Clinical, Biochemical, and Radiographic Responses to Rituximab Combined with Liposomal Doxorubicin (R-Dox) in HIV-Infected Patients with Severe Kaposi Sarcoma-Associated Herpes Virus (KSHV) – Associated Multicentric Castleman's Disease.

KSHV-associated multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder characterized by fever, splenomegaly, adenopathy, hypoalbuminemia, hyponatremia, cytopenias, elevated inflammatory markers, and a waxing and waning course. Most MCD arising in HIV-infected patients is KSHV-associated. Historically, prognosis has been poor. There is no standard therapy, although benefit has been reported with cytotoxic chemotherapy, interferon-á, retinoic acid and ganciclovir. Rituximab has reported activity in KSHV-MCD, but may not be sufficient as monotherapy in patients with severe disease, and can be associated with worsening of Kaposi's sarcoma (KS). Within a natural history study of KSHV-MCD, we evaluated the treatment effects of R-Dox on correlates of disease activity in patients with severe MCD or MCD with concurrent KS.

Patients with biopsy confirmed MCD that was severe or accompanied by severe KS were treated with liposomal doxorubicin 20mg/m2 plus rituximab 375 mg/m2 every 21 days until substantial clinical improvement or disease progression. Post R-Dox therapy, discussed below, was used to consolidate or maintain responses. Clinical, biochemical and radiographic response were evaluated individually using protocol-defined criteria. Overall complete responses (CR) required normalization of all clinical, laboratory or radiographic abnormalities attributed to MCD lasting at least 3 weeks.

Twelve patients (1 woman, 11 men) have been treated with R-Dox to date. Patient characteristics: median (med) age 43 (range 34-55); all were on HAART, med CD4 331 cells/μL (21-1598), HIV viral load <50 copies/mL in 10 patients. Med number of prior therapies 2 (0-8); concurrent KS (5); dependent on steroids (3); patients hospitalized during first cycle (6). Med baseline values for biochemical response parameters: C-reactive protein 9.7 mg/dL (0.4-21.0), albumin 2.7 mg/dL (1.5-3.4), sodium 133 mEq/L (126-140), platelets 70 K/uL (10-377), hemoglobin 9.4 g/dL (6.8-12.0). 11 had diffuse adenopathy and all had splenomegaly, med spleen 18.5 cm (12.5-28 cm). Patients received med 4 cycles (3-9) of R-Dox. All patients met criteria for clinical CR after a med 2 cycles (range 1-5). Best biochemical response was CR in 9 (75%) and partial response (PR) in 1 (8%); 2 (17%) had stable biochemical parameters. Best radiographic response was CR in 6 (50%) and PR in 6 (50%) with a med 5 cm (+0.5 cm, -10 cm) decrease in spleen size. Best biochemical response was achieved after med 3 cycles (1-7), and best radiographic response after med 3 cycles (2-5). 2 of 12 had an overall CR at completion of R-Dox. Post R-Dox therapy included: IFNá (8), high-dose AZT + valganciclovir (2), additional liposomal doxorubicin (1). To date, another 6 patients achieved overall CR with additional therapy. Concurrent KS improved in 4 of the 5 patients affected. With a median potential follow-up of 25.5 months (actual follow-up range from 5.5+ to 41+ months), 9 of 12 patients have had no MCD relapse after starting R-Dox, 2 patients had recurrent MCD flares (months 7 and 17) that responded to additional therapy and 1 patient had progressive MCD during cycle 6 associated with worsening KS, and died at month 6 of central pontine myelinolysis. He was found to have primary effusion lymphoma at autopsy. An additional patient died of pneumonia (month 17). Toxicity was minimal. 9 patients had infusion reactions (Gr. 1 = 3, Gr. 2 = 4, Gr. 3 = 2) with the first dose of rituximab. 9/55 cycles were complicated by neutropenia (Gr. 2 = 7, Gr. 3-4 = 2). There were no infectious complications.

R-dox is highly effective in heavily pretreated patients with severe KSHV-MCD or MCD with concurrent severe KS. Further evaluation of R-Dox in patients with severe KSHV-MCD is ongoing.

Off Label Use: Rituximab and Liposomal Doxorubicin are being explored in the treatment KSHV-MCD.