoimmunotherapy."The overall response rate (ORR) in the bendamustine, rituximab, and ibrutinib arm was 93.3%, which included a 16.7% complete response (CR) rate. In an ongoing long-term extension arm, patients received ibrutinib alone after receiving the combination. In this part of the study, the CR rate reached 40%.

Lymphocytosis, which is common following treatment with ibrutinib, does not generally indicate progression in patients treated with BTK inhibitors. In total, 1 patient in the study had a partial response with lymphocytosis. When including this individual in the ORR analysis, the response rate reached 96.7%.

HELIOS Supports Findings

Overall, 76% of patients with baseline cytopenias had sustained hematologic improvement. At the 12-month analysis, 86.3% of patients were progression-free. At a 3-year analysis, 70.3% of patients remained progression-free.Topline findings from the phase III HELIOS trial supported the efficacy and safety seen with ibrutinib plus bendamustine and rituximab, according to results announced in March 2015. A benefit was observed in the primary endpoint of progression-free survival. The study was unblinded following the discovery of these results. Patients in the bendamustine plus rituximab arm are now allowed to cross over to receive ibrutinib.

Full data from the HELIOS trial will be presented at the 2015 ASCO Annual Meeting and are being prepared for regulatory submission, according to Pharmacyclics, the company developing ibrutinib.

Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia.Blood