Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial)

Abstract

EPOCH is a preferred regimen for HIV-NHLs, which are frequently EBV+ or HHV-8+. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. To assess whether vorinostat increases EPOCH efficacy and/or HIV clearance we performed a randomized phase 2 study in 90 patients (45 per arm) with aggressive HIV-NHLs using dose-adjusted EPOCH (plus rituximab if CD20+) alone or with vorinostat 300 mg administered on days 1-5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary endpoint was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (n=61), plasmablastic lymphoma (n=15), primary effusion lymphoma (n=7), unclassifiable B-cell NHL (n=2), and Burkitt lymphoma (n=1), CR rates were 74% versus 68% for EPOCH versus EPOCH-vorinostat, respectively (1-sided P=0.72). Patients with CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs and resulted in more frequent grade 4 neutropenia and thrombocytopenia (47% and 29%, respectively) versus EPOCH (20% and 2%, respectively). The overall and event-free survival (EFS) rates were similar between arms. Overall, patients with Myc+ DLBCL had significantly lower EFS (44% at 3-yr, versus 83% in Myc- DLBCL). Low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, while pre-protocol therapy had no negative impact. In conclusion, EPOCH had broad efficacy against highly aggressive HIV-NHLs, while vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting pre-protocol therapy facilitated accruals without compromising outcomes. NCT0119384.

Use of viral motif mimicry improves the proteome-wide discovery of human linear motifs

“…Accordingly, roscovitine can potentially be repurposed as pharmacological therapy for HPV11 infections. Moreover, several other drugs that we identified (Figure 6) already have indications in ChEMBL or evidence for reducing the relevant viral infection, such as sirolimus and everolimus for influenza A infection (Alsuwaidi et al, 2017;Murray et al, 2012), vorinostat and cytarabine for human herpesvirus type 8 (hhv8) (Hogan et al, 2018;Ramos et al, 2020), and erlotinib, vatalanib, and dasatinib for hepatitis C virus (HCV) (Elsebai et al, 2016;Lupberger et al, 2011).…”

HIV-Associated Lymphomas: Progress and New Challenges

“…In addition to immunotherapies, the addition of epigenic agents that could disrupt the viral latency and induce an oncolytic effect is an interesting therapeutic concept. AMC recently published a sequential phase 2 randomized trial combining EPOCH (+/− rituximab based on the CD20 expression) with and without vorinostat in 90 patients with aggressive HIV-NHL [ 24 ]. The trial stemmed from a preclinical notion of the synergism between the histone deacetylase inhibitor (HDAC) vorinostat with etoposide, anthracycline, and rituximab and the ability of HDAC inhibitors to disrupt viral latency [ 25 , 26 , 27 , 28 ].…”

Reversing the restrictive trend in diffuse large B‐cell lymphoma trial eligibility: it’s time to open the gates!

“…Recent trial designs have taken steps to increase enrollment of patients in need of urgent therapy, including allowing pre-enrollment steroids or one cycle of chemotherapy to stabilize those presenting with poor PS and organ function as well as provide time for pathology-based trial eligibility to be assessed. [14][15][16]17 Trials are being designed specifically for frail and elderly patients, such as the recently reported SENIOR trial and the currently accruing NCTN SWOG S1818 trial, which both investigated reduced doses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) with novel agents. 18 Additional strategies to consider would be to tailor eligibility criteria to specific drugs under evaluation based on their pharmacokinetics and prior evidence of toxicities when setting thresholds for organ function-based criteria.…”

“…Considerable work is already under way in DLBCL in this area. Recent trial designs have taken steps to increase enrollment of patients in need of urgent therapy, including allowing pre‐enrollment steroids or one cycle of chemotherapy to stabilize those presenting with poor PS and organ function as well as provide time for pathology‐based trial eligibility to be assessed 14–16,17 . Trials are being designed specifically for frail and elderly patients, such as the recently reported SENIOR trial and the currently accruing NCTN SWOG S1818 trial, which both investigated reduced doses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‐CHOP) with novel agents 18 .…”