Drug Profile

Siltuximab for multicentric Castleman disease Expert Review of Hematology Downloaded from informahealthcare.com by University of Queensland on 03/13/15 For personal use only.

Expert Rev. Hematol. 7(5), 545–557 (2014)

Yi-Chang Liu1,2, Katie Stone1 and Frits van Rhee*1 1 Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA 2 Faculty of Medicine, College of Medicine, Kaohsiung Medical University and Department of Hematology-Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan *Author for correspondence: Tel.: +1 501 804 7020 Fax: +1 501 526 5075 [email protected]

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Dysregulated secretion of IL-6 plays a pivotal role in the pathogenesis of Castleman disease (CD), a rare lymphoproliferative disorder. In contrast to unicentric CD for which surgery is considered the treatment of choice, there is no standard therapeutic approach for multicentric CD (MCD). Siltuximab (trade name: Sylvant, formerly known as CNTO 328) is a chimeric monoclonal antibody with high binding affinity for human IL-6. In a recent randomized placebo-controlled Phase II trial, subjects with HIV-negative, HHV8-negative MCD who received siltuximab demonstrated a significantly higher rate of durable tumor and symptomatic response with a tolerable safety profile, leading to its approval for the treatment of HIV-negative HHV8-negative MCD by the US FDA and the European Commission in April and May 2014, respectively. This article will cover the current treatment options of MCD, the drug profile of siltuximab and future directions in the management of MCD. KEYWORDS: Castleman disease • IL-6 • monoclonal antibody • siltuximab • targeted therapy

Castleman disease (CD) is a rare, non-clonal lymphoproliferative disorder characterized by enlarged hyperplastic lymphadenopathy involving single or multiple lymph nodes. Clinically, CD can manifest as localized lymphadenopathy referred to as unicentric CD (UCD), or generalized lymphadenopathy known as multicentric CD (MCD). These entities have very different presentations and prognoses [1–3]. A subset of CD is associated with HIV infection and active human herpesvirus-8 (HHV8, also known as Kaposi sarcoma-associated herpesvirus) replication, and patients with CD are commonly categorized according to the centricity, HIV status and histopathological pattern [1–7]. The incidence and prevalence of CD in population remains unclear because the disease is rare and incompletely understood. A plausible strategy using a US claims database to identify a cohort of ‘likely’ CD patients reveals that the incidence rate of CD is 21 per million patient-years in the USA [8]. In a prospective HIV database with a 56,202 patientyears of follow-up in Europe, the incidence of MCD in HIV-infected patients measured 4.3/ 10,000 patient-years, which was increasing over time and occurred more frequently in older patients with well-preserved immune function [9]. A recent study estimated 10-year prevalence of MCD regardless of HIV status in the USA at 2.4 per million/adults based on 10.1586/17474086.2014.946402

the medical records of MCD patients identified between 2000 and 2009 at two US referral centers, though this is probably an underestimate of the true prevalence [10]. The diagnosis of CD is based on histopathological examination of the resected lymph nodes in the correct clinical setting, and review by experienced pathologists is recommended to assure accurate diagnosis. Several histopathological patterns have been recognized, including hyaline vascular variant, plasma cell variant and mixed type. Patients with UCD typically have the histopathological pattern of hyaline vascular variant, while patients with MCD more commonly present with plasma cell or mixed variants [4–7]. Another variant, plasmablastic CD, is characterized by large plasmablasts harboring HHV8 in the mantle zone of the hyperplastic follicles, which may coalesce to form so-called microlymphomas, and progression to aggressive plasmablastic lymphoma may occur [11,12]. The latter variety is virtually only seen in HIV-positive patients. Recognizing the extent of disease is clinically important, since UCD and MCD are considered separate entities with quite different characteristics, presentations, response to therapy and long-term outcomes [1–3]. In a large retrospective analysis of 404 CD patients, the overall survival (OS) is significantly higher in UCD (95.3%) than in MCD (61.1%) [1].


2014 Informa UK Ltd

ISSN 1747-4086

545

Drug Profile

Liu, Stone & van Rhee

Tocilizumab

Siltuximab

IL6

Activated IL6 receptor complex

sIL6R

Tocilizumab

Siltuximab

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IL6

Cell surface P

IL6R

JAK

JAK P

P

IL6R

P

IL6R JAK

gp130

gp130 STAT3 STAT3

P

STAT3 P

STAT3

Nucleus

P

Transcription

STAT3 P

Figure 1. Mechanism of action of IL-6 pathway blocking agents. sIL-6R: Soluble IL-6 receptor.

Similarly in a retrospective series of 113 CD patients, a higher 5-year OS rate was found in patients with UCD (91%) versus MCD (65%) [2]. In a further review of 416 CD patients, a 3-year disease-free survival rate of 92.5% was found in patients with HIV-negative UCD with hyaline vascular variant, compared with 45.7% in patients with HIV-negative MCD with plasma cell variant, and only 27.8% in patients with HIVpositive MCD (exclusively plasma cell variant) [3]. UCD is a more common, milder disease confined to a single lymph node chain or area, and is usually curable by surgical excision. In contrast, MCD has a wide clinical spectrum, ranging from waxing and waning lymphadenopathy with mild symptoms to a more aggressive systemic disease accompanied by a variety of manifestations such as fever, night sweats, anorexia, fatigue, weight loss, organomegaly, edema, effusions and ascites. A number of laboratory abnormalities are often observed in MCD including anemia, thrombocytopenia, thrombocytosis, leukocytosis, hypergammaglobulinemia, hypoalbuminemia and an increase of acute phase reactants such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fibrinogen is typically observed. An increase of serum IL-6 and VEGF is found in a majority of patients. Systemic therapy is required but the prognosis has been hitherto less favorable as previously detailed [1–7]. In severe cases, mortality may occur as a result of 546

multi-organ failure, infections or transformation to malignant lymphoma. Dysregulated secretion of the pleiotropic cytokine IL-6 plays a pivotal role in the pathogenesis of CD [4–7]. Binding of IL-6 to IL-6R, the latter of which is present both as a membrane-bound and a soluble protein (sIL-6R), produces a complex that subsequently binds gp130 at the cell surface resulting in activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway (FIGURE 1) [13,14]. IL-6 is involved in a wide range of diseases, mainly malignancies, autoimmune and inflammatory diseases. IL-6 has multiple systemic and local effects: it is a proinflammatory factor, promotes proliferation of B-lymphocytes and plasma cells, increases angiogenesis through upregulation of VEGF secretion and dysregulates the immune response accounting for autoimmune phenomena [15–18]. In an early study, the production of IL-6 by blastoid B cells in the germinal center of affected lymph nodes was identified, and the clinical and biological abnormalities including an elevated level of serum IL-6, which normalized after lymph node excision [19]. Transgenic expression of IL-6 in mice produced MCD-like features [20], which could be diminished by blocking IL-6 with anti-IL-6R antibody [21]. However, the exact cell types responsible for production of IL-6 have not been elucidated. Expert Rev. Hematol. 7(5), (2014)

Siltuximab for MCD

Drug Profile

Table 1. Comparisons of multicentric Castleman disease categorized by human herpesvirus-8 and HIV status.

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HHV8-positive

HHV8-negative

HIV-positive

HIV-negative

Histopathology

Plasma cell Mixed Plasmablastic

Plasma cell Mixed

Hyaline vascular Plasma cell Mixed

Key cytokines

vIL-6 IL-6 VEGF IL-10 IL-8

vIL-6 IL-6 VEGF

IL-6 VEGF IL-1

Common treatment strategies

Rituximab ± etoposide Ganciclovir/valganciclovir Highly active antiretroviral therapy

Rituximab ± etoposide

Rituximab ± steroids Tocilizumab Siltuximab

HHV8: Human herpesvirus-8; vIL-6: Viral IL-6.

In HIV-positive MCD, patients are nearly always co-infected with HHV8 [22,23]. HIV infection can result in an immunodeficiency status making patients more vulnerable to lytic HHV8 replication and subsequent HHV8-driven hypercytokinemia. HHV8 is responsible for the hypercytokinemia status, systemic inflammation and cellular proliferation through encoding a viral homolog of IL-6 (vIL-6) and inducing the production of human IL-6, two pivotal cytokines that contribute to the pathogenesis of HIV-positive MCD [4–7]. vIL-6 can either bind to human IL-6R, or directly activate gp130, independently of IL-6R, to activate the downstream JAK/STAT pathway [24]. Transgenic expression of vIL-6 in mice could induce a MCD-like phenotype, but the phenotype was abrogated when the vIL-6 transgene was transferred into IL-6 knockout mice, suggesting that endogenous IL-6 is also an important cofactor [25]. Clinically, higher HHV8 viral load in patients with HIV-positive MCD is associated with disease exacerbation and relapse [26,27]. In a recent study evaluating HHV8 viral load, IL-6, vIL-6 and other cytokines in patients with HIV-positive MCD during flares and remissions, investigators reported that IL-6 and vIL-6 can either independently or together lead to the disease flares, and more severe disease was found when both IL-6 and vIL-6 were elevated [28]. HHV8 is currently considered the cause to drive the hypercytokinemia status in HIV-positive MCD patients, and in some HIV-negative MCD patients. For rare MCD cases who are HIV-negative but HHV8-positive, the clinical and pathological features were similar to those described in patients with HIV-positive HHV8-positive MCD but different from patients with HIV-negative HHV8-negative MCD, suggesting that HHV8-positive MCD is possibly a single pathological entity regardless of HIV status [29]. Classifying MCD based on HHV8 status may be more appropriate than HIV status, which has thus far been commonly used. In addition to HHV8-positive MCD, there is a subset of patients who are both HIV-negative and HHV8-negative. It has recently been proposed to designate this entity as idiopathic informahealthcare.com

MCD (iMCD) [30]. These patients can be latently infected with HHV8, but do not have active viral replication of HHV8 and lymph nodes should stain negative for latencyassociated nuclear antigen. iMCD is also characterized by excess IL-6 secretion and hypercytokinemia but the etiology remains unknown. Several hypotheses have been proposed for driving iMCD hypercytokinemia. Autoantibodies, commonly seen in patients with autoimmune diseases as well as iMCD, may stimulate antigen-presenting cells in lymph nodes to release proinflammatory cytokines, which may have effects in downstream cells responsible for hypercytokinemia. Autoinflammatory responses involving a germ line aberration in genes of innate immunity may be another cause to drive hypercytokinemia. A small population of monoclonal stromal cells in lymph nodes may be the hypercytokine-secreting cells that trigger the subsequent responses. Another hypothesis is a non-HHV8 viral etiology that may directly signal vIL-6 or human IL-6 or may cause immune dysregulation to drive hypercytokinemia [30]. The features of MCD categorized by the HHV8 and HIV status are summarized in TABLE 1. In patients with UCD, complete surgical resection of involved lymph nodes is curative and is considered the treatment of choice [1]. Any clinical symptoms often resolve after surgery. Rituximab and steroids, embolization and radiotherapy are alternative choices when the lesion cannot be completely resected [31]. In contrast to UCD, the treatment of MCD is more complicated, but the prognosis has historically been less favorable. Prior to the introduction of monoclonal antibody (mAb) therapy, patients with MCD were usually managed by a variety of strategies, including cytotoxic chemotherapies, corticosteroids, antiviral agents and immunomodulators (TABLE 2). Despite a few objective responses, most of the studies revealed only modest effects with considerable toxicities, and were based on limited case reports or case series [4–7]. The backbone of treatment of HIV-positive MCD is the anti-CD20 mAb rituximab. However, there is presently no standard therapeutic 547

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Liu, Stone & van Rhee

responsible for hypercytokinemia via either single agent or multiple drugs comCategory Agent(s) binations commonly used in the treatment Cytotoxic chemotherapy of malignant lymphoma, were employed in earlier studies with small and heterogeSingle agent Vinblastine, etoposide, liposomal doxorubicin, cladribine, neous patient populations. Objective cyclophosphamide, chlorambucil, doxorubicin responses were seen in some patients Multiple drug • CHOP (cyclophosphamide, doxorubicin, vincristine, including severely ill patients, but toxiccombinations prednisone) ities and relapses were common [4–7,18]. • CVP (cyclophosphamide, vincristine, prednisone) • CVAD (cyclophosphamide, vincristine, doxorubicin, The response to corticosteroids was varidexamethasone) able and usually short-lived, and it was • ABV (doxorubicin, bleomycin, vinblastine) commonly used as part of combination • chlorambucil/prednisone chemotherapy [4–7]. • cyclophosphamide/prednisolone Marked progress in the treatment of • cyclophosphamide/bleomycin HIV-positive MCD was achieved with • vincristine/bleomycin/vinblastine the introduction of rituximab, a chimeric Antiviral agents anti-CD20 mAb which is currently indiAnti-HHV8 Ganciclovir, foscarnet, cidofovir, valganciclovir cated for the treatment of CD20-positive B-cell non-Hodgkin’s lymphoma (NHL), Zidovudine/valganciclovir chronic lymphocytic leukemia and Anti-HIV Highly active antiretroviral therapy Waldenstro¨m’s macroglobulinemia. In a Immunomodulators Corticosteroids study evaluating 21 patients with newly diagnosed HIV-positive MCD who were IFN-a treated with rituximab 375 mg/m2 All-trans retinoid acid weekly for 4 doses, the authors reported Thalidomide a radiologic response rate of 67%, 2-year OS of 95% and 2-year disease-free surLenalidomide vival of 79% [32]. In another study evaluProteasome inhibitor Bortezomib ating 24 patients with chemotherapydependent HIV-positive MCD treated Monoclonal antibodies with the same schedule, 1-year event-free CD20 Rituximab survival was observed in 71% of patients, IL-6 Siltuximab with a 1-year OS of 92% [33]. In a retrospective analysis of 61 patients, the 2IL-6R Tocilizumab and 5-year OS in 49 patients receiving IL-1R Anakinra rituximab-based therapy was 94 and Hematopoietic stem cell High-dose melphalan/autologous hematopoietic stem cell 90%, respectively, compared with 42 and transplantation transplantation 33% in patients treated before the introMiscellaneous Cimetidine duction of rituximab [34]. In another retrospective analysis of 52 patients, patients Suramin receiving rituximab-based therapies had a HHV8: Human herpesvirus-8. higher complete remission (CR) rate and a longer OS compared with patients approach or consensus regarding the treatment of iMCD. Until receiving chemotherapy alone or in combination with antiviral recently no randomized trials have been conducted for iMCD therapies [35]. In a larger cohort of 113 patients with HIVand no drugs were approved in the USA or Europe for iMCD. positive MCD, a significant decrease in the incidence of subseClearly, there is an unmet need for new treatment options for quent NHL was observed in patients who had been treated this serious condition. with rituximab [36]. An exacerbation of Kaposi’s sarcoma (KS) was found in patients with previously existing KS lesions after Body of review receiving rituximab [32,33,36]. Rituximab monotherapy failure Overview of the market was reported in cases with fulminant HIV-positive MCDHIV- & HHV8-positive MCD related multiple organ failure [37], therefore, cytotoxic chemoThe treatment of MCD should be considered according to the therapy with or without rituximab was suggested in patients HIV status based on currently available evidences. Cytotoxic who presented with aggressive disease or poor performance stachemotherapies, which eliminated a large portion of cells tus to eliminate a large portion of cytokine-secreting cells [38,39].

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Table 2. Therapeutic options for multicentric Castleman disease.

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Siltuximab for MCD

Experience is greatest with intravenous etoposide as additional therapy, although the optimal chemotherapy has not been established [38,39]. Antiherpesvirus agents, including ganciclovir, foscarnet and cidofovir which demonstrated anti-HHV8 activity in vitro, have been evaluated in the treatment of HIV-positive HHV8-positive MCD. Only limited clinical efficacy was noted in earlier reports, except ganciclovir, which was reported to be effective in a few patients [38,39]. Highly active antiretroviral therapy (HAART) is commonly integrated into the treatment of HIV-positive MCD; however, the effect of HAART in the treatment of HIV-positive MCD is unclear. Of interest is a study of 14 patients with HIV-positive, HHV8-positive MCD where high-dose zidovudine plus valganciclovir led to a major clinical response in 86% and a major biochemical response in 50% of patients, with an OS of 86% at 12 months [40]. Idiopathic MCD

The introduction of mAbs targeting IL-6 signaling pathway has expanded the therapeutic armamentarium for iMCD. Tocilizumab, a recombinant human IgG1 mAb which targets both membrane bound IL-6R and sIL-6R, inhibits the activity of IL-6 by preventing the binding of IL-6 to IL-6R (FIGURE 1). In an earlier study of seven patients with iMCD treated with the anti-IL-6R mAb rhPM-1, later known as tocilizumab, all patients had resolution of clinical symptoms followed by improvement of lymphadenopathy; however, disease recurred after treatment discontinuation [41]. In a further single-arm open-label prospective study of 28 patients with HIV-negative MCD (all iMCD except 2 were seronegative for HHV8) treated with tocilizumab 8 mg/kg every 2 weeks, the authors observed reduction of lymphadenopathy, improvement of clinical symptoms and normalization of inflammation parameters such as CRP, ESR and fibrinogen within 16 weeks, and chronic inflammatory symptoms were successfully managed over 60 weeks [42]. Toxicity was acceptable, and 27 (96.4%) patients continued tocilizumab for ‡3 years. Eight (28.6%) patients were able to tolerate a lower dose or a longer dosing interval, and corticosteroid dose was successfully tapered in 11 of 15 patients [42]. Siltuximab also demonstrates clinical efficacy and tolerability and will be discussed later. The mechanism of actions of siltuximab and tocilizumab are shown in FIGURE 1. Rituximab has been reported effective and tolerable, including long-term remission, in iMCD patients. These findings were described in case reports [43–45], but rituximab has not been systematically evaluated in clinical trials in iMCD. Tocilizumab has been used in two patients with HIVpositive MCD with a rapid clinical improvement, but the response was short-lived and re-induction therapy with rituximab led to remission [46]. Several immunomodulators, including IFN-a, thalidomide and lenalidomide, have shown efficacy in case reports in HIV-positive and HIV-negative MCD [4–7]. Bortezomib, a proteasome inhibitor, was found to lower IL-6 level and induce remission in several cases of informahealthcare.com

Drug Profile

iMCD [47,48]. Anakinra, a recombinant IL-1 receptor antagonist, has also been reported to induce durable response in two refractory patients with iMCD [49,50]. However, none of these treatments has been systematically studied and there may well be reporting bias. Introduction of drug IL-6 mAb development

The clinical application of anti-IL-6 mAb therapy was first reported in one patient with chemotherapy-refractory plasma cell leukemia who received the murine anti-IL-6 mAbs BE-4 and BE-8 and demonstrated a reduction in myeloma proliferation and a transient tumor cytostasis [51]. The first clinical application of anti-IL-6 mAb therapy in CD patient was reported in 1994. One patient with plasma cell variant CD demonstrated a rapid improvement of clinical symptoms and laboratory abnormalities following treatment with murine antiIL-6 mAb BE-8; however, symptoms returned after treatment discontinuation [52]. The development of anti-murine antibodies, the short half-life and the inability to block IL-6 production >18 mg/day were disadvantages of BE-8, which led to further exploration of a new generation of antiIL-6 mAb [53,54]. Chemistry

Siltuximab is a chimeric human-murine anti-IL-6 mAb, which contains the antigen-binding variable region of the murine anti-IL-6 antibody CLB8 and the constant region of the human IgG1 kappa immunoglobulin. The neutralizing antibody CLB8 blocks the binding of IL-6 to IL-6R, both membrane-bound IL-6R and sIL-6R, and has a high affinity for recombinant and native IL-6 [54–56] but not vIL-6 [57]. Pharmacokinetics

The pharmacokinetic parameters of siltuximab in patients with iMCD was first evaluated in a prospective, open-label, 7-cohort, Phase I study, which enrolled 67 subjects, including 37 with MCD, 17 with NHL and 13 with multiple myeloma (MM) [58]. Patients in cohorts 1–5 were administered siltuximab intravenously (i.v.) in a 2-h infusion at escalating doses of 3 mg/kg every 2 weeks, 6 mg/kg every 2 weeks, 12 mg/kg every 3 weeks, 6 mg/kg weekly and 12 mg/kg every 2 weeks, respectively. Cohort 6 evaluated a shorter 1-h infusion of 12 mg/kg every 3 weeks. Cohort 7 was an extension cohort, limited to patients with CD, which evaluated a 1-h infusion of siltuximab at 9 mg/kg every 3 weeks (cohort 7a) or 12 mg/kg every 3 weeks (cohort 7b). No obvious differences in pharmacokinetic profiles were observed among patients with CD, NHL or MM. The serum concentrations of siltuximab declined in a bi-exponential pattern. Following day 1 administration, the mean terminal-phase half-life (t1/2) ranged from 17.73 ± 6.9 to 20.64 ± 7.0 days across cohorts receiving 12 mg/kg every 3 weeks. At a dose of 12 mg/kg via a 1-h infusion every 3 weeks (cohort 6), the maximum concentration was 191.5 ± 52.3 mg/ml and the serum 549

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Drug Profile

Liu, Stone & van Rhee

area under concentration-time curve (AUC) was 1720.4 ± 674.4 mg*day/ml following day 1 of administration, and was 297.1 ± 88.3 mg/ml and 3044.4 ± 1180.6 mg*day/ml, respectively following day 43 after administration. An apparent doseproportional increase in the maximum concentration and the serum area under concentration-time curve was observed following the first dose and repeated doses. The clearance was dose independent, ranging from 4.03 ± 2.23 to 4.59 ± 3.06 ml/day/kg across cohorts receiving 12 mg/kg every 3 weeks. The accumulation following repeated doses was consistent with the t1/2 following the first dose suggesting no time-dependent changes in pharmacokinetics [58]. Immunogenicity

Serum samples from Phase I study subjects were collected to detect anti-siltuximab antibodies by a validated bridging immunoassay at baseline, and at 12, 18, 24 weeks, or at the time of a reaction during drug administration that led to siltuximab discontinuation. Of the 31 subjects who had sufficient samples, all were negative for antibodies to siltuximab [58]. An additional analysis of 411 patients in clinical trials evaluated antitherapeutic antibody responses to siltuximab. One patient (0.2%) tested positive for a low titer of anti-siltuximab antibodies with non-neutralizing capabilities [57]. Pharmacodynamics

IL-6 is the inducer of CRP synthesis by hepatocytes, and a decrease of CRP level following anti-IL-6 therapy has been observed in B-cell lymphoproliferative disorders and MM [54,55], which makes CRP a good pharmacodynamic surrogate marker for IL-6 bioactivity. IL-6 also induces the overproduction of hepcidin in the liver, which is a peptide hormone regulator of iron homeostasis and is associated with the anemia commonly seen in iMCD and MM [59,60]. In the interim analysis of the Phase I study focusing on 23 patients with HIV-negative CD, suppression of CRP, as well as ESR, fibrinogen and IgG, were observed as early as week 3 in a cohort of subjects receiving siltuximab at 9 mg/kg every 3 weeks, and the suppression was maintained through the treatment course [61]. A maximum median increase in hemoglobin of 2.1 g/dl (range 0.2–4.7) was observed among 19 patients who did not receive blood transfusion or erythropoietin-stimulating agents. In the final report of the Phase I study, a decrease in CRP from baseline was observed as early as day 8 in cohorts 1– 6 across all disease types, and remained low through the treatment course [58]. A greater decrease in CRP at cycle 3 was observed in CD subjects (cohort 7) who received 12 mg/kg every 3 weeks (77% median reduction) than 9 mg/kg every 3 weeks (52% median reduction). Circulating serum IL-6 level was not predictive of clinical response. A decrease of hepcidin was found in 97%, and an increase in hemoglobin of ‡1.5 g/dl was found in 75% of subjects with MM and CD. A trend of decreasing serum VEGF level was found in some subjects following treatment. A trend of decreasing expression level of phosphorylated STAT1, STAT3 and STAT5 in T cells, B cells 550

and monocytes was observed without association with clinical responses [58]. Clinical efficacy Phase I studies

The clinical efficacy of siltuximab in iMCD was first reported in the interim analysis of 23 subjects enrolled in the Phase I study (TABLE 3) [61]. Efficacy was evaluated by radiologic response, which was modified from Cheson criteria to include the assessment of cutaneous lesions, and by the clinical benefit response (CBR). The CBR was defined as improvement from baseline in one or more parameters, and no worsening in the remaining six parameters: ‡2 g/dl increase in hemoglobin without transfusions, ‡1 grade decrease in fatigue, ‡1 grade decrease in anorexia, ‡2˚C decrease in fever or return to 37˚C or improvement of night sweats, ‡5% increase in weight or ‡25% decrease bi-dimensionally in the size of the largest lymph node. The objective tumor response rate was 52%, including 1 CR and 11 partial responses (PR) (TABLE 3). A higher response rate (73%) was seen in subjects receiving 12 mg/kg, compared with 33% in subjects receiving lower doses. The median time to radiologic PR in responsive subjects was 185 days (range 57– 954). CBR was demonstrated in 78% of subjects, including 48% of subjects demonstrating improvement in ‡4 parameters. All subjects receiving 12 mg/kg achieved CBR, compared with 58% of subjects receiving lower doses. The involution of lymph nodes was gradual in contrast to the rapid improvement in symptomatology and laboratory abnormalities [61]. In the final report of this Phase I study in which 37 subjects with HIV-negative CD were enrolled, the clinical efficacy was evaluated in a similar fashion (TABLE 3). Among 36 evaluable subjects, 1 patient had a best radiologic response of CR, 11 had PR, 3 had unconfirmed PR, 20 had stable disease (SD) and 1 had progressive disease (PD). Among 12 radiologic responders, 11 did not progress during follow-up, 9 achieved the highest dose of 12 mg/kg and the median time to progression was not reached after a median follow-up of 29.4 months. Importantly, the radiologic response rate was similar across the three histological subtypes of CD. Furthermore, 87% of subjects demonstrated CBR, and 43% of improved in ‡4 parameters. The most improved parameters were fatigue (78%), lymphadenopathy (65%) and weight (60%). There were 65% of subjects treated for ‡12 months at study completion, with the longest treatment duration of 57.3 months in an extension protocol, suggesting a long-lasting clinical effect [58]. Phase II studies

The results of Phase I study prompted a subsequent Phase II trial, with results reported recently [62]. In this Phase II, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of siltuximab in patients with symptomatic iMCD, 79 subjects were randomly assigned 2:1 to siltuximab plus best supportive care (BSC) group (n = 53) or placebo plus BSC group (n = 26, allowing for prednisone 1 mg/kg [or equivalent]). Due to a difference in Expert Rev. Hematol. 7(5), (2014)

Siltuximab for MCD

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Table 3. Summary of basic demographic and disease characteristics and clinical efficacy in subjects with HIV-negative Castleman disease in Phase I and II trials. Phase I trial†

Phase I trial‡

Study design

Siltuximab dose escalation

Siltuximab dose escalation

Treatment

Siltuximab 3 mg/kg every 2 weeks to 12 mg/kg every 2 weeks

Siltuximab 3 mg/kg every 2 weeks to 12 mg/kg every 2 weeks

Siltuximab 11 mg/kg every 3 weeks plus BSC

Placebo plus BSC

Case number

23

37

53

26

Male (%)

57

51

66

Multicentric CD (%)

96

95

100

HHV8 serostatus (%)

0

3

0

Median age, y

49

47

48

Caucasian

70

73

39

Asian

NA

11

48

Black

NA

16

NA

61

76

58

Hyaline vascular

43

49

33

Plasma cell

52

46

23

Mixed

4

5

44

Durable tumor and symptomatic response (%)

NA

NA

34 (1 CR, 17 PR)

0

Tumor response rate by central radiology review (%)

52 (1 CR, 11 PR)

33§ (1 CR, 11 PR)

38

4

Clinical benefit response (%)

78

87

NA

NA

Durable symptomatic response rate (%)

NA

NA

57

19

Complete symptom resolution (%)

NA

NA

25

0

Median time to treatment failure (days)

NA

NA

NR

134

Median time to next treatment (days)

NA

NA

NR

280

Phase II trial Randomized, placebo-controlled

Race (%)

Prior therapy (%) Histopathology (%)

†

Interim analysis in 23 subjects with CD. Final result of Phase I trial enrolling 67 subjects including 37 subjects with CD. Among 36 evaluable subjects. BSC: Best supportive care; CR: Complete response; NA: Not available; NR: Not reached; PR: Partial response. ‡ §

the absorptivity constant used for calculating the dose of study drug administered in earlier studies versus later studies (~9% difference), the dose that was intended to be administrated (12 mg/kg) was actually 11 mg/kg [63]. Thus, in the Phase II trial siltuximab was administrated at a dose of 11 mg/kg given informahealthcare.com

by 1-h infusion every 3 weeks. Cross-over to unblinded siltuximab was allowed upon disease progression. The primary end point was durable tumor and symptomatic response, defined as PR or CR by modified Cheson criteria, and ‡18 weeks of improvement or stabilization of MCD-related symptoms. 551

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Table 4. Summary of safety data of siltuximab in patients with HIV-negative Castleman disease in Phase I and II trials.

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Case number

Key safety issues All grades

Grades 3–4

Phase I trial†

23

• 87% of patients did not experience AEs > grade 2 • 6 (26%) patients experienced ‡1 SAEs but no SAEs were attributed to siltuximab • 3 patients experienced mild infusion reaction

• 11 (48%) patients experienced ‡1 AEs of toxicity grade ‡3, 3 (13%) were reasonably related to siltuximab • AEs ‡ grade 3 among AEs reported in ‡20% of patients: nausea (n = 1), upper respiratory tract infection (n = 1), vomiting (n = 2), hypertriglyceridemia (n = 1), hypertension (n = 1)

Phase I trial‡

67

• 66% of patients experienced AEs of infection: upper respiratory tract infection (39%), urinary tract infection (16%), sinusitis (12), cellulitis (9%) • All-grade AEs possibly related to siltuximab: thrombocytopenia (25%), neutropenia (19%), hypertriglyceridemia (19%), leukopenia (18%), hypercholesterolemia (15%), anemia (10%) • 4 patients experienced infusion reaction

• AEs ‡ grade 3 among AEs reported in ‡15% of patients: neutropenia (21%), hypertension (9%) • AEs ‡ grade 3 among all-grade of AE of infection: upper respiratory tract infection (n = 1), cellulitis (n = 4) • AEs ‡ grade 3 among all-grade AEs possibly related to siltuximab reported in >1 patient: neutropenia (n = 11), thrombocytopenia (n = 3) • 1 patient experienced grade 3 infusion reaction

Phase II trial

79

• 23% of patients experienced SAEs (19% in control group), 3 (6%) patients experienced SAEs reasonably related to siltuximab • 8% of patients experienced low-grade infusion reaction, except 1 anaphylactic reaction leading to discontinuation

• 47% of patients experienced AEs of toxicity grade ‡3 (54% in control group) • AEs ‡ grade 3 reported with siltuximab group: fatigue (9%), night sweats (8%), hyperkalemia (4%), hyperuricemia (4%), localized edema (4%), hyperhidrosis (4%), neutropenia (4%), thrombocytopenia (4%), hypertension (4%) and weight increased (4%). • AEs ‡ grade 3 reasonably related to siltuximab in >1 patient: neutropenia (4%), thrombocytopenia (4%)

†

Interim analysis in 23 subjects with CD. Final result of Phase I trial enrolling 67 subjects including 37 subjects with CD. AE: Adverse event; SAE: Serious adverse event. ‡

A significantly higher rate of durable tumor and symptomatic response was observed in patients receiving siltuximab (34%, 1 CR and 17 PR) than placebo (0%, p = 0.0012) with a median duration of response of 340 days. Median time to treatment failure was not reached in the siltuximab arm versus 134 days in patients receiving placebo (p = 0.0084). Tumor response rate (p = 0.0022), durable symptomatic response rate (p = 0.0018) and complete symptom resolution (p = 0.0037) were all superior in patients receiving siltuximab (TABLE 3) [62]. Hemoglobin improvement by ‡1.5 g/dl at week 13 was observed in 61% of siltuximab-treated subjects who were anemic at study entry, compared with 0% in placebo (p = 0.0002). Furthermore, sustained decrease in CRP, ESR and fibrinogen, and increase in albumin were observed in subjects receiving siltuximab. In addition to durable tumor and symptomatic response, reversal of muscle wasting was found in iMCD patients treated 552

with siltuximab [64]. The effect of siltuximab on muscle mass was evaluated by CT scan in 34 of 37 subjects enrolled in Phase I trial. Muscle mass gain >1 kg was found in 38% of subjects, and stable muscle mass was found in an additional 47% of subjects, with a mean gain of 0.5 kg in the entire population, 0.9 kg in those with radiologic PR (n = 11) and 0.5 kg in those with SD. Among 17 subjects enrolled on the siltuximab arm of Phase II trial, the mean gain in muscle mass was 0.6 kg [64]. Safety & tolerability

The safety and tolerability of siltuximab across the Phase I and II trials are summarized in TABLE 4. In the Phase I trial, no doselimiting toxicities (DLT) were observed in cohorts 1–6 [58,61]. The safety profiles of siltuximab administered as a 1- or 2-h iv. infusion were similar, therefore, a 1-h infusion was employed in the subsequent study. The rate of adverse event (AE) of infection

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Siltuximab for MCD

per patient-year was 1.9 in patients with CD. All-grade AEs possibly related to siltuximab in 67 siltuximab-treated subjects were thrombocytopenia (25%), neutropenia (19%), hypertriglyceridemia (19%), leukopenia (18%), hypercholesterolemia (15%) and anemia (10%) [58]. None of them led to treatment delay or discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related death occurred. In 29 (43%) patients who received siltuximab for ‡1 year, no treatment discontinuation due to AEs and no increase in the incidence of ‡grade 3 AEs were observed. Focusing on a subgroup analysis of 37 CD patients in the Phase I trial, all-grade AEs possibly related to siltuximab were mostly grade 1–2, including hypertriglyceridemia (20–30%), hypercholesterolemia (20–30%), thrombocytopenia (10–20%), upper respiratory tract infection, nausea, abnormal hepatic function, hyperuricemia, anemia, leukopenia and neutropenia (5–10% each) [58]. In the Phase II study, treatment-emergent AEs were similar in both groups. More than grade 3 AEs likely related to siltuximab were neutropenia and thrombocytopenia (4% each). Mortality was observed in two patients (4%) in the siltuximab group due to PD after treatment discontinuation, and four non-crossover patients (15%, three PD and one AE) in placebo group [62]. In terms of long-term safety profile, an analysis of 19 patients who had sustained disease control in Phase I study and continue to receive siltuximab in an extension study was reported recently [65]. All patients are alive, continuing siltuximab and maintaining disease control, with a median treatment doses of 81 (maximum 129) and a median treatment duration of 5.1 years (3.4–7.2, 74% of patients >4 years). During the entire treatment period, the most frequently reported AEs were upper respiratory tract infection (89%), nausea (63%), vomiting (58%), diarrhea (53%), hypercholesterolemia (47%) and hypertriglyceridemia, pain in extremities, headache, rash and abnormal hepatic function (42% each). The incidence of AEs is similar or lower in the treatment periods of 2–4 years and ‡4 years, compared with 0–2 years. No evidence of new or cumulative toxicity or treatment discontinuations was identified with prolonged siltuximab treatment [65]. No specific cardiotoxicity has been reported in the Phase I and II trials of MCD. In a recent study evaluating the effect of siltuximab on the QT interval, no evidence of QTc prolongation was observed in 27 evaluable patients (13 with monoclonal gammopathy of undetermined significance, 13 with smoldering MM and 1 with low-volume MM) treated with 4 doses of single-agent siltuximab at a supratherapeutic dosage of 15 mg/ kg via a 1-h infusion every 3 weeks [66]. Regulatory affairs

Siltuximab has recently been approved by the US FDA for the treatment of patients with MCD who are not were HIV negative and HHV8 negative in April 2014. There is no indication for siltuximab in patients with MCD who are HIV positive or HHV8 positive. Siltuximab was not studied in such patients because siltuximab does not bind to vIL-6 [57]. However, in informahealthcare.com

Drug Profile

HIV-positive MCD human IL-6 is also elaborated and further studies are warranted in this setting. Siltuximab has also been approved by the European Commission in May 2014 and is indicated for the treatment of adult MCD patients who are HIV negative and HHV8 negative. Tocilizumab is approved for the treatment of MCD in Japan. The FDA-approved indications for tocilizumab include iv. or sc. use in adult patients with moderately to severely active rheumatoid arthritis (RA) who had an inadequate response to one or more disease-modifying anti-rheumatic drugs (approved in 2010), iv. use in children (‡2 years old) with active polyarticular juvenile idiopathic arthritis and iv. use in children (‡2 years old) with active systemic juvenile idiopathic arthritis (approved in 2011). Tocilizumab has also been approved in more than 95 countries worldwide for the treatment of adult moderate-to-severe RA. Conclusion

In contrast to UCD for which complete surgical resection is usually curative with a good prognosis, the treatment of MCD is more complex. Prior to the introduction of mAb therapy, patients with MCD were managed by a variety of strategies, based on limited case reports or case series, with only modest success. Rituximab with or without cytotoxic chemotherapies have been applied as first-line treatment of HIV-positive MCD; however, the optimum therapy of iMCD has been less clear. A number of therapeutic modalities, including corticosteroids, cytotoxic chemotherapies, rituximab, bortezomib and immunomodulators, have been applied. The use of rituximab and corticosteroids has been widespread, but is not based on any firm clinical evidence. It is likely that physicians feel comfortable with rituximab since it is widely used to treat B-cell malignancies, such as chronic lymphocytic leukemia, NHL, Waldenstro¨m’s macroglobulinemia and also autoimmune disorders. MAb therapy targeting the IL-6 signaling pathway seems a more rational approach. Tocilizumab has shown to be effective in a single-arm study in Japan. Siltuximab is the only drug studied in MCD in a randomized, placebo-controlled clinical trial. This study may have selected for less symptomatic patients due to its trial design, which included a placebo arm. A significantly higher rate of durable tumor and symptomatic response was observed in subjects receiving siltuximab when compared with placebo. Clinical benefits were also reflected by improvement of time to treatment failure, MCD-related symptoms, hemoglobin level and inflammatory markers. Long-term administration of siltuximab is required to prevent relapse, although the side effect profile is favorable with no cumulative toxicity over time. Currently, no data exist with regards to a direct comparison of tocilizumab or siltuximab versus rituximab, or a combination of tocilizumab or siltuximab with other modalities, in the iMCD setting. The role of mAb therapy targeting the IL-6 signaling pathway in the treatment of HIV-positive MCD is less clear. vIL-6 shares a 25% sequence homology with human IL-6 and 553

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Liu, Stone & van Rhee

siltuximab does not bind vIL-6 [57]. It is important to note that vIL-6 can bypass the IL-6 receptor and directly activate the gp130 complex. Because human IL-6 has a higher potency and is marked elevated and also contributes to the pathogenesis of HIV-positive MCD, neutralization of human IL-6 with siltuximab might still be of value and the same applies to blocking the IL-6R with tocilizumab, which is currently under investigation in clinical trials in the HIV-positive setting [67,68]. Expert Review of Hematology Downloaded from informahealthcare.com by University of Queensland on 03/13/15 For personal use only.

Expert commentary

Currently, there is no standard therapeutic approach or consensus for the treatment of MCD, both in the HIV-positive and HIV-negative settings. In recent years, the therapy for HIVpositive MCD has become more clearly delineated. Rituximabbased therapy, though not yet approved, has improved clinical outcome and reduced the risk of transformation to lymphoma. Rituximab should be considered the first-line therapy and addition of etoposide may be a valuable therapeutic option in sicker patients. However, attention should be paid in patients with poorly controlled HIV viral load, low CD4 counts or active KS lesions and good HIV control with HAART may be of importance as well. Anti-viral therapy with agents such as valganciclovir targeting HHV8 seems an attractive option as maintenance therapy. In patients with iMCD, tocilizumab has shown clinical benefit and acceptable toxicity leading to its approval for the treatment of MCD in Japan, but it has not been approved in the USA or Europe. Siltuximab targets a crucial cytokine driving iMCD, and is presently the only FDA and European Commission-approved agent for iMCD. It is also the only drug, which has been evaluated in a randomized, placebocontrolled clinical trial in MCD. Long-term follow-up studies attest to a favorable safety profile. Siltuximab is likely to be an important contribution to the therapeutic armamentarium for iMCD. It is difficult to directly compare the efficacy and safety of siltuximab and tocilizumab, as there are many differences between the studies in terms of trial design, patient population, stringentness of assessment of clinical responses and report of AEs. It seems unlikely that future clinical trials will be conducted, which compare siltuximab with tocilizumab or siltuximab with rituximab, given the rarity of the disease. Longer follow-up will be necessary to determine whether the high response rates with siltuximab will translate into a survival advantage. Five-year view

The mAb therapy has led to a remarkable progress in the treatment of MCD. Rituximab seems to be the frontrunner for the therapy of HIV-positive MCD. Although siltuximab or tocilizumab do not directly affect vIL-6 signaling in HIV-positive MCD, human IL-6 overproduction remains a major cause of clinical symptoms and blocking IL-6 signaling may still be of value. Tocilizumab is currently being evaluated alone or in 554

combination with zidovudine and valganciclovir in patients with HHV8-positive MCD [69]. Siltuximab and tocilizumab have been mainly studied in patients with iMCD. It seems likely that the use of tocilizumab will decline with the FDA-approval of siltuximab. Further, the largest-studied tocilizumab study was a non-randomized trial with a relatively small number of mainly Japanese subjects. Both tocilizumab and siltuximab require long-term administration and relapses have been reported on discontinuation of tocilizumab. Early experience with siltuximab suggests that some patients can be dosed at 6-weekly rather than 3-weekly intervals [65]. A number of tocilizumab-responsive patients could also be treated at a lower dose or a longer interval without clinical exacerbation [42]. Despite the lack of clinical evidence, the use of rituximab and steroids is firmly entrenched in the management of iMCD and is generally perceived as a short-term therapy with a durable response. The Castleman Disease Collaborative Network is in the process of establishing a Castleman Disease Registry [70]. It is hoped that future registry studies may shed further light on the durability of responses in rituximab-treated patients. One could speculate that patients with less bulky disease who are not severely symptomatic due to excess IL-6 production might be the beneficiaries from rituximab therapy, while more severely ill patients require direct neutralization of IL-6 with siltuximab and continued therapy to prevent relapse. Siltuximab and tocilizumab are not the only drugs designed to target the IL-6 signaling pathway. Other antibodies targeting IL-6, including sirukumab, clazakizumab and olokizumab, as well as antibodies targeting the IL-6R, including sarilumab and ALX-0061, are currently under investigation in various stages of clinical trials, mainly in RA and other autoimmune diseases [71]. Sirukumab and sarilumab have been evaluated in RA patients in several Phase III trials. Theoretically, these agents will be beneficial in the treatment of MCD, and it will be of interest to evaluate differences among mAbs in terms of efficacy and safety profiles. However, none of these mAbs is currently being investigated for MCD in clinical trials and it seems unlikely that these agents will replace FDA-approved siltuximab. Studies on the efficacy of siltuximab in hematological malignancies, especially those characterized by aberrant production of IL-6, are of interest. MM is one of the most evaluated diseases to date regarding the use of anti-IL-6 therapies. In an early Phase I study in patients with relapsed or refractory MM, single-agent siltuximab showed a decrease in CRP, exhibited low toxicity and immunogenicity and a long half-life; but no responses were seen [55]. In a Phase II trial evaluating the efficacy of siltuximab alone and in combination with dexamethasone in patients with relapsed or refractory MM, no responses to siltuximab monotherapy was observed, but an overall response rate (‡PR, primary efficacy end point) of 17% was observed in 47 evaluable subjects receiving combination therapy, including some dexamethasone-refractory patients [72]. In a randomized Phase II study of 106 newly diagnosed MM patients receiving bortezomib, melphalan and prednisone Expert Rev. Hematol. 7(5), (2014)

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(VMP) or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance, the differences between the CR rates (27% in VMP + siltuximab group, 22% in VMP group) did not confirm the hypothesis that siltuximab would increase the CR rate by ‡10%. Overall response rates of 88% in VMP + siltuximab group and 80% in VMP group and at least VGPR rates of 71 and 51% (p = 0.0382), respectively, were observed. Identical median PFS (17 months) and 1-year OS (88%) were reported in the two groups [73].

Drug Profile

Financial & competing interests disclosure

F van Rhee has received research funding from Johnson and Johnson and served on advisory boards. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Categorization of multicentric CD (MCD) by human herpesvirus-8 status rather than traditional HIV status is more appropriate based on the pathogenesis and clinical features. • IL-6 plays a central role in the pathogenesis of MCD. The clinical manifestations of MCD are mainly driven by activation of IL-6 signaling pathway. • In contrast to unicentric CD for which surgery is the treatment of choice with a good prognosis, MCD is more aggressive with more serious clinical symptomatology, which at times can be life-threatening. • Application of rituximab in patients with HIV-positive MCD has improved outcome in HIV-positive MCD and reduced the risk of progression to lymphoma. • Studies with siltuximab and tocilizumab in patients with idiopathic MCD show remarkable activity validating the IL-6 signaling cascade as important therapeutic target. • Siltuximab has demonstrated a durable tumor and symptomatic response and a tolerable safety profile in patients with idiopathic MCD in a multi-institutional, international, randomized, placebo-controlled clinical trial, leading to its approval by the FDA and the European Commission in April and May 2014, respectively.

an update on diagnosis, assessment, and therapy. Clin Adv Hematol Oncol 2010; 8(7):486-98

References Papers of special note have been highlighted as: • of interest •• of considerable interest 1.

••

Talat N, Belgaumkar AP, Schulte KM. Surgery in Castleman’s disease. a systematic review of 404 published cases. Ann Surg 2012;255(4):677-84 A large retrospective cohort of 404 patients with Castleman disease, demonstrating a separate entity between unicentric CD and multicentric CD (MCD) and providing the evidence that surgery is gold standard for unicentric CD.

2.

Dispenzieri A, Armitage JO, Loe MJ, et al. The clinical spectrum of Castleman’s disease. Am J Hematol 2012;87(11): 997-1002

3.

Talat N, Schulte KM. Castleman’s disease: systematic analysis of 416 patients from the literature. Oncologist 2011;16(9):1316-24

4.

El-Osta HE, Kurzrock R. Castleman’s disease: from basic mechanisms to molecular therapeutics. Oncologist 2011;16(4): 497-511

5.

van Rhee F, Stone K, Szmania S, et al. Castleman disease in the 21st century:

informahealthcare.com

6.

Dham A, Peterson BA. Castleman disease. Curr Opin Hematol 2007;14(4):354-9

7.

Casper C. The aetiology and management of Castleman disease at 50 years: translating pathophysiology to patient care. Br J Haematol 2005;129(1):3-17

8.

9.

10.

11.

Mehra M, Cossrow N, Stellhorn RA, et al. Use of a claims database to characterize and estimate the incidence of Castleman’s disease. Blood (ASH Annual Meeting Abstracts) 2012;120:abstract 4253 Powles T, Stebbing J, Bazeos A, et al. The role of immune suppression and HHV8 in the increasing incidence of HIV-associated multicentric Castleman’s disease. Ann Oncol 2009;20(4):775-9 Robinson D Jr, Reynolds M, Casper C, et al. Clinical epidemiology and treatment patterns of patients with multicentric Castleman disease: results from two US treatment centres. Br J Haematol 2014; 165(1):39-48 Dupin N, Diss TL, Kellam P, et al. HHV8 is associated with a plasmablastic variant of Castleman disease that is linked

to HHV8-positive plasmablastic lymphoma. Blood 2000;95(4):1406-12 12.

Du MQ, Liu H, Diss TC, et al. Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood 2001;97(7):2130-6

13.

Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 2012;52:199-219

14.

Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011;121(9):3375-83

15.

Middleton K, Jones J, Lwin Z, Coward JI. Interleukin-6: an angiogenic target in solid tumours. Crit Rev Oncol Hematol 2014; 89(1):129-39

16.

Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol 2010; 22(5):347-52

17.

Hong DS, Angelo LS, Kurzrock R. Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 2007;110(9):1911-28

555

Drug Profile

Expert Review of Hematology Downloaded from informahealthcare.com by University of Queensland on 03/13/15 For personal use only.

18.

Liu, Stone & van Rhee

Schulte KM, Talat N. Castleman’s disease – a two compartment model of HHV8 infection. Nat Rev Clin Oncol 2010;7(9):533-43

19.

Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood 1989;74(4):1360-7

20.

Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman’s disease in mice. J Clin Invest 1990;86(2):592-9

21.

22.

23.

24.

25.

26.

27.

28.

29.

Katsume A, Saito H, Yamada Y, et al. Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman’s disease like symptoms emerged in IL-6 transgenic mice. Cytokine 2002;20(6):304-11 Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood 1995;86(4):1276-80

disease in the absence of HIV infection. Clin Infect Dis 2013;56(6):833-42 30.

•

31.

32.

33.

Suda T, Katano H, Delsol G, et al. HHV8 infection status of AIDS-unrelated and AIDS-associated multicentric Castleman’s disease. Pathol Int 2001;51(9): 671-9 Adam N, Rabe B, Suthaus J, et al. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J Virol 2009;83(10): 5117-26 Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, et al. HHV8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood 2012;119(22): 5173-81 Stebbing J, Adams C, Sanitt A, et al. Plasma HHV8 DNA predicts relapse in individuals with HIV-associated multicentric Castleman disease. Blood 2011;118(2): 271-5 Oksenhendler E, Carcelain G, Aoki Y, et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric Castleman disease in HIV-infected patients. Blood 2000;96(6):2069-73 Polizzotto MN, Uldrick TS, Wang V, et al. Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Blood 2013;122(26): 4189-98 Dossier A, Meignin V, Fieschi C, et al. Human herpesvirus 8-related Castleman

556

34.

35.

Fajgenbaum DC, van Rhee F, Nabel CS. HHV8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood 2014;123(19):2924-33 A comprehensive review of human herpesvirus-8-negative MCD, proposing the concept of idiopathic MCD and candidate processes driving hypercytokinemia. Chronowski GM, Ha CS, Wilder RB, et al. Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy. Cancer 2001;92(3):670-6 Bower M, Powles T, Williams S, et al. Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med 2007;147(12): 836-9 Ge´rard L, Be´rezne´ A, Galicier L, et al. Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman’s disease: ANRS 117 CastlemaB Trial. J Clin Oncol 2007; 25(22):3350-6 Bower M, Newsom-Davis T, Naresh K, et al. Clinical features and outcome in HIV-associated multicentric Castleman’s disease. J Clin Oncol 2011;29(18):2481-6 Hoffmann C, Schmid H, Mu¨ller M, et al. Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease. Blood 2011;118(13): 3499-503

•

A large cohort analysis providing the evidence of improved outcomes in patients with HIV-positive MCD treated with rituximab.

36.

Ge´rard L, Michot JM, Burcheri S, et al. Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease. Blood 2012;119(10): 2228-33

•

A large cohort analysis showing the risk of lymphoma in HIV-positive MCD is reduced by rituximab treatment.

37.

38.

Buchler T, Dubash S, Lee V, et al. Rituximab failure in fulminant multicentric HIV/human herpesvirus 8-associated Castleman’s disease with multiorgan failure: report of two cases. AIDS 2008;22(13): 1685-7 Bower M. How I treat HIV-associated multicentric Castleman disease. Blood 2010; 116(22):4415-21

39.

Oksenhendler E. HIV-associated multicentric Castleman disease. Curr Opin HIV AIDS 2009;4(1):16-21

40.

Uldrick TS, Polizzotto MN, Aleman K, et al. High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. Blood 2011;117(26):6977-86

41.

Nishimoto N, Sasai M, Shima Y, et al. Improvement in Castleman’s disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 2000;95(1):56-61

42.

Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005;106(8): 2627-32

••

A prospective single-arm study of tocilizumab in patients with HIV-negative MCD, demonstrating a significant clinical response and a tolerable safety profile, which led to the approval of tocilizumab in the treatment of MCD in Japan.

43.

Ide M, Kawachi Y, Izumi Y, et al. Long-term remission in HIV-negative patients with multicentric Castleman’s disease using rituximab. Eur J Haematol 2006;76(2):119-23

44.

Gholam D, Vantelon JM, Al-Jijakli A, Bourhis JH. A case of multicentric Castleman’s disease associated with advanced systemic amyloidosis treated with chemotherapy and anti-CD20 monoclonal antibody. Ann Hematol 2003;82(12):766-8

45.

Ocio EM, Sanchez-Guijo FM, Diez-Campelo M, et al. Efficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena. Am J Hematol 2005;78(4):302-5

46.

Nagao A, Nakazawa S, Hanabusa H. Short-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two cases. J Hematol Oncol 2014;7(1):10

47.

Hess G, Wagner V, Kreft A, et al. Effects of bortezomib on pro-inflammatory cytokine levels and transfusion dependency in a patient with multicentric Castleman disease. Br J Haematol 2006;134(5):544-5

48.

Sobas MA, Alonso Vence N, Diaz Arias J, et al. Efficacy of bortezomib in refractory form of multicentric Castleman disease associated to poems syndrome (MCDPOEMS variant). Ann Hematol 2010;89(2): 217-19

Expert Rev. Hematol. 7(5), (2014)

Siltuximab for MCD

49.

El-Osta H, Janku F, Kurzrock R. Successful treatment of Castleman’s disease with interleukin-1 receptor antagonist (Anakinra). Mol Cancer Ther 2010;9(6):1485-8

50.

Galeotti C, Tran TA, Franchi-Abella S, et al. IL-1RA agonist (anakinra) in the treatment of multifocal Castleman disease: case report. J Pediatr Hematol Oncol 2008; 30(12):920-4

Expert Review of Hematology Downloaded from informahealthcare.com by University of Queensland on 03/13/15 For personal use only.

51.

52.

53.

54.

55.

56.

Klein B, Wijdenes J, Zhang XG, et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood 1991;78(5):1198-204 Beck JT, Hsu SM, Wijdenes J, et al. Brief report: alleviation of systemic manifestations of Castleman’s disease by monoclonal anti-interleukin-6 antibody. N Engl J Med 1994;330(9):602-5 Lu ZY, Brailly H, Wijdenes J, et al. Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments. Blood 1995;86(8): 3123-31 Trikha M, Corringham R, Klein B, Rossi JF. Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 2003;9(13):4653-65 van Zaanen HC, Lokhorst HM, Aarden LA, et al. Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: a phase I dose-escalating study. Br J Haematol 1998; 102(3):783-90 van Zaanen HC, Koopmans RP, Aarden LA, et al. Endogenous interleukin 6 production in multiple myeloma patients treated with chimeric monoclonal anti-IL6 antibodies indicates the existence of a positive feedback loop. J Clin Invest 1996;98(6):1441-8

57.

Sylvant. SylvantTM (siltuximab) for injection [package insert]. Janssen Biotech, Inc; Horsham, PA, USA: 2014. Available from: www.sylvant.com [Last accessed 8 July 2014]

58.

Kurzrock R, Voorhees PM, Casper C, et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in

patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res 2013; 19(13):3659-70 ••

59.

First Phase I study evaluating siltuximab in the treatment of HIV-negative MCD, establishing the dose-limiting toxicity and safety issues, as well as the pharmacokinetic and pharmacodynamic profiles. Song SN, Tomosugi N, Kawabata H, et al. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood 2010; 116(18):3627-34

60.

Sharma S, Nemeth E, Chen YH, et al. Involvement of hepcidin in the anemia of multiple myeloma. Clin Cancer Res 2008; 14(11):3262-7

61.

van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol 2010; 28(23):3701-8

62.

van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman’s disease: a randomized, double-blind, placebo-controlled trial. Lancet Oncol. 2014 july 17. pii: S1470-2045(14)70319-5. doi: 10.1016/S1470-2045(14)70319-5. [Epub ahead of print]

••

To date, the largest cohort of HIV-negative MCD patients prospectively studied in a randomized controlled therapeutic trial, demonstrating durable tumor and symptom response with a tolerable safety profile of siltuximab.

63.

Markham A, Patel T. Siltuximab: first global approval. Drugs 2014;74:1147-52

64.

Kirk M, Kurzrock R, van Rhee F, et al. Siltuximab reverses muscle wasting in patients with multicentric Castleman’s disease. Blood (ASH Annual Meeting Abstracts) 2013;122(21):abstract 4394

65.

van Rhee F, Casper C, Voorhees PM, et al. An open-label, phase 2, multicenter study of

Drug Profile

the safety of long-term treatment with siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman’s disease. Blood (ASH Annual Meeting Abstracts) 2013;122(21):abstract 1806 66.

Thomas SK, Suvorov A, Noens L, et al. Evaluation of the QTc prolongation potential of a monoclonal antibody, siltuximab, in patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or low-volume multiple myeloma. Cancer Chemother Pharmacol 2014;73(1):35-42

67.

Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHVMCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol 2012;3:73

68.

Uldrick TS, Polizzotto MN, Yarchoan R. Recent advances in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Curr Opin Oncol 2012; 24(5):495-505

69.

Tocilizumab for KSHV-associated multicentric Castleman disease. Available from: www.clinicaltrials.gov/ct2/results? term=NCT01441063&Search=Search

70.

CDCN. Available from: www. castlemannetwork.org

71.

Williams SC. First IL-6-blocking drug nears approval for rare blood disorder. Nat Med 2013;19(10):1193

72.

Voorhees PM, Manges RF, Sonneveld P, et al. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Br J Haematol 2013;161(3):357-66

73.

San-Miguel J, Blade´ J, Shpilberg O, et al. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 2014;123(26):4136-42

Notice of correction

The version of this article published online ahead of print on 9 August 2014 contained an error in the ‘Financial & competing interests disclosure’ section. The sentence “F van Rhee has received research funding from Janssen and Janssen and served on advisory boards” has been changed to “F van Rhee has received research funding from Johnson and Johnson and served on advisory boards”. This has been corrected in this version.

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