Addition of Ublituximab/Umbralisib to Ibrutinib Produces High uMRD Rate in CLL

The time-limited combination of ublituximab and umbralisib (Ukoniq; U2) plus ibrutinib (Imbruvica) resulted inan undetectable minimal residual disease (uMRD) rate of 77% in patients with chronic lymphocytic leukemia (CLL), according to findings from a phase 2 trial (NCT04016805) presented during the 47th Annual Oncology Nursing Society (ONS) Congress.¹

“This novel patient care approach of ‘add-on’ combination therapy was well tolerated and effective, with achievement of uMRD in 77% of evaluable patients allowing for tailored, time-limited therapy and sustained treatment-free observation [TFO],” lead study author Colleen Dorsey, RN, BSN, of Memorial Sloan Kettering Cancer Center, and coauthors, wrote in the poster. “This approach may assist nurses with patient care challenges such as management of adverse effects [AEs] due to indefinite ibrutinib therapy.”

The data with theregimen mirror those presented during the 2021 ASH Annual Meeting. In the phase 2 trial, the addition of U2 to ibrutinib led to a 77% uMRD rate in this patient population.² Moreover, 4% of patients came off treatment after 24 cycles and continued to have undetectable MRD.

Time-limited therapy has been shown to produce high and durable response rates in previous research; however, this approach has also been associated with an increase in AEsas well as a risk of overtreatment, according to the study authors.

In the data presented at the ONS Congress, investigators utilized an “add-on” and MRD-driven, time-limited treatment approach with U2 following ibrutinib monotherapy. To be eligible for enrollment, patients had to be receiving ongoing ibrutinib for at least 6 months and have detectable MRD.

In addition to ibrutinib, oral umbralisib was given at a daily dose of 800 mg and intravenous ublituximab was administered on days 1 and 2 at a split dose of 150 mg and 750 mg, and then at 900 mg total on days 8 and 15 of cycle 1, day 1 of cycles 2 through 6, and on day 1 every 3 cycles after cycle 6.

Following confirmation of uMRD, patients were entered into TFO. Those who did not have confirmed uMRD continued treatment for up to 24 cycles; this was followed by a TFO.

Outcome measures for the trial included uMRD rate, safety, and duration of clinical benefit after treatment discontinuation.

Among the 27 evaluable patients, the median age was 64 years and 79% were male. The median time to first uMRD was 7.4 months (95% CI, 4.6-20.2) and 77% of patients underwent at least 1 uMRD assessment.

Sixteen patients (67%) entered TFO and were off therapy for a median of 242 days (range, 5-538). At the last follow-up, 73% of these patients remained in uMRD. Retreatment was not required in any patients per International Workshop on CLL criteria.

The triplet regimen was found to be well tolerated. Overall all-causality grade 3/4 AEs of special interest included hypertension (7%), alanine aminotransferase/aspartate aminotransferase increase (4%), COVID-19 (4%), and diarrhea (4%). Two patients discontinued treatment due to rash (n = 1) and rash plus arthralgia (n = 1); both patients were in uMRD at the time of discontinuation and continued to haveuMRD status.

These results follow the April 2022 announcement that the pending biologics license application (BLA) and supplemental new drug application (sNDA) seeking the approval of the combination of ublituximab and umbralisib in adult patients with CLL and small lymphocytic lymphoma (SLL) had been voluntarily withdrawn by the developer of U2, TG Therapeutics, Inc.³

The decision follows updated overall survival data yielded from the phase 3 UNITY-CLL trial (NCT026112311), which demonstrated an increasing imbalance in survival in favor of the control arm.

TG Therapeutics also announced the decision to voluntarily withdraw umbralisib from sale for the approved indications of adult patients with marginal zone lymphoma (MZL) who have previously received at least 1 anti–CD20-based regimen and for adult patients with follicular lymphoma who previously received at least 3 systemic therapies.

In February 2021, the FDA granted an accelerated approval to umbralisib for these indications based on data from 2 single-arm cohorts of the open-label, multicenter, phase 2/3 UNITY-NHL trial (NCT02793583).⁴ Results showed that the objective response rate achieved with the agent was 49% (95% CI, 37.0%-61.6%) in patients with MZL (n = 69), which included a complete response (CR) rate of 16%. The ORR experienced by patients with follicular lymphoma (n = 117) was 43% (95% CI, 33.6%-52.2%), which included a CR rate of 3%.

References

1. Dorsey C, Falco V, Pena-Velasquez CP, 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: 47th Annual Oncology Nursing Society Congress; April 27-May 1, 2022; Anaheim, CA. Abstract P303.
2. 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. Blood. 2021;138(suppl 1):395. doi:10.1182/blood-2021-146999
3. TG Therapeutics announces voluntary withdrawal of the BLA/sNDA for U2 to treat patients with CLL and SLL. News release. TG Therapeutics, Inc.; April 15, 2022. Accessed April 15, 2022. https://bit.ly/36lqqZm 
4. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma. News release. FDA; February 5, 2021. Accessed April 15, 2021. http://bit.ly/3aCBqQa