Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease

Abstract

Kaposi sarcoma (KS) herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m(2) combined with liposomal doxorubicin 20 mg/m(2) (R-Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon-α, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months' potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222.

Figure 1

Photograph of representative area of Kaposi sarcoma (KS) in a patient with advanced KS and KSHV-associated multicentric Castleman disease. Photos taken at (A) baseline: >50 lesions on the left lower extremity, many nodular, with tumor-associated edema; (B) after completion of R-Dox: substantial flattening of nodular lesions, decreased tumor-associated edema; and (C) 1 year after completion of additional liposomal doxorubicin: resolution of nodular lesions, some residual pigmentation, and edema.

Figure 2

Kaplan-Meier survival estimates in patients with symptomatic KSHV-MCD receiving R-Dox. (A) Event-free survival; (B) overall survival.

Figure 3

Changes from baseline to end of R-Dox in select biomarkers of KSHV-MCD. (A) Peripheral blood mononuclear cell–associated KSHV viral load (P = .0002, Wilcoxon signed-rank test). (B) Serum viral interleukin-6 (vIL-6) (P = .25, exact McNemar test). (C) Serum human interleukin 6 (hIL-6) (P = .0026, Wilcoxon signed-rank test). (D) Serum human interleukin-10 (IL-10) (P = .0002, Wilcoxon signed-rank test). Log serum vIL-6 was less than the lower limit of detection (1560 pg/mL, or log 3.193) in 11 patients at baseline and 14 patients at the end of R-Dox therapy. *Patient with progressive symptoms and rising KSHV viral load, serum hIL-6, serum IL-10, and serum vIL-6; he subsequently died and was found to have PEL at autopsy.