Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology.
The outcome of acquired immunodeficiency syndrome-related lymphomas (ARLs) has improved since the era of highly active antiretroviral therapy, but median survival remains low. We studied dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with suspension of antiretroviral therapy in 39 newly diagnosed ARLs and examined protein expression profiles associated with drug resistance and histogenesis, patient immunity, and HIV dynamics and mutations. The expression profiles from a subset of ARL cases were also compared with a matched group of similarly treated HIV-negative cases. Complete remission was achieved in 74% of patients, and at 53 months median follow-up, disease-free and overall survival are 92% and 60%, respectively. Following reinstitution of antiretroviral therapy after chemotherapy, the CD4+ cells recovered by 12 months and the viral loads decreased below baseline by 3 months. Compared with HIV-negative cases, the ARL cases had lower bcl-2 and higher CD10 expression, consistent with a germinal center origin and good prognosis, but were more likely to be highly proliferative and to express p53, adverse features with standard chemotherapy. Unlike HIV-negative cases, p53 overexpression was not associated with a poor outcome, suggesting different pathogenesis. High tumor proliferation did not correlate with poor outcome and may partially explain the high activity of dose-adjusted EPOCH. The results suggest that the improved immune function associated with highly active antiretroviral therapy (HAART) may have led to a shift in pathogenesis away from lymphomas of post-germinal center origin, which have a poor prognosis. These results suggest that tumor pathogenesis is responsible for the improved outcome of ARLs in the era of HAART.
Little
Richard F
RF
Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD 20892, USA.
Pittaluga
Stefania
S
Grant
Nicole
N
Steinberg
Seth M
SM
Kavlick
Mark F
MF
Mitsuya
Hiroaki
H
Franchini
Genoveffa
G
Gutierrez
Martin
M
Raffeld
Mark
M
Jaffe
Elaine S
ES
Shearer
Gene
G
Yarchoan
Robert
R
Wilson
Wyndham H
WH
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D024882:Drug Resistance, Viral / Q000235:genetics; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D054303:HIV Reverse Transcriptase; D006801:Humans; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000032:analysis; D016483:Lymphoma, AIDS-Related / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011241:Prednisone / Q000008:administration & dosage* / Q000009:adverse effects; D011379:Prognosis; D018894:Reverse Transcriptase Inhibitors; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage* / Q000009:adverse effects; D019562:Viral Load
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D054303:HIV Reverse Transcriptase; D017493:Leukocyte Common Antigens; D011241:Prednisone