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

• Published in: Blood 2011-06, Vol.117 (26), p.6977-6986
• Main Authors: Uldrick, Thomas S., Polizzotto, Mark N., Aleman, Karen, O'Mahony, Deirdre, Wyvill, Kathleen M., Wang, Victoria, Marshall, Vickie, Pittaluga, Stefania, Steinberg, Seth M., Tosato, Giovanna, Whitby, Denise, Little, Richard F., Yarchoan, Robert
• Format: Article
• Language: English
• Subjects: Adult; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Anti-HIV Agents - therapeutic use; Biological and medical sciences; Castleman Disease - complications; Castleman Disease - drug therapy; Castleman Disease - virology; Clinical Trials and Observations; Dermatology; Drug Therapy, Combination - adverse effects; Female; Ganciclovir - administration & dosage; Ganciclovir - adverse effects; Ganciclovir - analogs & derivatives; Ganciclovir - therapeutic use; Hematologic and hematopoietic diseases; Herpesviridae Infections - complications; Herpesviridae Infections - virology; Herpesvirus 8, Human - drug effects; HIV Infections - complications; HIV Infections - drug therapy; Humans; Immunobiology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoid Neoplasia; Male; Medical sciences; Middle Aged; Other diseases. Hematologic involvement in other diseases; Pilot Projects; Plenary Paper; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - therapeutic use; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - therapeutic use; Protein Kinases - chemistry; Survival Analysis; Tumors of the skin and soft tissue. Premalignant lesions; Valganciclovir; Viral Load - drug effects; Viral Proteins - antagonists & inhibitors; Virus Activation - drug effects; Zidovudine - administration & dosage; Zidovudine - adverse effects; Zidovudine - therapeutic use
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-11-317610

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.