Combined Inhibition of HDAC and mTOR May Improve Outcomes in Patients with Relapsed/Refractory Hodgkin Lymphoma
PHILADELPHIA – The histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) in combination with the mTOR inhibitor sirolimus (Rapamune) or everolimus (Afinitor) showed clinical efficacy in patients with relapsed/refractory Hodgkin lymphoma, according to results from a phase I clinical trial published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
“While the majority of patients with Hodgkin lymphoma have favorable outcomes with standard treatment, approximately 20-30 percent of patients with advanced disease develop refractory disease after primary treatment,” said Filip Janku, MD, PhD, 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 percent.”
Histone deacetylases (HDACs) are cellular proteins that regulate gene expression. 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, he noted.
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 percent, 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.
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.
The study was 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, the National Center for Advancing Translational Sciences, and the National Institutes of Health through MD Anderson’s Cancer Center Support Grant.
Janku has received support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, Bristol-Myers Squibb, Asana, and Proximagen. Janku has served on the scientific advisory boards of Guardant Health, IFM Therapeutics, Synlogic, and Deciphera; is a consultant for Trovagene and Immunomet; and has ownership interests in Trovagene.