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EZH2 inhibition with valemetostat: A new frontier in non-hodgkin lymphoma treatment

Non-Hodgkin lymphoma (NHL) is a diverse group of blood cancers that originate in the lymphatic system. NHL is one of the most common cancers in the United States, accounting for about 4% of all cancers. While advancements in cancer research and treatment have improved survival rates for NHL patients, there is always room for innovation [1].


Current scenario of NHL


Non-Hodgkin lymphoma

The term "NHL" refers to a broad variety of lymphatic system tumors that impact lymphocytes. These cancers can appear in lymph nodes, bone marrow, spleen, and other lymphoid organs. NHL can either be aggressive or indolent (slow-growing). NHL will be diagnosed in about 80,550 people in 2023 (44,880 male and 35,670 female), according to the American Cancer Society. The number of patients with the NHL started declining after decades of increase. Since 2015, annual decreases in NHL incidence rates have averaged 1% [1].


Treatment for NHL typically involves a combination of chemotherapy, radiation therapy, targeted therapy, immunotherapy, and stem cell transplantation. The choice of treatment depends on the type of NHL, its stage, and the patient's overall health. However, the response to treatment is not enduring, relapse is frequent, and the prognosis is typically dismal. Thus, there is a need for new treatment alternatives [1].


Valemetostat: New star, new hope in NHL


Valemetostat tosilate (valemetostat) is a selective dual inhibitor of histone-lysine N-methyltransferases enhancer of zeste homolog 1 and 2 (EZH1/2). Valemetostat is being developed by Daiichi Sankyo Company, Ltd., to treat a variety of solid tumors and hematological malignancies, including different subtypes of NHL.


Valemetostat received approval in Japan in September 2022 to treat patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATL), the most rare and aggressive subtype of NHL. ATL is caused by peripheral T-cell lymphoma (PTCL), B-cell lymphomas, and T-cells infected with human T-lymphotropic virus type 1 (HTLV-1). Despite treatment, ATL has a dismal prognosis and a short overall survival rate [2,3].


Mechanism of action of valemetostat


The precise mechanism of action is uncertain, while it is believed that valemetostat prevents the methylation activity of EZH1/2. EZH2 is responsible for adding methyl groups to histones, which results in the suppression of certain genes.


The reduction in histone methylation alters gene expression patterns associated with cancer pathways, enhances transcription of certain target genes, and inhibits the proliferation of EZH1/2-expressing cancer cells by reactivating silenced genes. By inhibiting EZH2, valemetostat aims to restore normal gene regulation, effectively slowing down or stopping the proliferation of cancerous lymphocytes [2,3].


Clinical trials and promising results


The development of valemetostat has been accompanied by extensive clinical trials to evaluate its safety and efficacy. Significant promise has been seen in preliminary results. Regardless of the presence of an EZH2 mutation, valemetostat demonstrated antiproliferative effects in several hematological cancer cell lines and clinical activity in a phase 1 study in patients with relapsed or refractory NHL (NCT02732275) [2,3].


Moreover, valemetostat has shown a favorable safety profile, with the majority of adverse events being tolerable and non-severe. This is a critical consideration, as minimizing treatment-related toxicity is crucial in improving the quality of life for NHL patients. More research is needed to refine its use, determine optimal treatment regimens, and identify patient populations that will benefit most from this therapy [2,3].


Positive foresight


Valemetostat is a glimmer of light in the field of NHL treatment. It is a useful addition to the cancer toolkit due to its specific mechanism of action, encouraging clinical trial findings, and the potential to enhance the quality of life of NHL patients. Valemetostat has the potential to completely alter the landscape of available treatments for this difficult and complex disease as more research and development are necessary. With continued dedication to innovation and patient-focused care, we may be witnessing a new era in the fight against NHL.


References


1. 'View All Pages' [https://www.cancer.net/cancer-types/41246/view-all]. Cancer.Net.

2. Keam, S.J. 'Valemetostat Tosilate: First Approval'. Drugs. (2022) 82(16), 1621–1627. DOI: 10.1007/s40265-022-01800-5.

3. Izutsu, K. et al. 'An open-label, single-arm phase 2 trial of valemetostat for relapsed or refractory adult T-cell leukemia/lymphoma'. Blood. (2023) 141(10), 1159–1168. DOI: 10.1182/blood.2022016862.

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