Promising Activity of Ibrutinib Plus Rituximab in High-Risk CLL


Key Points

  • The combination of ibrutinib and rituximab was associated with an 18-month progression-free survival rate of 78.0% in high-risk patients.
  • The combination was well tolerated, with most toxicity being of grade 1 or 2.

In a phase II trial reported in The Lancet Oncology, Burger et al found that the combination of ibrutinib (Imbruvica) and rituximab (Rituxan) showed promising activity and an encouraging safety profile in patients with previously treated or untreated high-risk chronic lymphocytic leukemia (CLL).

In the trial, 40 adult patients at MD Anderson Cancer Center with high-risk disease, defined as high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or short progression-free survival (< 36 months) after previous first-line chemoimmunotherapy, were enrolled between February and September 2012 and treated with the ibrutinib/rituximab combination. The regimen consisted of 28-day cycles of once-daily ibrutinib at 420 mg plus rituximab at 375 mg/m² every week during cycle 1, then once per cycle until cycle 6, followed by continuous daily single-agent ibrutinib at 420 mg until disease progression or unacceptable toxicities or complications. The primary endpoint was progression-free survival.

Among the 40 patients, 20 had deletion 17p or TP53 mutation (16 previously treated, 4 untreated), 13 had relapsed CLL with deletion 11q, and 7 had progression-free survival < 36 months after first-line chemoimmunotherapy.

Survival and Responses

The 18-month progression-free survival rate was 78.0% (95% confidence interval [CI] = 60.6%–88.5%) among all patients and 72.4% (95% CI = 45.6%–87.6%) in patients with del(17p) or TP53 mutation, and 18-month overall survival was 83.8% (95% CI = 67.2%–92.4%) among all patients and 78.4% (52.0%–91.4%) among those with del(17p) or TP53 mutation.

Among 39 patients evaluable for response, 34 (87%) had partial remission and 3 (8%) had complete remission (95% response rate). The two patients without response discontinued treatment early due to adverse events (grade 3 mucositis in one and grade 3 recurrent ear and pulmonary infection in one). The median time to achieve response was 5.72 months and the median duration of response was 15.44 months (interquartile range, 10.55–18.27 months).

Adverse Events

The most common adverse events of any grade were lung infection (41%), nausea/vomiting/acid reflux (38%), upper respiratory tract infection (36%), bleeding events (33%), arthralgia (28%), and diarrhea (26%). The most common grade 3 or 4 adverse events were neutropenia (grade 3 in one patient and grade 4 in one patient) and lung infection (grade 3 in two patients). 

The investigators concluded: “The encouraging safety and activity of ibrutinib and rituximab in this population of patients with high-risk CLL merits further investigation of this combination.”

Jan A. Burger, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.

The study was funded by Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, National Cancer Institute, MD Anderson Cancer Center, and Pharmacyclics Inc. Dr. Burger and Susan O’Brien, MD, received research funding from Pharmacyclics Inc. Dr. Burger is a consultant for Janssen Pharmaceticals Inc.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.