Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075)

Juan C. Ramos, Joseph A. Sparano, Michelle Rudek-Renaut, Page C. Moore, Ethel Cesarman, Erin G. Reid, David Henry, Lee Ratner, David Aboulafia, Jeanette Y. Lee, Richard F Ambinder, Ronald Mitsuyasu, Ariela Noy

Research output: Contribution to journalArticle

Abstract

We performed a phase I trial of vorinostat (VOR) given on days 1 to 5 with R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) in patients with aggressive HIV-associated non-Hodgkin lymphoma. VOR was tolerable at 300 mg and seemingly efficacious with chemotherapy with complete response rate of 83% and 1-year event-free survival of 83%. VOR did not significantly alter chemotherapy steady-state concentrations, CD4+ cell counts, or HIV viral loads. Introduction: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). Patients and Methods: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. Results: The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). Conclusion: VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL.

Original languageEnglish (US)
Pages (from-to)180-190.e2
JournalClinical Lymphoma, Myeloma and Leukemia
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2018

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Non-Hodgkin's Lymphoma
HIV
Safety
Human Herpesvirus 4
Human Herpesvirus 8
Drug Therapy
Vincristine
Etoposide
CD4 Lymphocyte Count
Prednisone
Viral Load
Doxorubicin
Cyclophosphamide
Disease-Free Survival
vorinostat
Primary Effusion Lymphoma
Histone Deacetylase Inhibitors
Lymphoma, Large B-Cell, Diffuse
B-Cell Lymphoma
Therapeutics

Keywords

  • AIDS-related malignancies
  • Chemotherapy
  • Epstein-Barr virus
  • Histone deacetylase inhibitors
  • Lytic-inducing therapies

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075). / Ramos, Juan C.; Sparano, Joseph A.; Rudek-Renaut, Michelle; Moore, Page C.; Cesarman, Ethel; Reid, Erin G.; Henry, David; Ratner, Lee; Aboulafia, David; Lee, Jeanette Y.; Ambinder, Richard F; Mitsuyasu, Ronald; Noy, Ariela.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 18, No. 3, 01.03.2018, p. 180-190.e2.

Research output: Contribution to journalArticle

Ramos, JC, Sparano, JA, Rudek-Renaut, M, Moore, PC, Cesarman, E, Reid, EG, Henry, D, Ratner, L, Aboulafia, D, Lee, JY, Ambinder, RF, Mitsuyasu, R & Noy, A 2018, 'Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075)', Clinical Lymphoma, Myeloma and Leukemia, vol. 18, no. 3, pp. 180-190.e2. https://doi.org/10.1016/j.clml.2018.01.004
Ramos, Juan C. ; Sparano, Joseph A. ; Rudek-Renaut, Michelle ; Moore, Page C. ; Cesarman, Ethel ; Reid, Erin G. ; Henry, David ; Ratner, Lee ; Aboulafia, David ; Lee, Jeanette Y. ; Ambinder, Richard F ; Mitsuyasu, Ronald ; Noy, Ariela. / Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075). In: Clinical Lymphoma, Myeloma and Leukemia. 2018 ; Vol. 18, No. 3. pp. 180-190.e2.
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abstract = "We performed a phase I trial of vorinostat (VOR) given on days 1 to 5 with R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) in patients with aggressive HIV-associated non-Hodgkin lymphoma. VOR was tolerable at 300 mg and seemingly efficacious with chemotherapy with complete response rate of 83{\%} and 1-year event-free survival of 83{\%}. VOR did not significantly alter chemotherapy steady-state concentrations, CD4+ cell counts, or HIV viral loads. Introduction: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). Patients and Methods: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. Results: The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100{\%} (complete 83{\%} and partial 17{\%}) with a 1-year event-free survival of 83{\%} (95{\%} confidence interval, 51.6{\%}-97.9{\%}). Conclusion: VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL.",
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T1 - Safety and Preliminary Efficacy of Vorinostat With R-EPOCH in High-risk HIV-associated Non-Hodgkin's Lymphoma (AMC-075)

AU - Ramos, Juan C.

AU - Sparano, Joseph A.

AU - Rudek-Renaut, Michelle

AU - Moore, Page C.

AU - Cesarman, Ethel

AU - Reid, Erin G.

AU - Henry, David

AU - Ratner, Lee

AU - Aboulafia, David

AU - Lee, Jeanette Y.

AU - Ambinder, Richard F

AU - Mitsuyasu, Ronald

AU - Noy, Ariela

PY - 2018/3/1

Y1 - 2018/3/1

N2 - We performed a phase I trial of vorinostat (VOR) given on days 1 to 5 with R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) in patients with aggressive HIV-associated non-Hodgkin lymphoma. VOR was tolerable at 300 mg and seemingly efficacious with chemotherapy with complete response rate of 83% and 1-year event-free survival of 83%. VOR did not significantly alter chemotherapy steady-state concentrations, CD4+ cell counts, or HIV viral loads. Introduction: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). Patients and Methods: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. Results: The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). Conclusion: VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL.

AB - We performed a phase I trial of vorinostat (VOR) given on days 1 to 5 with R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) in patients with aggressive HIV-associated non-Hodgkin lymphoma. VOR was tolerable at 300 mg and seemingly efficacious with chemotherapy with complete response rate of 83% and 1-year event-free survival of 83%. VOR did not significantly alter chemotherapy steady-state concentrations, CD4+ cell counts, or HIV viral loads. Introduction: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). Patients and Methods: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. Results: The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). Conclusion: VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL.

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KW - Chemotherapy

KW - Epstein-Barr virus

KW - Histone deacetylase inhibitors

KW - Lytic-inducing therapies

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