Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases

Abstract

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

Conflict of interest statement

Conflict-of-interest disclosure: R.R., T.S.U., K.L., and R.Y. report receiving research support from Celgene through a cooperative research and development agreement (CRADA) at the NCI. R.R., T.S.U., K.L., and R.Y. report receiving a drug for a clinical trial from Merck through a CRADA with the NCI. R.R., K.L., and R.Y. report receiving a drug for a clinical trial from EMD-Serano through a CRADA at the NCI. R.Y. reports receiving a drug for preclinical studies from Janssen and CTI BioPharma. T.S.U. reports receiving other commercial research support from Roche through a clinical trial agreement with Fred Hutchinson Cancer Research Center. T.S.U., R.Y., and D.W. are co-inventors on US Patent 10 001,483 entitled “Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers.” R.Y. is also a coinventor on patents on a peptide vaccine for HIV and the treatment of Kaposi sarcoma with IL-12, and an immediate family member of R.Y. is a co-inventor on patents related to internalization of target receptors, KSHV vIL-6, and the use of calreticulin and calreticulin fragments to inhibit angiogenesis. All rights, title, and interest to these patents have been or should by law be assigned to the US Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). The remaining authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

Difference between flare and remission in IFN-γ, IL-6, and IL-10 in patients with MCD alone, MCD with KS, or MCD and PEL with or without KS.

Figure 2.

KSHV-VL differences in the first flare and remission or end of treatment (patients with concurrent PEL) in all patients, patients with MCD alone, and patients with MCD and KS. Among patients with MCD and PEL with or without KS, this was the difference between flare to the end of multiagent chemotherapy for PEL.

Figure 3.

Overall survival in KSHV-MCD. Kaplan-Meier curve of all patients (A) and by group (B) log-rank test (P = .004).