Despite a faster time to complete remission, the addition of rituximab (Rituxan) to ibrutinib (Imbruvica) did not improve PFS or overall survival OS compared with ibrutinib alone in patients with CLL.
Jan Burger, MD, PhD
Despite a faster time to complete remission, the addition of rituximab (Rituxan) to ibrutinib (Imbruvica) did not improve progression-free survival (PFS) or overall survival (OS) compared with ibrutinib alone in patients with chronic lymphocytic leukemia (CLL).
Results from a single-center clinical trial in 206 patients with CLL, 2-year PFS was 94% in the ibrutinib arm and 93% in the ibrutinib/rituximab arm (P = .788), and 2-year OS was 98% and 94% (P = .533) in the 2 arms, respectively, said Jan A. Burger, MD, PhD, at the 2017 meeting of the American Society of Hematology.
“At this time, single-agent ibrutinib remains the standard of care, although combination with rituximab is safe and can be considered in patients in whom a faster response to treatment is desirable,” said Burger, professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston.
Ibrutinib is currently approved as monotherapy for patients with treatment-naïve and relapsed CLL in the front-line and salvage settings. Ibrutinib induces high rates of remission in both settings and the responses to ibrutinib are durable in many CLL patients. A previous phase II study of ibrutinib in combination with rituximab in patients with high-risk CLL demonstrated an overall response rate (ORR) of 95% with a good safety profile. However, preclinical data suggest that ibrutinib may antagonize the activity of anti-CD20 antibodies.
The study presented here included 179 patients with relapsed/refractory disease and 27 treatment-naïve patients with a 17p deletion or TP53 mutation. They were randomized to ibrutinib, at the standard dosage of 420 mg per day until disease progression, death, or intolerable toxicity, or ibrutinib at the same dosage plus rituximab at 375 mg/m2 weekly for 4 weeks followed by monthly rituximab for cycles 2 to 6.
In both arms, about one-fourth of patients had 17p deletion. An 11q deletion was present in 25.5% of the ibrutinib arm and 14.4% of the ibrutinib/rituximab arm. About 60% of patients had unmutated IGHV and a similar proportion were positive for ZAP-70. Approximately 14.7% patients in the ibrutinib arm and 11.5% in the combination arm were previously untreated.
“There was a slightly higher ORR for the combination treatment arm, and a higher CR rate for the combination, and we saw 5% of patients achieving [minimal residual disease (MRD)] negativity in the bone marrow as assessed by flow cytometry,” Burger said. “This was more pronounced in the previously untreated patients, where 50% of patients achieved a CR and 25% of patients achieved MRD negativity in the bone marrow.” The difference in the rate of bone marrow MRD negativity did not reach statistical significance because there were only 27 treatment-naïve patients included.
At 12 months, 17 patients reached CR in the ibrutinib/rituximab group compared with 7 with single-agent ibrutinib. By 24 months, there was a similar number with CR in the single-agent arm and the combination arm, 14 versus 17, respectively. The time to achieve CR was significantly shorter with combination treatment at 11.5 months compared with single-agent ibrutinib at 21.1 months (P = .032).
At a median follow-up of 25.2 months in the ibrutinib arm and 22.7 months in the combination arm, there was no difference in the 2-year rates of PFS, the primary endpoint, and OS. In examining survival outcomes by 17p status, there was no difference in PFS or OS in those receiving ibrutinib alone or in combination with rituximab in patients with 17p deletion or wild type.
Adverse effects were consistent for patients taking ibrutinib established in other clinical trials. Similar frequencies of adverse events (AEs) were observed between the 2 arms. Nine percent of patients in each arm experienced atrial fibrillation.
At the time of analysis, 77.5% of patients randomized to ibrutinib and 68.3% randomized to the combination remained on study treatment. Three percent in the combination arm and 5% in the single-agent ibrutinib arm discontinued treatment due to progressive disease. A greater proportion in the combination arm discontinued due to AEs compared with the ibrutinib alone arm (16.3% vs 9.8%). There were 2 deaths in the single-agent arm and 3 in the combination arm. Three percent in the ibrutinib group and 4% in the combination group developed second malignancies.
The time to lymphocyte count normalization was significantly shorter in patients randomized to ibrutinib plus rituximab compared with ibrutinib alone (3.0 vs 8.9 months; P <.001). Hemoglobin and platelet counts improved similarly in both groups. According to Burger, there was a trend toward a faster normalization of immunoglobulin levels and T-cell counts in patients on combination therapy, “which may mirror the fact that these patients achieve remissions faster than patients treated with single-agent ibrutinib.” The faster peripheral blood clearance and deeper remissions in patients treated with rituximab plus ibrutinib indicates that ibrutinib does not antagonize rituximab in the clinical setting.
He concluded, “we cannot exclude that longer follow-up of treatment with anti-CD20 antibodies for a longer period of time or with different anti-CD20 antibodies may have a positive impact on PFS and OS.” Reference
Burger JA, Sivina M, Ferrajoli A, et al. Randomized trial of ibrutinib versus ibrutinib plus rituximab in patients with chronic lymphocytic leukemia (CLL). Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 427. https://ash.confex.com/ash/2017/webprogram/Paper107661.html.