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

Abstract

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; 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% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.

Trial registration: ClinicalTrials.gov NCT01193842.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Consort diagram. Patients with aggressive HIV-related B-cell non-Hodgkin lymphomas enrolled in AMC-075.

Figure 2.

EFS analysis. Kaplan-Meier curves of EFS after treatment with vorinostat-R-EPOCH and R-EPOCH alone for all study-eligible patients with aggressive HIV-NHL (n = 86) (A); all DLBCL (n = 61) (B); non-GCB (n = 26) (C) and GGB (n = 34) DLBCL subtypes (1 case was not classified) (D); and PBL (n = 15) (E) and PEL (n = 7) (F).

Figure 3.

EFS, according to Myc protein expression. Kaplan-Meier curves of EFS in evaluable Myc+ vs Myc− cases in all study-eligible patients with aggressive HIV-NHL (n = 51) (A); all DLBCL (n = 36) (B); non-GCB (n = 19) (C) and GGB (n = 17) (D) DLBCL subtypes; and PBL (9 of 9) (E) and PEL (3 of 3) (F).

Figure 4.

Survival analysis according to short vs long DTI in all subtype groups. Kaplan-Meier curves of EFS (A,C,E) and OS (B,D,F) in patients with a DTI of <15 days vs ≥15 days for all study-eligible patients with aggressive HIV-NHL (n = 86) (A-B)B); all DLBCL (n = 61) (C-D); non-GCB (n = 26) (E-F); and GGB (n = 34) (G-H) DLBCL subtypes (1 case was not classified).