Rituximab: Rituximab is highly active as mono­therapy in MCD. Its role in HIV-associated MCD is supported by prospective and retrospective trials demonstrating sustained remissions.34,50-55 Small case series have also demonstrated activity in patients with MCD who are HIV negative.56-59

A prospective study enrolled 24 patients with che­motherapy-dependent, HIV-associated MCD.50 Patients had received single-agent chemotherapy (etoposide, vinblastine, or liposomal doxorubicin) for a medi­an of 13 months and all patients had failed at least 1 attempt to discontinue chemotherapy.

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All patients re­ceived concurrent combination antiretroviral therapy. After 4 weekly infusions of rituximab at a dose of 375 mg/m2, 22 of 24 patients (92%) achieved the pri­mary endpoint of sustained remission at 60 days off treatment, and 17 patients (71%) were alive and in re­mission at 1 year.51

A second prospective trial enrolled 21 patients with previously untreated HIV-associat­ed MCD and treated with 4 weekly rituximab infu­sions.51 Clinical and radiological responses occurred in 20 (95%) and 14 (67%) patients, respectively, and the 2-year progression-free survival rate was 79%.51

These small prospective studies are also support­ed by a retrospective analysis of 49 patients naive to treatment with HIV-associated MCD who were given rituximab with or without etoposide.34 Combination therapy with rituximab/etoposide was reserved for patients with a poor performance status or evidence of end-organ involvement.

For the entire cohort, 5-year progression-free and overall survival rates were 61% and 90%, respectively.34 No difference was seen in outcomes between the 2 treatment arms; however, the 2 arms included distinct patient populations by design, and it is unknown whether patients treated with combination therapy would have performed as well if treated with rituximab alone.

This does add to a body of literature demonstrating favorable progres­sion-free and overall survival rates in patients treated with rituximab therapy.34

Patients with concomitant MCD and Kaposi sar­coma require vigilance for Kaposi sarcoma flareups during rituximab therapy. Exacerbations of Kaposi sarcoma during rituximab treatment was observed in all trials of rituximab in HIV-associated MCD, occur­ring in 36% to 67% of reported patients.34,50,51

Anti-Interleukin 6 Therapy: Siltuximab and to­cilizumab are monoclonal antibodies targeting IL-6 and its receptor (IL-6R), respectively. The US Food and Drug Administration (FDA) has approved siltuximab for the treatment of patients with HIV negative, HHV-8 negative MCD, where it shows significant clinical ac­tivity, resulting in control of IL-6–dependent systemic symptoms and laboratory abnormalities.60,61

A phase 2 study that included 19 patients with HIV negative and HHV-8 negative MCD reported 8 radiological re­sponses, including 1 complete response.61 At a me­dian follow-up of 5.1 years (range, 3.4–7.2 years), all 19 patients taking siltuximab therapy were still alive.61

The data from those studies prompted a multi­center, randomized, double-blind, placebo-controlled trial of siltuximab in patients with HIV negative, HHV-8 negative MCD.62 Patients were randomized 2:1 to siltuximab or placebo administered once every 3 weeks. Patients receiving placebo were permitted to cross over to open-label siltuximab at progression.

Of the 79 randomized patients, 53 received siltux­imab and 26 received placebo. The median age was 48 years and a 2:1 male predominance was seen.62 Hyaline-vascular, plasma cell, and mixed pathologies were observed in 33%, 23%, and 44% of patients, respectively.62

A total of 58% had received prior ther­apy and 30% were on corticosteroids at enrollment.62 The primary endpoint was durable radiological and symptomatic responses (improvement or stabilization of symptoms) lasting at least 18 weeks.

Treatment with siltuximab was associated with a higher rate of achieving the primary endpoint (34% vs 0%).62 Ra­diographic tumor response rates were seen in 38% and 4% of patients, favoring the siltuximab arm, and symptomatic response rates were 57% and 19%.62

Complete symptom resolution was observed in those receiving siltuximab (25% vs 0%).62 Patients receiv­ing siltuximab also had improvements in anemia and hypoalbuminemia, and a decrease in inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, and fibrinogen) relative to patients receiving placebo. These data demonstrate that siltuximab is highly active in MCD with durable disease control and improvement in clinically relevant outcomes.

However, an important caveat is that patients with HIV and HHV-8-associated MCD were excluded from this study. Siltuximab was also compared against a placebo rather than rituximab.

The anti-IL-6R humanized monoclonal antibody tocilizumab is also active in MCD. Twenty-eight pa­tients with symptomatic MCD were enrolled in a phase 2 trial,63 all of whom were HIV negative and only 2 of whom were positive for HHV-8. All pa­tients had pathological findings consistent with the plasma cell variant.

Patients received tocilizumab ev­ery 2 weeks for 16 weeks and the study drug was continued thereafter at the discretion of the treating investigator. The alleviation of systemic inflammatory symptoms was universal and weight gain occurred in all patients. Laboratory abnormalities, including anemia, hypoalbuminemia, and elevated C-reactive protein, all improved with therapy, as did lymphade­nopathy.

Eleven of the 15 (73%) patients receiving corticosteroids at enrollment were able to decrease or discontinue concomitant corticosteroid therapy.63 It is worth noting, however, that tocilizumab is cur­rently FDA approved only for rheumatoid arthritis and systemic or polyarticular juvenile idiopathic arthritis.

Monoclonal antibodies targeting IL-6 remain large­ly unevaluated in patients with HIV and HHV-8-asso­ciated MCD. It is not known whether targeting IL-6 is similarly effective in this population, yet several features make these patients appealing candidates for therapies targeting IL-6. Although vIL-6 is impli­cated in the pathogenesis of HHV-8-associated MCD and is not targeted by the current monoclonal anti­bodies, human IL-6 is also elevated in the majority of patients with HIV-associated MCD and likely re­mains a significant contributor to disease activity and symptomatology.12

Three cases in the literature have demonstrated activity of IL-6 targeted therapy in HIV and HHV-8-associated MCD,64,65 speaking to the need for prospective clinical trials in these patients.

Antiherpesvirus Therapy: Antiherpesvirus agents have been explored as therapy for HIV-associ­ated MCD given the pathogenetic link with HHV-8.66-68 Lytic replication of HHV-8 is common in MCD and may be important in its pathogenesis, as opposed to Kaposi sarcoma in which HHV-8 infection most often remains latent. Many HHV-8–derived gene products, including vIL-6, are expressed during the lytic cycle of HHV-8 replication.69

Therefore, MCD is potentially tar­getable with antiviral therapy, particularly in patients with detectable HHV-8 viral loads. An early report of 3 patients with MCD treated with intravenous or oral ganciclovir was promising.70 Two patients expe­rienced flares of symptomatic disease less frequently and a third patient had prolonged remission.70

This report prompted a prospective study evaluating the use of high-dose zidovudine (600 mg orally every 6 hours) and valganciclovir (900 mg orally every 12 hours) given for 1 out of every 3 weeks.67,68

Four­teen patients with symptomatic HIV-associated, HHV-8 positive MCD were enrolled and demonstrated overall clinical and complete response rates of 86% and 50%, respectively. The overall radiographic re­sponse rate was lower at 36%, with 29% of patients experiencing a complete radiographic response. Three patients who achieved a complete clinical and radiographic response remained in sustained remis­sion at a median of 29 months after the completion of therapy.68

Antiherpesvirus agents have not been studied in patients who were HIV negative in whom HHV-8 is often present but whose role in patho­genesis is less clearly defined. Among small reports, success has not been observed with cidofovir.71

Bortezomib: Bortezomib is a proteasome inhibi­tor active in plasma cell neoplasms by multiple mech­anisms; it also decreases the production of IL-6 via the NFκB blockade.72 Anecdotal reports of durable clinical and radiographic responses in MCD warrant further study in the context of clinical trials.73-76