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EHA 2021 Top Pick #7: Long Term Results of a Phase I/Ib Study of Ibrutinib in Combination with Umbralisib for Patients with Relapsed/Refractory (R/R) CLL (Chronic Lymphocytic Leukemia) or MCL (Mantle Cell Lymphoma)

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Dr. Matt Davids of Dana Farber presented this abstract at the 2021 European Hematology Association Virtual Congress, (EHA 2021) that updated the results of combining two different oral targeted therapies that both block B-cell receptor (BCR) signaling: Ibrutinib through BTK inhibition and umbralisib, an experimental inhibitor of PI3K.

We know that CLL cells are addicted to BCR signaling, so blocking the pathway leads to powerful control of the cancer. But unfortunately in the R/R setting, the cancerous chronic lymphocytic leukemia cells often mutated around the block.

Blocking it with two different molecules at two different points offers the potential for deeper and more durable responses.



  • The median follow-up among survivors was 43.5 months when the data were collected.
  • No cumulative or recurrent late-onset toxicities were observed, including no new episodes of atrial fibrillation (rate still 10%), and still no dangerous bleeding events.
  • Hypertension was noted in 14%.
  • Mild liver inflammation (transaminitis) was noted in 38%, with only one serious case.
  • No other new immune-mediated toxicities arose with the extension of the trial, with a cumulative rate of more severe diarrhea of 7% and no colitis or life-threatening diarrhea.


  • The overall response rate (ORR) in CLL was 95%.
  • Complete response was seen in 29%. This is higher than usually seen with BTK or PI3K inhibitors when used as monotherapy.
  • Median progression-free survival (PFS) and overall survival (OS) have not been reached.
  • Four-year PFS and OS are estimated to be 78% and 90%.


A combination of a PI3K and BTK inhibitor holds promise if it is well tolerated and leads to more durable responses and/or helps more patients than either drug used alone. Ibrutinib plus umbralisib may prove to meet that standard with good tolerability and excellent PFS and OS at four years. Whether the simultaneous use of the two or their use sequentially offer the best OS will need to be studied, but that is a ways off. Let’s get umbralisib approved first. It is good news that any new adverse events were rare with longer follow-up as the combination is not a limited duration therapy. This duo could prove to be helpful for many CLL patients including those who have failed venetoclax based therapies, a significant unmet need.

Here is a link to the EHA 2021 interactive poster and abstract which is pretty cool.

Please enjoy the video:

Stay strong.  We are all in this together.


Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.