Multi-Center Phase II Study of Oral Azacitidine (CC-486) Plus CHOP As Initial Treatment for Peripheral T-Cell Lymphoma (PTCL)

Today, at the 2020 Annual Meeting of the American Hematology Society (ASH), the Weill Cornell Medicine T-cell lymphoma research team reported the outcome of the first phase 2 study evaluating the novel combination of oral azacitidine plus CHOP as initial treatment for patients with peripheral T-cell lymphoma (PTCL).

This multi-center phase 2 study, led by Dr. Jia Ruan, is the first of its kind to incorporate epigenetic priming with a hypomethylating agent in the frontline setting as a chemo-sensitizing strategy for PTCL. 

The study enrolled 21 PTCL patients, with the majority of them (17 patients) having the diagnosis of angioimmunoblastic T-cell lymphoma, also known as PTCL with T-follicular helper phenotype (PTCL-TFH). This phenotype is known to have recurrent genetic mutations in epigenetic regulation, providing therapeutic targets for hypomethylating agents such as azacitidine. During study treatment, the patients received CHOP on day 1 of each cycle for 6 cycles, while oral azacitidine was given for 7 days prior to CHOP cycle 1, and for 14 days before CHOP cycles 2-6.  The primary study objective was to see if the novel combination would improve complete response rates following 6 cycles of treatment.  

The study treatment was well tolerated with expected side effects associated with CHOP chemotherapy. Eighteen patients were able to complete all 6 cycles of treatment without the need for chemotherapy dose reduction. Ten patients underwent successful stem cell transplant while in remission. Complete remission (CR) was achieved in 75% of clinical trial participants at the end of 6 cycles of treatment, exceeding the pre-determined efficacy threshold (60%) to declare the treatment as effective. Notably, within the subgroup of patients with the PTCL-TFH subtype, the treatment appears to work even better with a CR rate of 88%. The one-year progression-free survival (PFS) for all patients was 66%, and for the PTCL-TFH subgroup was 70%. The one-year overall survival (OS) for all patients was 81% and PTCL-TFH patients 94%. The research team is further analyzing sequencing biomarkers to correlate with response and survival. 

This study provides the first demonstration that the addition of epigenetic hypomethylating agent oral azacitidine (CC486) to CHOP as initial therapy is safe, and highly effective to induce complete remission in PTCL. This combination will be further evaluated in the upcoming ALLIANCE/Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P with duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL.

Abstract 40: Multi-Center Phase II Study of Oral Azacitidine (CC-486) Plus CHOP As Initial Treatment for Peripheral T-Cell Lymphoma (PTCL)

Type: Oral presentation
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Clinical Studies in T/NK Cell Lymphoma
Saturday, December 5, 2020: 7:45 AM PST

ASH 2020 Weill Cornell Medicine Lymphoma Program research coverages continues throughout the conference.

2020 American Society of Hematology (ASH) Annual Meeting

The American Society of Hematology (ASH) is the world’s largest professional society serving clinicians and scientists who work to conquer blood diseases. This year the 62nd ASH Annual Meeting & Exposition – the premier conference in malignant and non-malignant hematology – will bring together approximately 25,000 hematology professionals from around the world virtually.

As always, our team is proud to contribute new lymphoma discoveries for presentation at the meeting. We’ll be covering the conference research updates on our social media channels and here on our blog throughout the duration of the meeting.

Dr. Peter Martin, Chief of the Weill Cornell Lymphoma Program shares some personal thoughts regarding the 2020 ASH Annual Meeting.

While it’s impossible to ignore the trauma that accompanied the year 2020, every December brings a display of the hopes and efforts of thousands of international researchers presenting their data at the Annual Meeting of the American Society of Hematology (ASH). I’m so proud to say that research is alive and well in the Lymphoma Program at Weill Cornell Medicine.

Over the next 3 days, our team of physicians and scientists will be presenting ground breaking research on the world’s top stage. Min Xia, PhD has the distinction of being selected to deliver a presentation in the ASH Plenary Session, the forum for the top 6 research abstracts of the entire conference. Dr. Ari Melnick is being honored for his work in epigenetics and will be delivering the prestigious Ernest Buetler lecture. We have numerous oral and poster presentations, including several from our fellows, residents, and medical students — the future leaders of our field.

Peter Martin, MD, MS

Additionally, Dr. John Leonard continued his #LeonardList tradition of selecting 10 noteworthy lymphoma abstracts leading up to the meeting. In addition to posting his selections on Twitter, he discussed this research in detail in the third-annual Leonard List CancerCast Podcast episode – with 5 bonus podcast-only abstracts. Dr. Leonard selects this research from all the lymphoma-related abstracts, looking at both oral and poster sessions.

Tune in!

Listen to the full episode and other great CancerCast topics on Apple Podcasts, Google Podcasts, or online at Weill Cornell Medicine.

Follow our Twitter feed for additional updates throughout the conference.

New Research Points to HDAC3 Inhibition as a Potential Game-Changing Treatment for Specific Lymphoma Subtypes

By Sucharita Mistry, PhD

B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are blood cancers of the immune cells. A vast majority of B-cell lymphomas typically display a high frequency of genetic alterations. Since lymphomas show remarkable genetic diversity, a big challenge for scientists is not only to determine which genes are mutated in these diseases, but also to identify “actionable” genetic alterations that can respond to targeted therapies.

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“Discovering how different mutations are involved in causing the disease is a major key to advancing novel mechanism-based precision therapies and immunotherapies for lymphomas, with potentially less toxic side-effects,” says Dr. Ari Melnick, a world-renowned physician-scientist at Weill Cornell Medicine.

Dr. Melnick led groundbreaking research that defines the genetic underpinnings of CREBBP mutation in lymphomas, paving the way for new therapeutic avenues. The findings of this study were recently published in Cancer Discovery.

The CREBBP gene encodes a kind of histone acetyltransferase (HAT), an enzyme that introduces small chemical tags called acetyl groups on histones, which are the major structural proteins of chromosomes. The chemical modifications on histones are termed as epigenetic changes, and they determine whether genes are turned on or off. The CREBBP gene, which is an epigenetic modifier, is frequently mutated in DLBCL and FL.

The Melnick research team, in collaboration with scientists at the MD Anderson Cancer Center, characterized the functional consequences of CREBBP mutation in lymphomas. Using a powerful CRISPR gene-editing technology, the researchers engineered lymphoma cell lines that differed only in the CREBBP mutation status. The research team discovered two different types of CREBBP mutations that either truncate the protein or inactivate the HAT domain, the latter associated with poor clinical outcomes.

This study showed that CREBBP mutation disrupts key biological pathways resulting in abnormal silencing of tumor-suppressive and antigen-presenting pathway genes. This disruption allows lymphoma cells to hide from the immune system so that they cannot be recognized and attacked by the T-cells that play an essential role in the body’s immune response.

More importantly, the malfunction in immune surveillance was restored by an HDAC3 inhibitor, a drug that specifically reverses the histone acetylation defect caused by CREBBP mutation. Notably, selective inhibition of HDAC3 reversed the epigenetic abnormalities, halted lymphoma growth and induced the expression of major histocompatibility (MHC) class II protein, enabling the T cells of the immune system to recognize and kill lymphoma cells. The research team also demonstrated that combination of an HDAC3 inhibitor with an immune checkpoint inhibitor (PD-1/PD-L1 blockade) results in synergistic anti-lymphoma immunity effects.

These findings uncover a novel mechanistic link between CREBBP mutation and immune surveillance dysfunction in lymphomas that can be counteracted by an HDAC3 inhibitor, providing a potentially game-changing approach for restoring anti-tumor immunity.

“HDAC3 inhibition provides an attractive therapeutic avenue for DLBCL and FL and may have enhanced potency in CREBBP-mutant tumors,” says Dr. Melnick. “We are very excited to translate this research into clinical trials that could potentially lead to the development of novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas.”

 

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