The histone deacetylase (HDAC) inhibitor vorinostat (Zolinza®; Merck & Co/MSD) in combination with the mTOR inhibitor sirolimus (Rapamune®; Pfizer/Wyeth) or everolimus (Afinitor®; Novartis) showed clinical efficacy in patients with relapsed/refractory Hodgkin lymphoma.[1]

The results of the phase I study, supported by the Non-Standard of Care Clinical Charge Program at MD Anderson, the Sheikh Khalifa Al Nahyan Bin Zayed Institute for Personalized Cancer Therapy at MD Anderson, and others, were published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

According to data from the National Cancer Institute, each year between 8,000 and 9,000 people are diagnosed with Hodgkin lymphoma in the United States and aproximately 970 pateints will die of the disease. And in majority of cases the disease is diagnosed among people between the ages of 20-34.[2]

“While the majority of patients with Hodgkin lymphoma have favorable outcomes with standard treatment, approximately 20-30% of patients with advanced disease develop refractory disease after primary treatment,” said Filip Janku, M.D., Ph.D., an associate professor at The University of Texas MD Anderson Cancer Center and lead author on the study.

“These patients typically have poor outcomes with five-year survival rates as low as 30%,” Janku added.

Histone deacetylases and mTOR
Histone deacetylases (HDACs) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightlyand regulate gene expression.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase which is frequently deregulated in human cancer. Activating somatic mutations of mTOR have been identified in several types of human cancer and hence mTOR is therapeutically targeted. mTOR inhibitors were commonly used as immunosuppressors and currently, it is approved for the treatment of human malignancies.[3]

“Aberrant HDAC expression is associated with cancer, and HDAC inhibitors have been approved for the treatment of certain blood cancers. Resistance to HDAC inhibition in Hodgkin lymphoma has been suggested to develop through activation of mTOR signaling, which regulates cellular proliferation and cell death,” explained Janku.

“Thus, combining HDAC inhibition with an mTOR inhibitor could help prevent resistance and improve responses to treatment,” Janku noted.

Inhibition of HDACs and mTOR signaling 
Prior preclinical research demonstrated that combined inhibition of HDACs and mTOR signaling had antitumor effects against Hodgkin lymphoma. Furthermore, a patient with relapsed/refractory Hodgkin lymphoma who received treatment with vorinostat and sirolimus as part of a phase I clinical trial had a partial response to the treatment.

In this study, Janku and colleagues examined the clinical efficacy of vorinostat in combination with either sirolimus or everolimus in a larger cohort of patients with heavily pretreated relapsed/refractory Hodgkin lymphoma who had received a median of five prior therapies. The cohort included 40 adult patients; of these patients, 22 received the vorinostat and sirolimus combination, and 18 received the vorinostat and everolimus combination.

The objective response rate for patients in the vorinostat and sirolimus arm was 55%, with six complete responses and six partial responses. After a median follow-up of 43.3 months, the median progression-free survival was 5.3 months. Median overall survival had not been reached at the time of analysis.

The objective response rate for patients in the vorinostat and everolimus arm was 33 percent, with two complete responses and four partial responses. After a median follow-up of 21 months, the median progression-free survival was 4.8 months. Median overall survival had not been reached at the time of analysis.

All 40 patients were evaluated for adverse events. The most common grade 3 or 4 treatment-related adverse events in both treatment groups were thrombocytopenia, neutropenia, and anemia. There were no treatment-related deaths.

“In our study, we observed a relatively high objective response rate in a patient population that would otherwise have poor outcomes,” said Janku. “Based on our results, I believe further investigation is warranted for these combination treatments.”

Janku added that his future research will examine the efficacy of these combinations with immune checkpoint inhibition.

“There is evidence that both mTOR and HDAC inhibitors affect the tumor microenvironment, so there may be a benefit to combining these inhibitors with immunotherapy,” he noted.

Study limitation
A limitation of the study is that it was conducted prior to the approval of immune checkpoint inhibitors for relapsed/refractory Hodgkin lymphoma and therefore does not account for prior treatment with immune checkpoint inhibitors.

An additional limitation is that the trial was conducted at a single institution.

Clinical trials
Sirolimus or Everolimus or Temsirolimus and Vorinostat in Advanced Cancer – NCT01087554

Highlights of Prescribing Information
Vorinostat (Zolinza®; Merck & Co) [Prescribing Information]
Sirolimus (Rapamune®; Pfizer)[Prescribing Information]
Everolimus (Afinitor®; Novartis)[Prescribing Information]

Patient Information
Vorinostat (Zolinza®; Merck & Co) [Patient Information]

Reference
[1] Janku F, Park H, Call SG, Madwani K, Oki Y, Subbiah V, Hong DS, Naing A, Velez-Bravo VM, et al. Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma Clin Cancer Res October 14 2020 DOI: 10.1158/1078-0432.CCR-20-1215
[2] Adult Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version. National Cancer Institute. Online. Last accesses on October 14, 2020.
[3] Murugan AK. mTOR: Role in cancer, metastasis and drug resistance. Semin Cancer Biol. 2019 Dec;59:92-111. doi: 10.1016/j.semcancer.2019.07.003. Epub 2019 Aug 10. PMID: 31408724.

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