Natural History Study of the KSHV Inflammatory Cytokine Syndrome (KICS) Incorporating Pilot Evaluation of KSHV Targeted Therapies
KSHV inflammatory cytokine syndrome (KICS) is a newly recognized syndrome caused by Kaposi
sarcoma-associated herpesvirus (KSHV). It is characterized by severe inflammatory symptoms
including fevers, wasting, cytopenias, hypoalbuminemia, and hyponatremia, associated in some
cases with lymphadenopathy or effusions, without pathological evidence of MCD. Patients with
KICS exhibit elevated KSHV viral loads and cytokine dysregulation, with elevations of IL-6,
IL-10, and a KSHV-encoded IL-6 homolog, viral IL-6.
The primary study objective is to enable intensive study and description of the natural
history of KICS. Secondary objectives include assessment in affected persons of KSHV viral
loads and cytokine levels, evaluation of tissue pathophysiology, exploration of FDG-PET
abnormalities, and pilot assessment of response to two therapies: high dose
zidovudine/valganciclovir or rituximab/liposomal doxorubicin.
Adults of any HIV status with:
- At least two symptoms, laboratory or radiographic abnormalities which are at least
possibly attributable to KICS (including fever, fatigue, cachexia, edema, respiratory
or gastrointestinal symptoms, hematologic cytopenias, hypoalbuminemia, hyponatremia,
- C-reactive protein > 3mg/dL.
- Evidence of KSHV infection or a risk exposure for KSHV infection
- No evidence of KSHV-associated multicentric Castleman disease
Patients with these characteristics will be further evaluated to identify those whose
clinical and laboratory features are consistent with the working KICS working case
definition to be followed in the natural history phase of the study.
This is a single center natural history cohort with an observation arm and two nested open
label pilot treatment arms, and an accrual ceiling of 40 patients to the overall natural
history arm. Natural history patients will undergo clinical, laboratory and correlative
assessment every 3 months until sustained resolution. Patients with clinical and laboratory
manifestations of KICS, elevated inflammatory markers and KSHV viral load will be eligible
for therapy with high dose zidovudine/valganciclovir or, if they have intercurrent KS
requiring cytotoxic therapy, rituximab/liposomal doxorubicin. Each treatment arm uses a two
stage design, with interim analysis at 8 patients in each arm and potential accrual of 14
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Assessment of the natural history of KICS, including the spectrum of clinical, laboratory and radiographic abnormalities seen in affected patients.
Robert Yarchoan, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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