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ASH 2020: Dr. Paul Barr’s Update on the Combination of Umbralisib, Ublituximab, and Venetoclax for Treatment of Chronic Lymphocytic Leukemia (CLL)

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

In order to expand the toolkit for treating chronic lymphocytic leukemia (CLL), scientists have been studying new combinations of drugs in an effort to find treatment regimens that are well-tolerated, time-limited, and produce deep remissions for patients. Last year, Dr. Paul Barr, an Associate Professor of Medicine at the Wilmot Cancer Institute in Rochester, NY, told us about a phase 1/2 clinical trial testing a novel combination of three different drugs (umbralisibublituximab, and venetoclax) for treatment of relapsed or refractory chronic lymphocytic leukemia (CLL)At the time of our last interview, the trial was in its early stages and only had very preliminary results. At the 2020 annual meeting of the American Society of Hematology (ASH), Dr. Brian Koffman interviewed Dr. Barr again for an update on the trial results. 

The combination being tested is umbralisib and ublituximab followed by venetoclax (U2-Ven) 

  • Umbralisib is an experimental PI3Kδ inhibitor. Even though it has not yet been approved by the FDA, current data suggests that it might be better tolerated than other drugs in this class such as idealisib or duvelisib. 
  • Ublituximab is an anti-CD20 antibody. These types of antibodies (i.e., rituximab and obinutuzimab) have been used with chemotherapy and targeted agents for enhanced efficacy. 
  • Venetoclax is a BCL2 inhibitor that is very effective for treating CLL.  


  • This early-stage clinical trial is ongoing, and it is studying the safety and efficacy of the combination of umbralisibublituximab, and venetoclax in patients with relapsed or refractory CLL. 
  • Treatment starts with umbralisib and ublituximab (U2) for three months for debulking (reducing the number of cancer cells to avoid tumor lysis syndrome), after which venetoclax is introduced and continued for nine additional months 
  • Forty patients have been treated thus far, about half of whom had previously been treated with a BTK inhibitor. 
  • The adverse events observed in this trial were expected based on what is known about the individual drugs and have been mostly manageable. 
  • At cycle 3 (three months), three out of four patients had responded to umbralisib in combination with ublituximab, meaning that their cancer shrank or even disappeared. 
  • At cycle 7 (seven months), all patients had responded to treatment (U2-Ven), and this continued through cycle 12 (12 months). 
  • After 12 months of treatment, 95% of patients had undetectable minimal residual disease (uMRD) in the peripheral blood and 68% had uMRD in the bone marrow. 
  • After 12 cycles of treatment, patients with uMRD in the bone marrow and peripheral blood stopped therapy. Patients who had detectable MRD continued on umbralisib by itself. 
  • Researchers are continuing to monitor patients to see how long treatment effects last. 
  • Thus far, only one patient has experienced disease progression, ten months after achieving uMRD and stopping therapy.  
  • For all pts treated to date, the most common adverse event (AE) was infusion related reaction, specifically with the IV monoclonal antibody (mAb) ublituximab (63%), something that is commonly seen with other mAbs used in CLL. 
  • With all medications, the most common problems were anemia (55%), low platelet counts (53%), low neutrophil counts (53%), low white blood cell counts (50%), decreased kidney function, (50%), fatigue (45%), diarrhea (43%), nausea (38%), and AST (a liver enzyme and maker for liver inflammation) increase (30%).  
  • Umbralisib associated toxicities that were of particular interest for any PI3Kδ inhibitor occurred in two patients (one severe colitis, and one severe diarrhea). 


The results of this trial are promising and suggest that this chemotherapy-free regimen can provide uMRD after only 12 cycles of treatment. Researchers are still monitoring patients in order to determine how long these effects last. This research may provide a highly effective treatment option for patients with relapsed or refractory CLL. 

Please enjoy this brief interview with Dr. Barr from the virtual ASH meeting which was held December 2020. 

You can read the actual abstract hereA Phase 1/2 Study of UmbralisibUblituximab, and Venetoclax (U2-Ven) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) 

Take care of yourself first. 

Ann Liu, PhD