The addition of the anti-CD20 monoclonal antibody ublituximab to ibrutinib significantly improved outcomes compared with ibrutinib monotherapy among relapsed/refractory chronic lymphocytic leukemia (CLL) patients with high-risk cytogenetics.
"The BTK inhibitor ibrutinib has advanced the treatment for patients with CLL; however, among patients with high-risk CLL, disease control with ibrutinib is less durable," the study author noted. "Ublituximab is a is a novel, glycoengineered, type I, anti-CD20 monoclonal antibody.
"As a single agent, ublituximab is active in rituximab-refractory CLL and non-Hodgkin's lymphoma (NHL) patients," they continued. "Phase II study in relapsed/refractory CLL patients demonstrated that combination of ublituximab with ibrutinib is highly active (95% ORR in high-risk CLL) and well-tolerated."
Early data from the GENUINE study demonstrated improvements in overall response rate (ORR) and undetectable minimal residual disease (uMRD), according to the investigators. "At previous cutoff, progression-free survival (PFS) was still immature. While PFS favored ublituximab plus ibrutinib, it was not statistically significant."
With a median follow-up of more than 3.5 years, the final results from the GENUINE phase III study were presented during the ASCO 2020 Annual Meeting (Abstract 8022).
Research Details
The GENUINE trial is an open-label, multi-center, randomized, phase III study in relapsed or refractory high-risk CLL. Eligible patients had relapsed/refractory CLL with centrally confirmed del17p, del11q, and/or a TP53 mutation.
Patients were randomized to receive ibrutinib orally at 420 mg once daily alone or in combination with intravenous infusions of ublituximab at 900 mg dosed on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2-6. In the combination arm, patients who had not progressed received quarterly infusions of ublituximab maintenance at 900 mg.
The primary endpoint was ORR. The secondary endpoints included PFS and complete response (CR) rate as well as uMRD.
The trial included 117 patients treated with either ublituximab plus ibrutinib (n=59) or ibrutinib alone (n=58). As of the September 1, 2019, cut-off date, the median follow-up time was 41.9 months.
In each arm, the median age was 66 years and the median number of prior therapies was one (range 1-5). The researchers reported relatively balanced baseline features, including ECOG, gender, and median time since diagnosis.
17p deletion was greater in the ibrutinib arm (50% vs. 44%) as was TP53 mutation (47% vs. 17%). Bulky disease was greater in combination arm (47% vs. 28%); IGHV-unmutated was 83 percent for both groups.
Compared to ibrutinib monotherapy, the combination treatment significantly improved ORR (93% vs. 78%; p=0.019), complete response/complete response with incomplete blood count recovery (CR/CRi) rate (20% vs. 5%; p=0.024), and increased rates of uMRD (46% vs. 7%; p<0.001).
Median PFS was not reached in the ublituximab plus ibrutinib arm and was 35.9 months in the ibrutinib monotherapy arm (hazard ratio 0.46), with del17p/TP53mut patients seeing the greatest difference in PFS.
Adding ublituximab to ibrutinib did not significantly change the safety profile of ibrutinib. However, the researchers did note that the combination resulted in slightly higher rates of neutropenia (36% vs. 21%) and atrial fibrillation (14% vs. 7%).
"The addition of ublituximab to ibrutinib significantly improved ORR, CR rate, and increased rates of uMRD compared with ibrutinib monotherapy in patients with relapsed/refractory CLL with high-risk cytogenetics," the study authors concluded. "At a median follow-up of 41.9 months, PFS was significantly improved in patients treated with ublituximab plus ibrutinib compared with ibrutinib monotherapy.
"Improvement in PFS was driven by patients with del17p/TP53 mutation," they noted. "Deletion of 11q is no longer categorized as a high-risk feature with ibrutinib monotherapy, and PFS was not significant in this population."
Currently, ublituximab, in combination with umbralisib, is in phase III development for patients with CLL. It is also in phase IIb study for patients with NHL.
Catlin Nalley is a contributing writer.
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