“The primary endpoint of overall response rate is superior for the combination of ublituximab plus ibrutinib compared with ibrutinib alone in high-risk CLL, without altering the safety profile of ibrutinib monotherapy.”

— Jeffrey Sharman, MD

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The addition of ublituximab (a glycoengineered anti-CD20 antibody) to ibrutinib (Imbruvica) improved response rates, depth of response, and led to quicker resolution of ibrutinib-associated lymphocytosis in patients with high-risk chronic lymphocytic leukemia (CLL) in the phase III GENUINE trial, the first randomized phase III study to assess the addition of a novel agent to ibrutinib in high-risk CLL. Results were reported at the 2017 ASCO Annual Meeting.¹ 

“Ibrutinib has been a great addition to our CLL armamentarium. However, we have long believed that ibrutinib alone may not be enough, particularly for patients with high-risk disease. The primary endpoint of overall response rate is superior for the combination of ublituximab plus ibrutinib compared with ibrutinib alone in high-risk CLL, without altering the safety profile of ibrutinib monotherapy. At the time of this report, there is a trend toward improved progression-free survival with the combination, but it has not reached statistical significance yet,” said lead author Jeffrey Sharman, MD, of the US Oncology Network and Willamette Valley Cancer Institute, Springfield, Oregon. 

The study was originally designed to assess overall response rate and progression-free survival, but due to slow accrual, the study was redesigned to drop the coprimary endpoint of progression-free survival. 

Ublituximab is the latest entry into the anti-CD20 monoclonal antibody category, joining drugs such as rituximab (Rituxan), ofatumumab (Arzerra), and obinutuzumab (Gazyva). 

Study Details 

In the GENUINE trial, 126 high-risk relapsed/refractory CLL patients were randomized in a 1:1 ratio to receive either ublituximab plus ibrutinib or ibrutinib alone. For the purposes of the study, high risk was defined as having one or more of the following abnormalities: 17p deletion, 11q deletion, or TP53 mutation. Patients had to have measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower, no history of CLL transformation, and no previous treatment with a Bruton tyrosine kinase inhibitor. 

The intent-to-treat population included all 126 randomized patients, and the treated population included 117 intent-to-treat patients who received at least 1 dose of either study drug. Patients were randomly assigned to receive ibrutinib at 420 mg/d with or without infusions of ublituximab at 900 mg on days 1, 8, and 15 of the first cycle, then day 1 of the next 5 cycles, then every third cycle. 

According to independent review of the intent-to-treat population, the best overall response rate was 78% for the combination vs 45% with ibrutinib alone (P < .001). Complete responses were seen in 7% and 0%, respectively. The minimal residual disease negativity rate was 19% vs 2%, respectively (P < .001). 

Adverse Events 

Patients in both arms of the study developed lymphocytosis, but the peak was markedly higher in the ibrutinib arm, and the elevation in lymphocytosis lasted longer. 

“Lymphocytosis was rapidly increased in the ibrutinib arm compared with the combination arm, and patients treated with ublituximab had more rapid resolution of lymphocytosis,” Dr. Sharman said. 

At a median follow-up of 11.4 months, 15 patients in the combination arm and 26 patients in the ibrutinib monotherapy arm had dropped out; 2 and 5 patients in the two arms, respectively, discontinued treatment due to adverse events. Rates of grade 3 and 4 neutropenia were similar between the two treatment arms. 

Infusion-related reactions were the most common adverse event with ublituximab, occurring in 44% of patients (grade 3–4, 5%). “With the exception of infusion-related reactions, ublituximab did not alter the safety profile of ibrutinib monotherapy,” Dr. Sharman said. ■

DISCLOSURE: Dr. Sharman has a leadership role with US Oncology and a consulting or advisory role with Celgene, Genentech, Gilead Sciences, Pharmacyclics, and TG Therapeutics. He is a member of the speakers bureau and has provided expert testimony for Gilead Sciences and has received institutional research funding from Acerta Pharma, Celgene, Genentech, Gilead Sciences, Merck, Pharmacyclics, Seattle Genetics, Takeda, and TG Therapeutics. 

REFERENCE 

1. Sharman JP, Brander DM, Mato AR, et al: Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study. 2017 ASCO Annual Meeting. Abstract 7504. Presented June 3, 2017.