High Rate of MRD Negativity Achieved With Time-Limited Ublituximab/Umbralisib Plus Ibrutinib in CLL

Undetectable minimal residual disease may be achieved with time-limited ublituximab and umbralisib added to ibrutinib in patients with chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) who previously received ibrutinib and still had detectable minimal residual disease (MRD) had deep remissions with the addition of ublituximab and umbralisib (Ukoniq; U2) to ibrutinib (Imbruvica), and the treatment with tolerable, according to data from a phase 2 trial (NCT04016805) presented during the 2021 ASH Annual Meeting.1

Results indicated that 77% of those who went on to receive the triplet combination achieved undetectable minimal residual disease (MRD). Moreover, 4% of patients came off treatment after 24 cycles and continued to have detectable MRD. Nineteen percent of patients remain on therapy with detectable MRD, with the possibility of achieving undetectable levels. The median time to undetectable MRD achievement was 7.4 months (95% CI, 4.6-10.2).

“This is the first non–venetoclax (Venclexta)-containing, MRD-driven, time-limited approach utilizing the combination of a BTK inhibitor, a PI3K inhibitor, and an anti-CD20 monoclonal antibody,” Lindsey E. Roeker, MD, lead study author and member of the CLL Program at Memorial Sloan Kettering Cancer Center, said in a presentation on the data. “This ‘add-on’ approach for patients on continuous ibrutinib resulted in deep remissions that allowed for a tailored, time-limited therapy and sustained treatment-free observation.”

Time-limited combination strategies have induced high objective response rates that have also proven to be durable in patients with CLL; however, these regimens have also been associated with high rates of toxicities and overtreatment of favorable-risk patients. Additionally, those who receive continuous treatment with single-agent ibrutinib are known to be at risk of cumulative toxicity and acquired resistance.

This led to the hypothesis that after a period of treatment with ibrutinib, it would be possible to identify a subgroup of patients who had responded to the BTK inhibitor but had detectable MRD and would derive benefit from a combination approach.

“We asked, could we convert their planned continuous therapy into a time-limited one?” Roeker noted. “In this study, we utilized an add-on approach in which we took patients after an initial period of ibrutinib monotherapy exposure who had detectable MRD, this way, preventing overtreatment of those who could have achieved a deeper remission with fewer agents, and add a combination approach until patients achieved undetectable MRD.”

At the time that undetectable MRD was achieved, investigators had patients enter a treatment-free observation, where they would determine what the durability of remission was following treatment discontinuation, Roeker added.

Investigators chose to add the U2 regimen to ibrutinib. An oral, once-daily, inhibitor of PI3Kð and CK1ε, umbralisib has been shown to have greater retention of T-reg suppressive capacity than agents like idelalisib (Zydelig) and duvelisib (Copiktra), and to have low rates of immune-mediated toxicity. The novel, glycoengineered anti-CD20 monoclonal antibody ublituximab has been shown have enhanced antibody-dependent cellular cytotoxicity vs rituximab (Rituxan).

Data from the phase 3 UNITY CLL trial (NCT0212311) showed that the U2 combination significantly improved progression-free survival (PFS) over obinutuzumab (Gazyva) plus chlorambucil in patients with CLL.2,3 The median PFS was 31.9 months (95% CI, 28.2-35.8) with U2 vs 17.9 months (95% CI, 16.1-22.6) with the control regimen (HR, 0.546; 95% CI, 0.413-0.720; P < .0001).

In November 2021, the FDA scheduled a meeting of the Oncologic Drugs Advisory Committee to review the pending biologics license application/supplemental new drug application for the U2 combination as an option for adult patients with CLL or small lymphocytic lymphoma.4 The meeting is anticipated to take place in March or April 2022.

The phase 2 trial included patients who had received ibrutinib for at least 6 months. Patients could have received the BTK inhibitor in any line, who still had detectable MRD.

Patients continued ibrutinib at the previously tolerated dose and then the U2 regimen was added. Umbralisib was administered at a daily dose of 800 mg. Ublituximab was given at 900 mg as a split dose on day 1, and then on days 8 and 15, during cycle 1; then, it was given on day 1 of cycles 2 through 6, and on day 1 of every 3 cycles thereafter. Every 3 treatment cycles, MRD was checked.

“For patients who had undetectable MRD, we would then repeat that test 28 days later, and if patients had 2 sequential peripheral blood undetectable MRD results, they would then enter a period of treatment-free observation,” Roeker noted. “Patients would receive a maximum of 24 cycles of cycles of triplet therapy before entering treatment-free observation, and this could occur regardless of MRD status.”

If patients experienced progression after being on treatment-free observation for at least 6 months, they were then retreated with U2 plus ibrutinib in accordance with the study protocol.

The primary end point of the trial was the rate of undetectable MRD in this population. “We hypothesized that this combination approach would be promising if at least 25 patients were able to convert from detectable to undetectable MRD [status],” Roeker added.

Secondary end points of the trial comprised safety, time to undetectable MRD, PFS, time to progression, overall survival, and response to retreatment.

Twenty-eight patients were evaluable for the safety analysis of the trial, and 27 were evaluable for the efficacy assessment. The median age of patients was 64 years (range, 48-81), 79% were male, and the majority (n = 26) had an ECOG performance status of 0. The median duration of treatment with prior ibrutinib was 21 months (range, 7-67), and the best response to treatment was a partial response.

Moreover, 68% of patients received ibrutinib as their first-line treatment, and 32% received it for relapsed or refractory disease. The number of prior lines of treatment in patients, excluding current ibrutinib, was 1 (range, 1-2), and all patients had previously received chemotherapy.

Regarding molecular and cytogenetic features, 67% of patients had unmutated IGHV, 21% had deletion 11q, and 7% had deletion 17p.

“Of those who have been on the triplet therapy, 77% achieved undetectable MRD. Seventeen patients have gone into treatment-free observation,” Roeker reported. “We had 1 patient in treatment-free observation who progressed and required subsequent therapy; this was within 6 months of treatment discontinuation, so the patient was not eligible for retreatment per protocol.”

The median time in treatment-free observation was 11 months, and the median time to first undetectable MRD was 6 months, Roeker added. Of the 17 patients who stopped therapy, 53% remain with undetectable MRD.

“We have had 1 progression event on this study, but overall, the PFS [data observed with the triplet have] been excellent,” Roeker said.

When looking at absolute MRD levels over time, Roeker reported that these levels were found to decline over time for those on the triplet combination.

Regarding safety, the most common all-grade toxicities reported with treatment included diarrhea (32%), hypertension (18%), anemia (18%), contusion (18%), fatigue (18%), alanine transaminase (ALT) or aspartate transaminase (AST) increased (14%), cough (14%), headache (14%), nausea (14%), COVID-19 (11%), decreased appetite (11%), and weight decreased (11%).

The most frequently reported grade 3 or 4 toxicity was diarrhea (4%), followed by hypertension (7%), ALT/AST increased (4%), and COVID-19 (4%).

Two patients discontinued all treatment because of toxicities; 1 did so because of rash and the other did so because of rash and arthralgias. Both patients had undetectable MRD status at the time of discontinuation. Moreover, 1 patient died because of COVID-19–related complications 103 days after stopping treatment with the U2 regimen.

Investigators continue to enroll patients to the trial. Other cohorts will explore the addition of U2 to agents like acalabrutinib (Calquence) or venetoclax.


1. Roeker LE, Leslie LA, Soumerai JD, et al. A phase 2 study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib in patients with chronic lymphocytic leukemia (CLL): a minimal residual disease (MRD)-driven, time-limited approach. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 295. https://bit.ly/31J25KR

2. Gribben JG, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL Study. Blood. 2020;136(suppl 1):37-39. doi:10.1182/blood-2020-134783

3. Lunning M, Vose J, Nastoupil L, et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2019;134(21):1811-1820. doi:10.1182/blood.2019002118

4. TG Therapeutics provides regulatory update. News release. TG Therapeutics; November 30, 2021. Accessed December 12, 2021. https://bit.ly/3d6biPa