Ublituximab Plus Ibrutinib Improves Objective Response Rates in High-Risk CLL

Patients with chronic lymphocytic leukemia (CLL) and high-risk genetic mutations typically have a poor response to ibrutinib monotherapy. Adding ublituximab, a novel anti-CD20 monoclonal antibody, to their treatment could improve on this, according to results of the phase III GENUINE study presented at the 2017 ASCO Annual Meeting.

“Despite the introduction of ibrutinib and other targeted agents, patients with CLL continue to relapse and complete remissions are rare,” said author Jeff P. Sharman, MD, director of research at Willamette Valley Cancer Institute and Research Center in Springfield, Oregon. “The GENUINE study met its primary endpoint, demonstrating that ublituximab in combination with ibrutinib yields a superior overall response rate to ibrutinib alone in [this patient population].”

The researchers enrolled adult patients with relapsed/refractory CLL who had at least one high-risk genetic feature (del17p, del11q, or TP53 mutation) and an Eastern Cooperative Oncology Group score of 0-2. Patients were excluded from the trial if they received any anti-cancer therapy 21 days prior to enrollment or autologous hematopoietic cell transplantation 3 months prior to enrollment. There was no limit on the number of prior therapies patients received, but patients were excluded if they were previously treated with ibrutinib or other Bruton tyrosine kinase inhibitors.

A total of 126 patients (median age = 67 years; range = 43-87 years) were randomized 1:1 to receive ibrutinib 420 mg once daily with or without ublituximab 900 mg (administered intravenously on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, then every third day). At data cutoff (February 15, 2017), 117 patients had been treated: 59 in the ublituximab plus ibrutinib arm, and 58 in the ibrutinib alone arm.

Patients had received a median of three prior therapies (range = 1-8 therapies). “High-risk cytogenetics were relatively balanced,” the authors noted, “with approximately 50 percent of patients having del17p.”

The ublituximab combination was well tolerated, Dr. Sharman reported, with “negligible” additive toxicity.

Infusion reactions were the most common adverse event (AE) in the ublituximab arm (all-grade = 44%; grade 3/4 = 5%), and rates of other AEs were similar between both study arms:

  • diarrhea: 43% vs. 40% (ublituximab plus ibrutinib vs. ibrutinib alone)
  • fatigue: 27% vs. 33%
  • nausea: 22% vs. 21%
  • headache: 20% vs. 28%
  • arthralgia: 19% vs. 17%
  • anemia: 14% vs. 17%

Rates of neutropenia were also comparable between the groups (3% vs. 2%).

After a median follow-up of 11.4 months, the objective response rate (per independent central review) was nearly doubled in patients treated with ublituximab plus ibrutinib, compared with ibrutinib alone (78% vs. 45%; p<0.001).

Among the 53 patients in each arm who were evaluable for minimal residual disease (MRD), “MRD-negativity was attained almost exclusively in the experimental arm,” Dr. Sharman noted, though most patients did not reach MRD status (19% vs. 2%; p<0.001).

“This is the first randomized study to verify that adding an anti-CD20 monoclonal antibody has at least additive activity,” Dr. Sharman told ASH Clinical News. “There was some preclinical doubt that maybe ibrutinib would interfere with anti-CD20 monoclonal antibody, and I think we can put that theory to rest.”

The study’s findings are limited by the small patient population, and the trial was not powered to determine secondary endpoints (including rates of complete response, progression-free and overall survival, and safety). Future trials will need to compare ublituximab combinations with other combinations, including the anti-CD20 monoclonal antibody rituximab.

Dr. Sharman reports research funding from TG Therapeutics.


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. Abstract #7504. Presented at the 2017 ASCO Annual Meeting, June 3, 2017; Chicago, Illinois.