Results from a nonrandomized, dose-escalation phase I clinical trial investigating the histone deacetylase (HDAC) inhibitor vorinostat in combination with the mTOR inhibitors sirolimus or everolimus found the combination therapies showed activity in heavily pretreated patients with relapsed or refractory Hodgkin lymphoma. The study by Janku et al was published in Clinical Cancer Research.
Although the majority of patients with Hodgkin lymphoma have favorable outcomes, approximately 10% of patients with early-stage Hodgkin lymphoma and between 20% and 30% of patients with advanced Hodgkin lymphoma develop refractory disease after initial therapy and have poor outcomes, with a 5-year survival rate of about 32%.
"Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation."— Janku et al
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Study Methodology
The researchers examined the clinical activity of vorinostat in combination with either sirolimus or everolimus in 40 patients with refractory Hodgkin lymphoma.
Twenty-two of the patients received vorinostat plus sirolumus and 18 received the combination of vorinostat and everolimus. The patients had received a median of five prior therapies, including brentuximab (n = 39), autologous stem cell transplantation (n = 26), and allogeneic stem cell transplantation (n = 12).
Toxicity and Response
The researchers found that the most frequent grade ≥ 3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with vorinostat/sirolimus and vorinostat/everolimus, respectively.
Complete response was reported in six (27%) patients treated with vorinostat/sirolimus and in two (11%) patients treated with vorinostat/everolimus; partial response was reported in six patients (27%) treated with vorinostat/sirolimus and four (22%) patients treated with vorinostat/everolimus (objective response rate of 55% and 33%, respectively).
“Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation,” concluded the study authors.
This study had several limitations: the small number of patients enrolled in the phase I study; none of the patients received prior PD-1 inhibitors, and it is unclear, according to the study, if the same salutary activity can be achieved in a post–PD-1 inhibitor setting; and the trial was conducted at a single institution, among others.
Translational Relevance
“In our study, we observed a relatively high objective response rate in a patient population that would otherwise have poor outcomes,” said first study author Filip Janku, MD, PhD, Associate Professor in the Department of Investigational Cancer therapeutics at The University of Texas MD Anderson Cancer Center, in a statement. “Based on our results, I believe further investigation is warranted for these combination treatments.”
Disclosure: Funding for this study was provided by The University of Texas MD Anderson Cancer Center, the National Center for Advancing Translational Sciences, and the National Institutes of Health. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.
