Final GENUINE Data Support Addition of Ublituximab to BTK Inhibitors in Relapsed/Refractory, High-Risk CLL

Feburary 23, 2021 — The addition of the anti-CD20 monoclonal antibody ublituximab to ibrutinib led to a statistically higher overall response rate over ibrutinib alone with acceptable safety in patients with relapsed/refractory, high-risk, chronic lymphocytic leukemia.

The addition of the anti-CD20 monoclonal antibody ublituximab to ibrutinib (Imbruvica) led to a statistically higher overall response rate (ORR) over ibrutinib alone with acceptable safety in patients with relapsed/refractory, high-risk, chronic lymphocytic leukemia (CLL), according to the final results from the phase 3 GENUINE trial (NCT023301156) published in the Lancet Hematology.

After a median follow-up of 41.6 months, the ORR achieved with ublituximab/ibrutinib in the intent-to-treat (ITT) population was 83% (n = 53/64) per independent review committee (IRC) assessment versus 65% (n = 40/62) with ibrutinib monotherapy (P = .20). 

Of those who responded to treatment with the doublet, 17% (n = 11) achieved a complete response (CR), 2% (n = 1) experienced a CR with incomplete marrow recovery, 64% (n = 41) had a partial response (PR), 3% (n = 2) experienced a PR with lymphocytosis, and 3% (n = 2) had stable disease. Two patients were not evaluable for response and 5 patients were not treated. 

“Clinically meaningful improvements in ORR, CR, and minimal residual disease (MRD)–negative response were observed and translated to improved progression-free survival [PFS],” Jeff P. Sharman, MD, of Willamette Valley Cancer Institute, US Oncology Research, and colleagues, wrote. “These findings indicate the benefit of adding the next-generation anti-CD20 antibody ublituximab to ibrutinib in patients with relapsed and refractory high-risk CLL.”

In the multicenter phase 3 trial, investigators set out to compare ublituximab/ibrutinib compared with single-agent ibrutinib in patients with relapsed/refractory CLL and high-risk cytogenetics to examine whether the addition of ublituximab would improve outcomes.

To be eligible for enrollment, patients had to be aged 18 years or older with CLL who had previously received at least 2 cycles of at least 1 standard regimen, had an ECOG performance status of 0 to 2, and had high-risk cytogenetics, which was defined as the presence of at least 1 del(17p), del(11q), or TP53 mutation confirmed via central laboratory. Patients also needed to have measurable lymphadenopathy and acceptable organ function to participate.

If treatment with ibrutinib was medically contraindicated, if patients needed to receive treatment with moderate or strong CYP3A inhibitors or inducers, if they previously received BTK inhibition or any anticancer treatment within 21 days of randomization, they were excluded. Moreover, any patient who had undergone autologous stem cell transplantation or allogeneic stem cell transplantation within 3 months of study entry, or who had known histologic transformation from CLL to an aggressive lymphoma, were also not included.

A total of 224 patients were evaluated for trial eligibility; 98 were determined to be ineligible and thus, 126 were enrolled and randomized. Study participants were randomized 1:1 to receive either ublituximab/ibrutinib (n = 59) or single-agent ibrutinib (n = 58). Oral ibrutinib was given at a daily dose of 420 mg, while ublituximab was administered intravenously on day 1 (≤150 mg over 4 hours), day 2 (750 mg over 4 hours), and days 8 and 15 (900 mg over 3 hours) of cycle 1; and on day 1 of cycles 2 through 6 (900 mg over 3 hours). Maintenance ublituximab was administered every 3 treatment cycles following cycle 6. 

Both ublituximab and ibrutinib were administered until either progressive disease, intolerable toxicity, or withdrawn consent. Additionally, participants were given an antihistamine and a corticosteroid prior to ublituximab. The decision of whether to give premedication with corticosteroids following cycle 6 was made by the study investigator.

The primary end point of the trial was ORR per IRC evaluation, while secondary end points included PFS, MRD negativity rate, CR rate, duration of response (DOR), time to response, and safety reported with the addition of ublituximab to ibrutinib.

The median age of participants was 66 years in the doublet arm versus 67 years in the monotherapy arm. Across arms, patients had received a median of 1 prior line of treatment. The arms were generally well balanced; however, the number of patients with bulky disease in the investigational arm was 48% (n = 29) versus 28% (n = 16) in the control arm. 

The median duration of treatment with ibrutinib was 31.5 months in the doublet arm and 17.0 months in the monotherapy arm. The median duration of treatment with ublituximab was 30.3 months. Forty-six percent of patients in the ublituximab/ibrutinib group were still on treatment at the time of data cutoff, compared with 26% of those in the ibrutinib-only group.

Additional results showed that the median DOR had not yet been reached in both the doublet (95% CI, not estimable [NE]) and the monotherapy (95% CI, 27.7-NE) arms. The median time to first PR was 2.0 months and 4.4 months in the investigative and control arms, respectively, while the median time to first CR was 22.1 months and 24.8 months, respectively.

At a median follow-up of 41.6 months, the median PFS in the ublituximab/ibrutinib arm had not yet been reached (95%, NE) versus 35.9 months (95% CI, 17.0-NE) in the ibrutinib-only arm (HR, 0.46; 95% CI, 0.24-0.87; P = .016).

Moreover, the rate of MRD negativity was higher in those who received ublituximab plus ibrutinib versus single-agent ibrutinib, at 42% (n = 26) and 6% (n = 4), respectively (P <.0001). In the doublet arm, 41% (n = 26) of patients achieved MRD negativity in the peripheral blood, while 2% (n = 1) had negativity in the bone marrow.

Results from a post-hoc analysis showed that the ORR including PR with lymphocytosis was 86% (n = 55) in the ublituximab/ibrutinib group versus 73% (n = 45) in the ibrutinib-only group (P = .066). Moreover, the addition of the anti-CD20 monoclonal antibody led to a reduction in ibrutinib-associated lymphocytosis, including in those who were refractory to prior anti-CD20 treatment.

The median PFS had not been reached in those who received the doublet and whose tumors harbored del(17p) TP53 mutation or both versus 18.9 months in those who were given single-agent ibrutinib (HR, 0.25; 95% CI, 0.10-0.65; P = .0040). The median PFS in patients without del(17p) or TP53 mutation had not been reached in the doublet arm versus 47.2 months in the monotherapy arm. The median PFS in those with del(11q) who received ublituximab/ibrutinib was not reached versus 47.2 months in those given ibrutinib alone (HR, 0.97; 95% CI, 0.36-2.61; P = .94).

With regard to safety, any-grade toxicities were reported in all study participants. Seventy-six percent of patients in the doublet arm experienced adverse effects (AEs) that were grade 3 or higher in severity versus 83% of those in the monotherapy arm. Notably, atrial fibrillation and neutropenia more commonly occurred in those who received the doublet versus the monotherapy. One participant in the ublituximab/ibrutinib arm experienced tumor lysis syndrome.

The most commonly experienced serious AEs (SAEs) comprised pneumonia (10%, doublet; 7%, monotherapy), atrial fibrillation (7% vs 2%, respectively), sepsis (7% vs 2%), and febrile neutropenia (5% vs 2%). The most frequently reported SAEs considered to potentially be related to treatment included febrile neutropenia (5% vs 0%), pneumonia (3% vs 3%), atrial fibrillation (3% vs 2%), dysphagia (3% vs 0%), sepsis (3% vs 0%), and pleural effusion (0% vs 3%).

Treatment with ublituximab was delayed in 14%, while 10% of patients withdrew from treatment due to toxicities that were potentially associated with ublituximab or ibrutinib. Although dose reductions of ublituximab were not allowed per study protocol, 15% of patients in the doublet group experienced dose reductions of ibrutinib versus 14% of those in the monotherapy arm. 

Fifteen percent of patients in the doublet arm discontinued treatment because of toxicities; 2 patients did so because of atrial fibrillation, 1 patient because of dysphagia, 1 due to neutropenia, 1 due to staphylococcal cellulitis, 1 due to diarrhea, 1 because of anemia, 1 due to pneumonia, and 1 due to pneumonitis. Ten patients on the doublet arm died versus 28% on the monotherapy arm.


  1. Sharman JP, Brander DM, Mato AR, et al. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. Published online February 22, 2021. doi:10.1016/S2352-3026(20)30433-6