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

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.

Figure 1

Best radiographic responses. (A) Percentage change in sum of the products of 6 representational lymph nodes at time of best radiographic response compared with baseline, in the 11 patients with pathologic lymphadenopathy at baseline evaluable. Patients can have a radiographic complete response with < 100% decrease in sum of the products of representational lymph nodes as long as there is no pathologic adenopathy at time of evaluation. (B) Percentage change in longest dimension of spleen size (normalized to spleen upper limit of normal = 12 cm) at time of best radiographic response compared with baseline, 10 patients with splenomegaly at baseline evaluable, maximum normalization = 100%.

Figure 2

Kaplan-Meier survival function. (A) Progression-free survival. (B) Overall survival. Hatch marks represent time subjects censored.

Figure 3

Changes in C-reactive protein and viral IL-6 in patients with symptomatic KSHV-MCD from baseline to time of best clinical response. Wilcoxon matched-pair signed-rank test comparing changes from baseline laboratories to a time point of best clinical response is performed on all evaluable patients (14 patients evaluable for CRP, 12 patients evaluable for vIL-6) and then repeated with exclusion of 1 patient whose assessment was confounded by development endocarditis *(■----■) in (A) C-reactive protein (mg/dL), (P = .0085, *P = .0002) and (B) vIL-6 (pg/mL; not significant). In 6 patients, vIL-6 was undetectable both at baseline and time of best clinical response.