High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

Author:

Uldrick Thomas S.1,Polizzotto Mark N.1,Aleman Karen1,O'Mahony Deirdre1,Wyvill Kathleen M.1,Wang Victoria1,Marshall Vickie2,Pittaluga Stefania3,Steinberg Seth M.4,Tosato Giovanna5,Whitby Denise2,Little Richard F.1,Yarchoan Robert1

Affiliation:

1. HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, MD;

2. Viral Oncology Section, AIDS and Cancer Virus Program, SAIC-Frederick, NCI-Frederick, Frederick, MD;

3. Laboratory of Pathology,

4. Biostatistics and Data Management Section, and

5. Laboratory of Cellular Oncology, Center for Cancer Research, NCI, Bethesda, MD

Abstract

Kaposi sarcoma herpesvirus (KSHV)–associated multicentric Castleman disease (MCD) is a lymphoproliferative disorder most commonly observed in HIV-infected patients. It is characterized by KSHV-infected plasmablasts that frequently express lytic genes. Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6. There is no standard therapy and no established response criteria. We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties. In a pilot study, 14 HIV-infected patients with symptomatic KSHV-MCD received high-dose zidovudine (600 mg orally every 6 hours) and the oral prodrug, valganciclovir (900 mg orally every 12 hours). Responses were evaluated using new response criteria. A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses. Median progression-free survival was 6 months. With 43 months of median follow-up, overall survival was 86% at 12 months and beyond. At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load. The most common toxicities were hematologic. These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD. This trial was registered at www.clinicaltrials.gov as #NCT00099073.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference51 articles.

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