Adding ibrutinib to a standard treatment regimen of bendamustine and rituximab for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) led to significant improvements in progression-free survival (PFS) and overall response rate (ORR), according to a study led by Asher Chanan-Khan, MD, from the Mayo Clinic Cancer Center in Jacksonville, Florida, and published in Lancet Oncology. Safety profiles were similar between the three-drug regimen and the control arm, the authors noted, without added toxicities.
“The results of this trial demonstrate that ibrutinib has added benefit beyond the current standard-of-care chemoimmunotherapy in previously treated patients with CLL or SLL,” Dr. Chanan-Khan and colleagues wrote. “Ibrutinib can be administered safely with bendamustine plus rituximab and represents an alternative option to traditional chemoimmunotherapy.”
The international, double-blind, placebo-controlled, randomized, cross-over, phase III HELIOS trial included 578 adult patients enrolled at 133 sites in 21 countries in North America, Europe, Latin America, and Asia between September 2012 and January 2014.
Patients were eligible for the study if they had:
- Relapsed/refractory CLL or SLL following at least one previous line of therapy consisting of at least two cycles of a regimen containing chemotherapy
- An Eastern Cooperative Oncology group performance status of 0-1
- Lymph node disease >1.5 cm as measured by a computerized tomography (CT) scan
- Absolute neutrophil count >1×109/L
- Platelet count >50×109/L
- Adequate liver and kidney function
Patients were excluded from the study if they had del17p13 CLL or SLL; had received previous treatment with ibrutinib or other Bruton tyrosine kinase inhibitors; were refractory or relapsed within 24 months with a previous regimen containing bendamustine; received hematopoietic cell transplant; or had a history of a stroke, intracranial hemorrhage, or clinically significant cardiovascular disease within six months prior to the study.
Eligible patients were randomized 1:1 to receive a four-week treatment regimen of:
- bendamustine: 70 mg/m2 intravenously on days 2 and 3 in cycle 1 and days 1 and 2 in cycles 2-6
- rituximab: 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2-6
- ibrutinib: 420 mg orally once daily (n=289) or placebo (n=289)
“A large proportion of [these patients had] high-risk features such as unmutated IGHV status (81% of 519 patients), del11q (26%), and bulky disease (56%),” the authors added. “The median time between previous treatment and study treatment was 24 months or less in both treatment groups, indicating a population with poor prognosis.”
Patients receiving placebo were allowed to crossover to the ibrutinib arm if disease progression was confirmed.
In addition to PFS (the study’s primary endpoint), secondary endpoints of the study included overall survival (OS), ORR, proportion of patients with a negative response for minimal residual disease (MRD), and safety.
The majority of patients in both the ibrutinib and placebo cohorts received the maximum six cycles of treatment (81% [n=235] and 77% [n=222], respectively). Patients in the ibrutinib cohort had a median of 14.7 months of treatment exposure compared with 12.8 months in the placebo cohort, with 73 percent (n=210) and 55 percent (n=160) of patients, respectively, receiving treatment for 12 months or more.
PFS outcomes were also consistent irrespective of whether the patient had received one or more than one previous line of therapy. “This result suggests that there might be a benefit of treating patients with CLL with ibrutinib in addition to bendamustine plus rituximab earlier in their disease course rather than later,” according to the authors.
At an interim analysis, after a median follow-up of 17 months (range = 13.7-20.7 months), PFS was significantly longer in the ibrutinib cohort compared with the placebo group: not reached versus 13.3 months (hazard ratio [HR] = 0.203; 95% CI 0.15-0.276; p<0.0001). At 18 months, PFS was 79 percent in the ibrutinib group and 24 percent in the placebo cohort (HR=0.203; 95% CI 0.15-0.276; p<0.0001).
However, there was no statistically significant difference in OS between the ibrutinib and placebo groups (HR=0.628; 95% CI 0.385-1.024; p=0.0598), with median OS not reached in either cohort. When adjusting for crossover, patients in the ibrutinib group had significantly longer OS compared with those in the placebo group (HR=0.577; 95% CI 0.348-0.957; p=0.033).
“OS data should be interpreted with some caution because most OS events have not yet occurred,” the authors noted. “Long-term follow-up for OS is planned and intended to be reported at a later date.”
ORR was significantly higher in the ibrutinib group (n=239; 83%) than the placebo cohort (n=196; 68%; risk ratio = 1.22; 95% CI 1.11-1.34; p<0.0001). The proportion of patients with MRD-negative status was also higher in the ibrutinib group than in the placebo group: 37 (13%) versus 14 (5%; p=0.0011).
Thirty-one percent (n=90) of patients originally receiving placebo had crossed over to receive ibrutinib monotherapy, and follow-up is continuing for all patients.
Grade 3 or 4 adverse events (AEs) were similar between the treatment groups: 77 percent (n=222) in the ibrutinib group and 74 percent (n=212) in the placebo group. The most common grade 3 or 4 AEs were neutropenia and thrombocytopenia, while the most common all-grade AEs were neutropenia and nausea. Diarrhea occurred more frequently in the ibrutinib group, but it was predominantly grade 1. Bleeding events also occurred more frequently in the ibrutinib group, though the events were mostly grade 1 or 2, the authors noted.
Dr. Chanan-Khan and co-authors noted a few limitations: the study was not designed to evaluate ibrutinib as a single agent, or ibrutinib plus rituximab compared with ibrutinib, bendamustine, and rituximab. “While it seems clear that ibrutinib adds to the efficacy of bendamustine plus rituximab, the question remains if bendamustine plus rituximab is necessary to achieve good patient outcomes in this relapsed/refractory population.”
Because PFS had not yet been reached in the ibrutinib cohort, follow-up and more mature data are required to truly interpret the effects of ibrutinib in combination with bendamustine and rituximab, they added.
Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17:200-11.