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ASCO 2020 Top 12” #10: Initial results of a multicenter, investigator initiated study of MRD driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax

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In short videos with accompanying text, Dr. Brian Koffman, the Executive Vice President (EVP) and Chief Medical Officer (CMO) of the CLL Society, takes us through his “Top 12” abstracts from ASCO or the American Society of Clinical Oncology Annual Meeting held virtually in May, 2020.

#10

ASCO 2020: Initial results of a multicenter, investigator initiated study of MRD driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax

Venetoclax (Ven)-Obinutuzumab (O) or OVen (also shortened to VenG in other trials) is approved for front line chronic lymphocytic leukemia (CLL) therapy, achieving a remarkable 76% rate of undetectable minimum residual disease (uMRD) in the peripheral blood.

The combination of venetoclax and ibrutinib has also proven synergistic in clinical trials, such as CLARITY, with ∼3/4 of patients reaching uMRD in the peripheral blood.

Zanubrutinib (B) is a 2nd generation irreversible BTK inhibitor, approved to treat mantle cell lymphoma but still in trials for CLL, that might be more selective and therefore easier to use in combinations with other drugs.

In this trial zanubrutinib, obinutuzumab, and venetoclax (BOven) were combined with the hope of achieving high levels of uMRD and then using MRD status to drive treatment decisions.

Takeaways:

  • 39 untreated CLL patients were enrolled.
  • The treatment used 2 cycles of only zanubrutinib and obinutuzumab to reduce the tumor burden and therefore the risk of tumor lysis syndrome (TLS) when venetoclax was added.
  • 72% had unmutated IgVH and 15% had a TP53 aberration.
  • Results
    • Side effects and risk
      • At the time of initial screening to join the trial, 72% were consider high risk for TLS, but after the run of 2 cycles of zanubrutinib and obinutuzumab (BO) only 5% were high risk, and no patient actually developed TLS with the standard venetoclax ramp up.
      • Neutropenia of any grade was seen in about half of the patients, but only 15% were more severe (grade 3 or 4).
      • 46% of patients had low platelet counts, again mostly mild.
      • 41% had some grade of infusion reaction to the IV obinutuzumab.
      • 41% had bruising and 41% had diarrhea.
      • 1 patient died of a bleeding complication after being started on a blood thinner.
    • Efficacy
      • At a median follow-up of 11 months, uMRD was seen in 84% of patients in the peripheral blood and in 73% in the bone marrow.
      • 100% of patients responded, but only 57% of those who reached uMRD were in some form of complete remission when treatment was discontinued. Most were in a partial remission (PR) due to some slightly enlarged lymph nodes.

Conclusions:

These results are remarkably good, but we have become accustomed to seeing few and mostly manageable adverse events, little tumor lysis syndrome and high rates of uMRD in venetoclax based combinations, especially when used in treatment naïve patients.

What is remarkable about this trial is what’s to come. Therapy was stopped when patients became uMRD, whether or not they were in a complete remission.  How the patients do off meds once achieving uMRD is the really important question.

Think about that for a minute.

This is a fixed duration therapy that stops treatment when the CLL become undetectable to a level of 1 in 10,000 cells, regardless of whether the patient is in a complete remission or not.

Treatment decisions are being guided by MRD status and not by the traditional measure of depth of remission.

My bet is that this will lead to a sea change for the better in how CLL is treated in the future. But we need trials such as this to prove that hypothesis.

Here is a link to the ASCO 2020 abstract: ASCO 2020: Initial results of a multicenter, investigator initiated study of MRD driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax.

Stay strong.  We are all in this together.

Brian

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