Umbralisib Plus Ublituximab Improves PFS in Frontline and Relapsed/Refractory CLL

A doublet combining umbralisib and ublituximab improved progression-free survival in patients with chronic lymphocytic leukemia.

John Gribben, MD, DSc, FRCP, FRCPath, FMed Sci.

A doublet combining the PI3K-delta inhibitor umbralisib and the anti-CD20 monoclonal antibody ublituximab (U2 regimen) improved progression-free survival (PFS) compared with obinutuzumab (Gazyva) plus chlorambucil in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL), according to topline findings from the pivotal phase 3 UNITY-CLL trial.1

An independent review panel determined that the chemotherapy-free U2 combination induced a statistically significant improvement in PFS (P <.0001), and recommended that the trial be stopped early.

“It’s extremely gratifying to see positive results for this important trial exploring the combination of umbralisib and ublituximab in patients with both front-line and relapsed/refractory CLL. Today’s outcome marks the first successful phase 3 trial of a PI3K delta-based regimen in a CLL patient population that included previously untreated patients,” John Gribben, MD, DSc, FRCP, FRCPath, FMed Sci, global study chair for the UNITY-CLL study and professor of Medical Oncology, Barts Cancer Institute, UK, stated in a press release. “CLL remains incurable and new treatment options are still very much needed, particularly those that provide a differentiated mechanism and safety profile from our currently available treatment options.”

The phase 3 UNITY-CLL trial, which is being conducted under a special protocol assessment agreement with the FDA, accrued patients with both treatment-naïve and relapsed/refractory CLL. Patients were initially randomized into 1 of 4 treatment arms: single-agent ublituximab; single-agent umbralisib; U2; or obinutuzumab plus chlorambucil. The trial design allowed for the discontinuation of the 2 monotherapy arms following a positive assessment of the U2 combination. Randomization at that point continued with only 2 arms: U2 and the obinutuzumab plus chlorambucil arm. Overall, the trial enrolled 420 patients across these 2 arms, comprising approximately 60% treatment-naïve patients and 40% relapsed/refractory patients.

Various doublet and triplet combinations involving umbralisib and/or ublituximab have shown promising activity in CLL. For example, the triplet regimen of pembrolizumab (Keytruda) plus umbralisib and ublituximab reached a 90% response rate in patients with relapsed/refractory CLL.2 Nine of 10 patients with CLL receiving the triplet achieved a response, including 1 complete response (CR) and 8 partial responses (PRs), according to data from a phase I/II study presented at the 2018 ASH Annual Meeting.

A phase 1/2 dose-escalation study showed that the triplet of umbralisib, ublituximab, and venetoclax (Venclexta) induced a CR rate of 44% as a treatment for patients with relapsed/refractory chronic CLL.3 At the end of 12 cycles of treatment with the regimen, the objective response rate (ORR) was 100%, which included the CR rate of 44%. In an assessment of peripheral blood, all patients were negative for minimal residual disease (MRD). In the bone marrow, 78% were MRD-negative (<.01%) and 22% were MRD intermediate (.01% to 1.0%). At a median follow-up of 6.4 months (range, 0.7-19.0+), no patients had progressed.

Additionally, the combination of ublituximab and ibrutinib (Imbruvica) improved PFS, as determined by an independent review committee, compared with ibrutinib alone in patients with relapsed/refractory high-risk CLL, according to final long-term findings of the phase III GENUINE study.4 The ORR was 78% with the combination, which included a CR rate of 7%, compared with a 45% ORR in the single-agent ibrutinib arm where there were no CRs. Additionally, 19% of patients in the ublituximab arm were MRD negative versus 2% of patients on ibrutinib alone. Overall, 66% of patients had a >75% decrease in lymph node size with ublituximab plus ibrutinib compared with 52% for single-agent ibrutinib.


  1. TG Therapeutics Announces Positive Topline Results from the UNITY-CLL Phase 3 Study Evaluating the Combination of Umbralisib and Ublituximab (U2) for the Treatment of Patients with Chronic Lymphocytic Leukemia. Published May 5, 2020. Accessed May 5, 2020.
  2. Mato AR, Svoboda J, Luning Prak ET, et al. Phase I/II Study of umbralisib (TGR-1202) in combination with ublituximab (TG-1101) and pembrolizumab in patients with relapsed/refractory CLL and Richter’s Transformation. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 297.
  3. Venetoclax (U2-Ven) in Patients with Relapsed/Refractory CLL. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 360.
  4. 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. J Clin Oncol. 2017;35 (suppl; abstr 7504). doi: 10.1200/JCO.2017.35.15_suppl.7504.