Pilot Study of Tocilizumab in Patients with HIV and Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-Associated Multicentric Castleman Disease
Authors: Ramaswami Ramya , Lurain Kathryn , Widell Anaida , Polizzotto Mark N. , Goncalves Priscila H. , Lindsley Matthew , Steinberg Seth M. , Whitby Denise , Uldrick Thomas S. , Yarchoan Robert 
Published: October 2019

Abstract
BACKGROUND: Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a rare lymphoproliferative disorder that occurs primarily in HIV-infected patients and is characterized by inflammatory symptoms with a waxing and waning course. If untreated, it leads to multiorgan failure and death, usually within 2 years. KSHV-MCD symptoms are caused by increased levels of inflammatory cytokines, including human interleukins (IL) 6 and 10, and a KSHV-encoded IL-6 analog (vIL-6). Rituximab is an effective therapy in KSHV-MCD but can result in the development or worsening of Kaposi sarcoma (KS) in those with concurrent diagnoses. Other therapies include rituximab plus liposomal doxorubicin and zidovudine (AZT) plus valganciclovir (VGC). Tocilizumab, a humanized anti-IL-6 receptor (gp80) antibody, has demonstrated benefit in KSHV-negative MCD, although its utility in patients with KSHV-MCD is unknown. We explored the safety and efficacy of tocilizumab in KSHV-MCD and the effect of the addition of AZT and VGC in cases where tocilizumab alone does not lead to clinical benefit.
PATIENTS & METHODS: Patients enrolled on this prospective pilot study had symptomatic KSHV-MCD. They received 8mg/kg of tocilizumab every 2 weeks for up to 12 weeks, or 6 cycles. Patients with HIV were required to continue antiretroviral therapy. Treatment responses were assessed using a KSHV-MCD clinical benefit response (CBR) criteria, which consists of 8 indicator abnormalities (4 symptom groups and 4 laboratory parameters) that are closely associated with disease activity. If patients had evidence of progression or lack of improvement with tocilizumab monotherapy, AZT 600mg orally every 6 hours and VGC 900mg orally every 12 hours on days 1-5 of a 14-day cycle could be administered with tocilizumab. Peripheral blood mononuclear cell (PBMC)-associated KSHV viral loads were quantified by PCR using primers to the KSHV gene K6 after each cycle of treatment. The primary objective of the study was to estimate the clinical benefit of tocilizumab in patients with symptomatic KSHV-MCD using a modified KSHV-MCD CBR criteria.
RESULTS: Eight HIV positive patients (7 male, 1 female) with a median age of 48.8 years were enrolled. All patients were taking combined antiretroviral therapy and had a baseline CD4+ T cell count of 254 cells/mL. Four patients (50%) had prior KSHV-MCD therapy with rituximab and 3 patients (38%) had KS at the time of enrollment. With tocilizumab alone, the overall response rate (partial and complete responses using the CBR criteria for all patients was 63% (95% confidence interval 25% to 92%). Three patients required the addition of AZT and VGC; one patient required AZT and VGC after 1 cycle and 2 required the combination treatment after 3 cycles of tocilizumab. Two out of 3 patients had a complete response after the addition of AZT and VGC to tocilizumab. Among all patients, 3 patients stopped therapy prior to 6 cycle due to progression of symptoms despite combination therapy, worsening pulmonary KS symptoms and deterioration in performance status due to progressive KSHV-MCD. Two remaining patients with concurrent KS had stable disease at the end of treatment. Among all patients, the median time to next therapy for symptomatic KSHV-MCD was 3.2 months (range 1 - 37 months); subsequent therapies included rituximab alone (3 patients), or in combination with liposomal doxorubicin (2 patients), or treatment with pomalidomide and liposomal doxorubicin (2 patients). One patient had a durable complete response over 3 years of follow-up. Treatment was well tolerated; the most common grade 3 and 4 adverse events included thrombocytopenia and neutropenia as well as hyperuricaemia, which were attributed to KSHV-MCD rather than study therapies. Furthermore, tocilizumab alone or in combination with AZT and VGC did not interfere with the CD4+ T cell count (net increase of 16 cells cells/mL) or HIV viral load. There was an overall decrease in KSHV viral load of 4577 copies/mL from baseline to the final cycle, reflecting clinical response.
CONCLUSION: Tocilizumab is safe in patients with HIV and may have a role in the management of symptoms associated with KSHV-MCD. Incomplete responses to tocilizumab may occur because tocilizumab binds to the gp80 IL-6 receptor and KSHV vIL-6 can bind to the gp130 receptor subunit without the requirement for gp80. The addition of AZT and VGC to tocilizumab also showed clinical benefit.

Disclosures
Uldrick: Celgene: Research Funding; Celgene: Patents & Royalties: 10,001,483 B2; Merck: Research Funding. Yarchoan:NIH: Patents & Royalties: Patents on IL-12 for KS and cereblon-binding drugs for KSHV diseases. Spouse has patent on KSHV IL-6. Patents assigned to DHHS/NIH.; Celgene Corp.: Research Funding.