Ibrutinib + Bendamustine/Rituximab in Patients with Previously Treated CLL/SLL

The combination of ibrutinib and bendamustine/rituximab (BR) was well-tolerated and did not significantly affect the safety profile of BR in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), according to an analysis of the HELIOS trial presented at the 2015 ASH Meeting on Hematologic Malignancies.

In this update of HELIOS, a randomized, double-blind, placebo-controlled phase III study investigating ibrutinib versus placebo in combination with bendamustine and rituximab, Asher Alban Chanan-Kahn, MD, from the Division of Hematology and Oncology at the Mayo Clinic in Jacksonville, Florida, examined the safety and management of adverse events.

All patients enrolled in HELIOS had active CLL/SLL following one or more prior systemic therapies. Patients were randomized to receive six or fewer cycles of bendamustine/rituximab (BR) with either ibrutinib 420 mg daily or placebo (n=289 for each group).

Median exposure to ibrutinib and placebo was 14.7 and 12.8 months, respectively, and rates of infection were similar between both arms (TABLE). After exposure-adjusted analysis, however, the authors found that patients treated with ibrutinib experienced a lower rate of infections, compared with placebo-treated patients (10.3 vs. 11.2 infections per 100 patient-months). Incidence of grade ≥3 infections were similar though (2.4 per 100 patient-months for each arm).

As seen in the TABLEgrade 3/4 neutropenia was the most common adverse event among all patients, but fewer patients discontinued due to treatment-related neutropenia in the ibrutinib arm compared with the placebo arm (1.0% vs. 2.8%).

Ibrutinib was associated with reduced rates of anemia and transfusional support, Dr. Chanan-Khan and co-authors reported. “Patients required fewer transfusions with ibrutinib + BR (23%) versus placebo + BR (29%), the majority of which were red blood cell transfusions.”

“Consistent with its known toxicity profile, patients in the ibrutinib + BR arm had higher rates of bleeding (mostly grade 1 or 2) and atrial fibrillation (AF),” the authors observed, however, only four patients with grade 3/4 AF discontinued ibrutinib therapy. One-third of patients with AF did temporarily stop ibrutinib treatment to manage their condition; all restarted at the same dose (420 mg).

“Importantly, in those with a prior history of AF or abnormal heart rhythm, only seven of 25 patients receiving ibrutinib + BR and two of 22 patients receiving placebo + BR developed AF/atrial flutter on study,” Dr. Chanan-Khan added, suggesting that treatment with ibrutinib did not lead to recurrent episodes in the majority of cases. “Taken together, the results from HELIOS establish the significant efficacy of ibrutinib and also the overall positive risk-benefit profile of ibrutinib + BR,” they concluded, however, statistical significance was not reported for all results and the clinical significance of these results could not be determined.


Reference

Chanan-Khan AA, Cramer P, Demirkan F, et al. Insights into the management of adverse events in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma: experience from the phase 3 Helios study of ibrutinib combined with bendamustine/rituximab. Abstract #6. Presented at the 2015 ASH Meeting on Hematologic Malignancies; September 19, 2015; Chicago, IL.

TABLE. Rates of Adverse Events among Patients Treated With Bendamustine/Rituximab Plus Ibrutinib or Placebo

Ibrutinib + bendamustine/rituximab (%)

Placebo + bendamustine rituximab (%)

All-grade infection

70.4

70.0

Grade ≥3 infection

26.8

22.6

Anemia

22.3

28.9

Grade 3/4 anemia

3.5

8.0

Grade 3/4 neutropenia

53.7

50.5

Thrombocytopenia

30.7

24.0

Grade 3/4 thrombocytopenia

15.0

15.0

Atrial fibrillation

7.3

2.8

Grade 3/4 atrial fibrillation

2.8

0.7

Bleeding

31.0

14.6
Grade 3/4 major bleeding

2.1

1.7

Lymphocytosis

7.0

5.9

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