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Lymphoma/CLL Highlights: ASH 2021

CME

Key Studies in Lymphomas and CLL: Independent Conference Coverage of ASH 2021

Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™

Released: May 10, 2022

Expiration: May 09, 2023

John M. Burke
John M. Burke, MD
Peter Martin
Peter Martin, MD
CME/CE Information

Activity

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Course Completed

Valemetostat for R/R ATL: Study Design

Peter Martin, MD:
This is a small but important phase II trial conducted in Japan looking at valemetostat in patients with R/R ATL. Valemetostat is an EZH1/2 inhibitor. EZH1 and EZH2 are parts of the polycomb repressive complex that ultimately are responsible for methylation of lysine 27 on histone 3 and the subsequent transcriptional silencing of key genes that might be responsible for apoptosis, survival, and proliferation of lymphoma cells. Valemetostat is different from tazemetostat, for example, which only inhibits EZH2.

ATL is a rare disease but is probably the worst T‑cell lymphoma that exists anywhere in the world. It has a 5‑year OS of approximately 10%. Frontline therapies are rarely effective, and therapies in the R/R setting do even worse. Mogamulizumab is an anti‑CCR4 antibody that is approved in Japan for the treatment of R/R ATL. In a similar trial in Japan, the treatment of patients with mogamulizumab resulted in a median PFS of only 5.2 months.13 So, clearly, ATL is a disease with an unmet need, making this an important trial.

In this single-arm, open-label, pivotal phase II trial in Japan, valemetostat was given to 25 patients with previously treated ATL.14 These patients received 200 mg of valemetostat daily until disease progression or intolerance. The primary endpoint was overall response rate by independent review.

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Valemetostat for R/R ATL: Baseline Characteristics

Peter Martin, MD:
The median age of the patient population in this trial was age 69, which is older than the median age of patients with ATL seen in the United States. Of note, there may be some differences in how ATL presents in different geographical regions of the world. In this trial, 96% of the patients previously had received mogamulizumab, and approximately two thirds of the patients had acute ATL, whereas 12% of the patients had an aggressive form of the disease.

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Valemetostat for R/R ATL: Response

Peter Martin, MD:
The overall response rate was 48%, including a 20% CR rate. Responses were seen across all disease subtypes but were most frequently reported in the acute subtype, which is very interesting. Responses also were seen in all disease sites, and valemetostat seemed to be particularly effective in the peripheral blood with an overall response rate of 88.9%. Valemetostat has demonstrated activity regardless of whether patients had recurrent disease or whether the disease was refractory to the prior line of therapy with an overall response rate of 66.7% and 45.5%, respectively.

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Valemetostat for R/R ATL: Safety

Peter Martin, MD:
Valemetostat demonstrated a good and manageable safety profile with the most commonly experienced adverse events being cytopenias. Overall, this is a very well tolerated drug, particularly considering the patient population and the treatment options that are available to them.

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Valemetostat for R/R ATL: Clinical Implications

Peter Martin, MD:
The only good that can be said about ATL is that, globally, it is a very rare disease. Unfortunately, it is not as rare in certain geographical regions; for example, it may be up to one third of all T‑cell lymphomas in some parts of southern Japan. The only approved treatment specifically for ATL in Japan is mogamulizumab, which has limited efficacy, as demonstrated by the fact that all except 1 of the patients in this trial had previously received mogamulizumab. This is a population that clearly has an unmet need. Although this was a small trial, it is hard to deny that the results were excellent, with an overall response rate of 48% and a well tolerated safety profile. Since the median follow-up was only 6.5 months, longer follow-up is needed to determine the durability of these responses. In addition, it will be important for this trial to be replicated in other parts of the world to determine whether valemetostat has similar efficacy in geographic regions other than Japan.

Which of the following patients with relapsed lymphoma would you consider discussing potential enrollment on a clinical trial with valemetostat, a novel EZH1/2 inhibitor, based on promising evidence of efficacy and safety presented by Yoshimitsu and colleagues?
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