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Rationale and Evidence for EZH1/2 Inhibitors in PTCL

Steven M. Horwitz, MD
Program Director

Member, Memorial Sloan Kettering Cancer Center
Attending Physician, Memorial Hospital
Professor of Medicine, Weill Cornell Medical College
New York, New York

Steven M. Horwitz, MD: consultant/advisor/speaker: Acrotech, Affimed, Cimeio Therapeutics, Daiichi Sankyo, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Secura Bio, Shoreline Biosciences, Takeda, Trillium, Tubulis, Vividion Therapeutics, Yingli Pharma; researcher: ADC Therapeutics, Affimed, C4 Therapeutics, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Millennium/Takeda, Seattle Genetics, Verastem/Secura Bio.

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Pamela B. Allen, MD, MSc

Assistant Professor
Department of Hematology/Oncology
Emory University, Winship Cancer Institute
The Emory Clinic
Atlanta, Georgia

Pamela B. Allen, MD: advisor: Daiichi Sankyo.

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Pierluigi Porcu, MD

Professor and Director
Division of Hematology Malignancies
Department of Medical Oncology
Thomas Jefferson University
Philadelphia, Pennsylvania

Pierluigi Porcu, MD: consultant/advisor/speaker: Daiichi Sankyo, Dren Bio, Innate Pharma, Loxo Oncology, MorphoSys, Viracta.

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Released: August 8, 2022

Key Takeaways

  • Peripheral T-cell lymphoma is a heterogenous disease with no clear standard of care in the relapsed/refractory setting.
  • Drugs targeting epigenetic mechanisms regulating gene expression, including DNA methylation and histone modifications, are among the most studied in peripheral T-cell lymphoma.
  • Preliminary data with valemetostat, an inhibitor of the EZH1/2 methyltransferases, have demonstrated its activity in the relapsed/refractory setting across peripheral T-cell lymphoma subtypes; the most common hematologic toxicity is thrombocytopenia, and the most common nonhematologic toxicities are dysgeusia and alopecia.

In this commentary, Steven M. Horwitz, MD; Pamela B. Allen, MD; and Pierluigi Porcu, MD, describe the rationale supporting dual EZH1/2 inhibition in peripheral T-cell lymphoma (PTCL) and the emerging evidence of efficacy and safety. In addition, they answer questions about challenges with therapy selection in PTCL submitted by the audience at a live Clinical Care Options satellite symposium during the 2022 American Society of Clinical Oncology Annual Meeting.

Peripheral T-Cell Lymphoma: Overview of the Current Landscape

Pamela B. Allen, MD:
PTCL is a heterogeneous disease consisting of many subtypes (see Figure). Tissue biopsy, expert hematopathology review, and symptoms of clinical presentation are all important to accurately diagnose patients with a specific subtype of PTCL. First-line therapy for patients with most PTCL subtypes is typically combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a similar multiagent chemotherapy regimen. To date, the addition of novel agents such as lenalidomide, pralatrexate, romidepsin, and alemtuzumab to standard CHOP combination therapy has not resulted in significantly improved overall survival, the exception being brentuximab vedotin added to cyclophosphamide, doxorubicin, and prednisone for patients with CD30-positive PTCL. Unfortunately, most patients with PTCL , and there is no standard of care in this setting, with limited available single-agent options and generally poor efficacy and tolerability. 

Figure. PTCL subtypes.

Epigenetic Modifiers and PTCL Subtypes

Pierluigi Porcu, MD:
Deregulation of direct DNA methylation and histone modifications including acetylation, methylation, and phosphorylation are epigenetic mechanisms that contribute to the development of cancers, including T-cell lymphomas. Epigenetic modifiers targeting these mechanisms are among the most studied therapies in T-cell lymphomas. Studies in T-follicular helper origin (T-FH) lymphoma have shown mutations in regulators of gene expression, including epigenetic modifying genes RHOA, TET2, DNMT3A, IDH2, and EZH1/2. EZH2 and, less efficiently, EZH1 are the only enzymes that catalyze the trimethylation of histone H3K27 (H3K27me3), which is both a key mechanism of gene silencing and, when genome wide, a hallmark of cancer. EZH2 is overexpressed in most T-cell lymphomas. In tumor cell lines of both T-cell and B-cell lymphoma, EZH1/2 dual inhibition results in greater inhibition of tumor cell growth and increased apoptosis compared with the inhibition of EZH2 alone. 

Efficacy and Safety of Anti-EZH1/2 Therapy in PTCL

Steven M. Horwitz, MD:
Valemetostat is a dual EZH1/EZH2 inhibitor currently being evaluated in s. A phase I dose-escalation study of valemetostat was conducted in patients with relapsed or refractory non-Hodgkin lymphoma, which then followed expansion cohorts with valemetostat 200 mg daily in patients with relapsed/refractory (R/R) adult T-cell leukemia/lymphoma (ATL) and . Among 44 patients with various subtypes of PTCL, the preliminary overall response rate (ORR) was 54.5%; ORR was 65% in the 17 patients with angioimmunoblastic T-cell lymphoma. The responses appeared durable, with a median duration of response of 56 weeks and a median progression-free survival of 52 weeks for patients with R/R PTCL. The most frequent grade 3 or higher adverse events (AEs) with valemetostat included thrombocytopenia, decreased neutrophil count, and anemia. Notable reported AEs that can affect the quality of life for patients receiving long-term therapy were alopecia (~34%) and dysgeusia (~52%). 

Similar findings were reported from a phase II study of valemetostat in patients with R/R ATL after previous standard therapy, including mogamulizumab. Patients with refractory disease did not appear to have worse outcomes compared with those who had relapsed or recurrent disease. Currently, the phase II VALENTINE study assessing valemetostat in R/R PTCL of all subtypes, including a separate cohort for ATL, is ongoing (NCT04703192). This phase II confirmatory study will be important to help us determine how we may use valemetostat in clinical practice.

Audience Questions and Answers

Steven M. Horwitz, MD:
What is the role of combination regimens with epigenetic agents in untreated PTCL and/or relapsed/refractory disease?

Pamela B. Allen, MD:
Currently, epigenetic agent combinations should be used only in the context of a clinical trial. Several clinical trials have explored different combinations with these agents in the relapsed disease setting, some of which have had excellent responses. We are fortunate at our institution to have a study with valemetostat open, and if I had a patient with the T-FH subtype of PTCL who was eligible, we would consider this trial.

Pierluigi Porcu, MD:
I agree. It is difficult to get approval for these combination therapies outside of clinical trials. However, studies have demonstrated high response rates with combinations, including those with pralatrexate and romidepsin, although the number of patients enrolled on these trials is small. Outside of a trial, I recommend the use of currently available single-agent therapy options.

Steven M. Horwitz, MD:
Most studies with new agents are in the relapsed disease setting, but some combination therapy trials have allowed untreated patients to enroll. How do you consider that in terms of your approach for a given patient compared with a standard chemotherapy approach?

Pamela B. Allen, MD:
If I am not choosing standard chemotherapy for a patient, there is a specific reason, such as ineligibility. For anaplastic large-cell lymphoma, I have used rituximab as a single-agent, front-line therapy option for older patients who I think may not tolerate CHOP chemotherapy. For angioimmunoblastic T-cell lymphoma, the combination chemotherapy data are still relevant. I think it is difficult to justify a nonchemotherapy agent in the frontline setting. I will add that, like how we approach diffuse large B-cell lymphoma, mini-CHOP has been studied in older populations of patients with PTCL.

Pierluigi Porcu, MD:
The older, frail population is where cytotoxic chemotherapy would ideally be avoided, even as frontline therapy. However, the available data do not yet support that approach. In my practice, I give 1 cycle of conventional cytotoxic chemotherapy and see how it is tolerated by the patient. If the patient tolerates the treatment, I continue. If 1 or 2 cycles are not well tolerated, then I consider switching to an available single agent.

Steven M. Horwitz, MD:
As we have agents that are providing complete responses in the relapsed setting, how do you view aggressive approaches such as stem cell transplant vs maintenance therapy approaches?

Pamela B. Allen, MD:
It is an individualized approach. I consider relapsed and refractory scenarios differently. Patients who are refractory and have had a relapse, which I consider within the first 6 months of therapy, generally do not have a great response to chemotherapy. In general, I recommend that these patients should get an allogeneic stem cell transplant. For those patients who have relapsed after already receiving an autologous stem cell transplant in first remission, I consider an allogeneic stem cell transplant.

Pierluigi Porcu, MD:
From the patient perspective, this is a difficult choice. Because for patients—like the one you describe with primary refractory disease who may have a very good response to an oral drug that is relatively safe—it is difficult to present allogeneic stem cell transplant as an option. I have a patient in his 70s who is in a similar situation with primary refractory disease. He is having the best quality of life now. Why would you take him to an allogeneic stem cell transplant at that point? It is a difficult decision.

Your Thoughts?
What are your biggest challenges when caring for patients with PTCL? We encourage you to answer the polling question and join the conversation in the discussion box below.

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