In a randomized, open-label, single-center, phase II study, researchers found that the addition of rituximab to ibrutinib did not improve progression-free survival (PFS; primary endpoint) in patients with relapsed and high-risk chronic lymphocytic leukemia (CLL), compared with single-agent ibrutinib. However, the combination did lead to more rapid remissions and lower levels of minimal residual disease (MRD), according to lead author Jan A. Burger, MD, PhD, of the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas, who presented the findings at the 2017 ASH Annual Meeting.
“At this time, single-agent ibrutinib remains the standard of care,” Dr. Burger said during his presentation.
The study included 206 patients (median age = 65 years; range not provided) with relapsed CLL or treatment-naïve high-risk disease, including 27 (37%) with del17p or TP53 mutations. Patients were randomized to receive ibrutinib 420 mg daily alone (n = 102) or in combination with rituximab 375 mg/m2 weekly during cycle one, then monthly for cycles two through six (n=104). Ibrutinib was administered until the development of adverse events (AEs), disease progression, or death.
Most patients (70%) were male, 72 percent had unmutated immunoglobulin heavy-chain variable, and 38 percent had advanced stage disease (defined as Rai stage 3-4).
After a median observation time of 25.2 months in the ibrutinib monotherapy arm and 22.7 months in the combination cohort (ranges not provided), 79 (77%) and 71 (68%) patients, respectively, were still receiving treatment.
A total of 188 patients were evaluable for response, and the overall response rates (ORRs) were 98 percent in the single-agent group and 100 percent in the combination group. There were no significant differences in complete remission (CR) or partial remission (PR):
- CR: 20 patients (21%) in the single-agent group vs. 26 (28%) in the rituximab/ibrutinib group (p=0.309)
- PR: 72 (77%) vs. 68 (72%; p value not reported)
While patients in the rituximab/ibrutinib cohort appeared to reach CR faster than patients in the single-agent group (11.5 vs. 21.1 months; p=0.032), two-year PFS rates did not significantly differ between the ibrutinib-only and rituximab/ibrutinib cohorts (91.2% vs. 90.4%; p=0.788).
There also were no differences in survival by del17p status.
Bone marrow flow cytometry assessments conducted at the time of last follow-up showed a significantly lower level of residual CLL cells in the ibrutinib/rituximab cohort (median = 4.9% CLL cells; range not provided), compared with the ibrutinib group (median = 17.1% CLL cells; range not provided; p=0.002).
Five patients in the combination cohort and one in the monotherapy cohort experienced CR with MRD-negativity. The median time to normalization of absolute lymphocyte count (defined as ≤4.0 K/uL) was significantly shorter in the combination cohort (3.0 vs. 8.9 months; p<0.001).
Dr. Burger reported that the safety profiles were similar between treatment groups, with the most common AEs being arterial hypertension, neutropenia, diarrhea, and atrial fibrillation. However, more patients in the ibrutinib monotherapy group discontinued treatment; of the 56 patients who discontinued, 23 (23%) were receiving ibrutinib-only and 33 (32%) were receiving rituximab/ibrutinib. Most patients stopped treatment because of AEs (n=28). Six patients developed second malignancies, including one each of colorectal cancer, liposarcoma, melanoma, and pleomorphic sarcomatoid tumor, and two cases of new-onset chronic myeloid leukemia. Five patients died during study follow-up because of renal failure, cerebral hemorrhage, bowel perforation with colon hematoma, pneumonia, and respiratory failure.
Eight patients experienced disease progression (5 in the monotherapy group and 3 in the combination arm), and three patients reported disease transformation, which occurred between 11 and 16 months on treatment.
The trial is limited by its single-center design, and, Dr. Burger noted, “longer follow-up of treatment with anti-CD20 antibodies for a longer period, or with different anti-CD20 antibodies, may have a positive impact on PFS and OS.”
The authors report financial relationships with Genentech and Janssen.
Burger JA, Sivina M, Ferrajoli A, et al. Randomized trial of ibrutinib versus ibrutinib plus rituximab (Ib+R) in patients with chronic lymphocytic leukemia (CLL). Abstract #427. Presented at the 2017 American Society of Hematology Annual Meeting, December 10, 2017; Atlanta, GA.