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High-dose Zidovudine + Valganciclovir in the Treatment of Kaposi’s Sarcoma-associated Herpesvirus-associated Multicentric Castleman’s Disease: A Targeted Therapy Using Antiviral Drugs that Are Activated to Toxic Moieties by Kaposi’s Sarcoma-associated Herpesvirus Lytic Genes
Thomas Uldrick*1, D O'Mahoney1, K Aleman1, K Wyvill1, D Whitby2, W Bernstein1, S Pittaluga1, S Steinberg1, R Little3, and R Yarchoan1
1Ctr for Cancer Res, NCI, Bethesda, MD, US; 2AIDS and Virus Cancer Prgm, NCI, Frederick, MD, US; and 3Cancer Therapy Evaluation Prgm, NCI, Bethesda, MD, US
Background: Multicentric Castleman’s disease (MCD)
is a B cell lymphoproliferative disorder. In HIV-infected patients, it is
almost always caused by Kaposi’s sarcoma-associated herpes virus (KSHV).
KSHV-MCD is characterized by fatigue, fevers, lymphadenopathy, and edema, as
well as cytopenias, elevated serum C-reactive protein (CRP), and
hypoalbuminemia. These features are largely caused by KSHV viral interleukin-6
(IL-6), a lytic gene product. Previously, we demonstrated that 2 lytic KSHV
kinases, encoded by ORF21 and ORF36, can phosphorylate zidovudine (AZT) and
ganciclovir to toxic triphosphate moieties and that the combination of AZT and
ganciclovir is cytotoxic to KSHV-infected, lytically activated cells. We have
translated these observations to the clinic in patients with symptomatic
KSHV-MCD.
Methods: Ten patients with symptomatic KSHV-MCD
received AZT 600 mg every 6 hours, and valganciclovir 900 mg every 12 hours.
First-cycle treatment length ranged from 7 to 21 days. In subsequent cycles,
treatment was on days 1 to 7 of a 21-day cycle. Treatment continued until
clinical and biochemical complete response, plateau in response, or progressive
disease. Objective measures of response included changes in CRP, albumin,
platelets, and performance status (ECOG-PS).
Results: Patient characteristics were: median age
40 years (33 to 56); median ECOG-PS 2 (1 to 3); median CD4 count 189 cells/µL
(range 19 to 1319); and median HIV viral load <50 copies/mL3
(range <50 to 27,500). All patients were on combination ART, 8 had a history
of KS. Baseline median CRP (14 mg/dL, range 1.1 to 38.7), median albumin (2.8
g/dL, range 1.7 to 3.5) and median platelets (126,000/µL, range 27,000 to 204,000)
were abnormal. A median of 10 (1 to 29) cycles per patient was administered. Of
10 patients, 9 had clinical improvement after the first cycle, as evidenced by
improved ECOG-PS (median +1, range 0 to +2), decreased CRP (median –12.7 mg/dL,
range –1 to –25.1), increased albumin (median +0.3 g/dL, range 0 to +1), and
increased platelets (median +60,000/µL, range –77,000 to +255,000). Median
progression-free survival was 5.4 months; 12-month overall survival was 70%. In
addition, 3 patients with 11- to 27-month follow-up needed no additional
therapy. Grade 3 or 4 toxicities were: fatigue (n = 2), nausea (n = 1), transaminitis
(n = 1), insomnia (n = 1), and hematologic toxicity not attributable to MCD (n =
2). There were 3 infections, none neutropenia-associated; and 2 patients
developed KSHV-associated lymphoma.
Conclusions: These preliminary data suggest that
high-dose AZT combined with valganciclovir is active in KSHV-MCD. Further
evaluation of these agents in KSHV-MCD is warranted, and accrual continues.
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