0884 Siltuximab -Sylvant- (1) (1)

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Siltuximab (Sylvant) - Medical Clinical Policy Bulletins | Aetna of 26

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Siltuximab (Sylvant)

Policy History

Last Review

11/06/2020

Effective: 07/18/2014

Next

Review: 02/11/2021

Review History

Definitions

Additional Information

Clinical Policy Bulletin

Notes

Number: 0884

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

Aetna considers siltuximab (Sylvant) medically necessary for

the treatment of active multicentric Castleman’s disease with

no organ failure or relapsed / refractory unicentric Castleman’s

disease when both of the following criteria are met:

▪ Member is human immunodeficiency virus (HIV)

negative and human herpesvirus-8 (HHV-8) negative;

and

▪ Sylvant is used as a single agent.

Aetna considers continuation of siltuximab (Sylvant) medically

necessary for members meeting initial selection criteria for

multicentric or unicentric Catleman's disease and have not

experienced disease progression or an unacceptable toxicity.

Aetna considers siltuximab experimental and investigational

for the treatment of the following cancers/tumors (not an all-

inclusive list) because of insufficient evidence:

▪ Breast cancer

▪ Colorectal cancer


https://www.aetna.com/




▪ Head and neck cancer

▪ Multiple myeloma (including smoldering multiple

myeloma)

▪ Myelodysplastic syndrome

▪ Myeloma bone disease

▪ Non-Hodgkin lymphoma

▪ Non-infectious uveitis (including sarcoidosis, uveitis

associated with Behcet disease, and Vogt-Koyanagi-

Harada syndrome)

▪ Non-small cell lung cancer

▪ Ovarian cancer

▪ Pancreatic cancer

▪ Pancreatitis

▪ Plasma cell cancer

▪ Prostate cancer

▪ Renal cancer

▪ Rheumatoid arthritis

▪ Rosai-Dorfman disease

▪ Waldenstrom macroglobulinemia.

See also

CPB 0799 - Tocilizumab (Actemra) (../700_799/0799.html).

Dosing Recommendations

Sylvant (siltuximab) is available for injection as 100 mg and

400 mg of lyophilized powder in a single-dose vial. Sylvant is

for intravenous (IV) infusion only.

The recommended dose for member's with multicentric

Castlemans's disease, who are human immunodeficiency virus

(HIV) negative and human herpesvirus-8 (HHV-8) negative, is

11 mg/kg given over 1 hour by intravenous infusion every 3

weeks until treatment failure.

Source: Janssen Biotech, 2018





Background

Castleman's disease (CD), also known as angio-follicular

lymph node hyperplasia and giant lymph node hyperplasia, is

a heterogenous group of lympho-proliferative disorders

associated in a subset of cases with the human

immunodeficiency virus (HIV) and human herpes virus 8

(HHV-8). There are 2 forms of CD: unicentric and multicentric;

with very different prognoses. Castleman's disease may also

be associated with other malignancies, including Hodgkin

lymphoma, Kaposi sarcoma, non-Hodgkin lymphoma (NHL),

as well as polyneuropathy, organomegaly, endocrinopathy,

monoclonal gammopathy, and skin changes syndrome

(POEMS). Patients with multicentric CD (MCD) usually

present at a median age of 50 to 65 years, although those who

are HIV-infected tend to be younger; and 50 % to 65 % are

male. The incidence of HIV-associated MCD has increased in

the years since the introduction of anti-retroviral therapy for the

management of HIV (Astor et al, 2014).

Interleukin-6 (IL-6) has emerged as a key factor in the

pathogenesis of CD. Siltuximab, an anti-IL-6, chimeric

monoclonal antibody derived from a new Chinese hamster

ovary (CHO) cell line, has been demonstrated to exhibit

potential therapeutic benefit in patients with CD.

van Rhee et al (2010) reported interim results from an open-

label, dose-finding, phase I study in which patients with

symptomatic, MCD or unresectable, unicentric CD received

siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end

point of clinical benefit response (CBR) was defined as a

composite of clinical and laboratory measures (e.g., anorexia,

fatigue, fever/night sweats, hemoglobin, weight loss, and

largest lymph node size) relevant to the management of CD.

In addition, radiologic response was independently assessed

by using modified Cheson criteria. A total of 18 (78 %) of 23

patients (95 % confidence intervals [CI]: 56 % to 93 %)

achieved CBR, and 12 patients (52 %) demonstrated objective




tumor response. All 11 patients (95 % CI: 72 % to 100 %)

treated with the highest dose of 12 mg/kg achieved CBR, and

8 patients (73 %) achieved objective tumor response. Overall

objective-response duration ranged from 44 to greater than or

equal to 889 days, and 1 patient had complete response (CR)

for greater than or equal to 318 days. Hemoglobin increased

markedly in 19 patients (median increase, 2.1 g/dL; range of

0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-

stimulating agents. No dose-limiting toxicity (DLT) was

reported, and only 3 patients had grade 3 or higher adverse

events (AEs) after a median exposure of 331 days (range of 1

to 1,148 days). The authors concluded that these interim

results strongly suggested that siltuximab is an effective

treatment with favorable safety for the management of CD.


In an open-label, dose-finding, phase I clinical trial, Kurzrock et

al (2013) evaluated the safety and pharmacokinetics of

siltuximab in patients with B-cell NHL, multiple myeloma (MM),

or CD. Patients with NHL, MM, or symptomatic CD received

siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every

3 weeks. Response was assessed in all disease types.

Clinical benefit response was also evaluated in CD. A total of

67 patients received a median of 16 siltuximab doses for a

median of 8.5 (maximum 60.5) months; 29 were treated 1 year

or longer. There was no DLT, antibodies to siltuximab, or

apparent dose-toxicity relationship. The most frequently

reported possible drug-related AEs were thrombocytopenia

(25 %), hypertriglyceridemia (19 %), neutropenia (19 %),

leukopenia (18 %), hypercholesterolemia (15 %), and anemia

(10 %). None of these events led to dose

delay/discontinuation except for neutropenia and

thrombocytopenia (n = 1 each). No treatment-related deaths

occurred; C-reactive protein (CRP) suppression, a surrogate

marker of IL-6 inhibition, was most pronounced at 12 mg/kg

every 3 weeks. Mean terminal-phase half-life of siltuximab

ranged 17.73 to 20.64 days. Thirty-two of 37 (86 %) patients

with CD improved in 1 or more CBR component; 12 of 36

evaluable CD patients had radiologic response [CR, n = 1;





partial response (PR), n = 11], including 8 of 19 treated with 12

mg/kg; 2 of 14 (14 %) evaluable NHL patients had PR; 2 of 13

(15 %) patients with MM had CR. The authors concluded that

no dose-related or cumulative toxicity was apparent across all

disease indications. A dose of 12 mg/kg every 3 weeks was

recommended on the basis of the high response rates in CD

and the sustained CRP suppression. Moreover, they noted

that randomized studies are ongoing in CD and MM.

In a phase II, randomized-controlled, double-blind, multi-center

study, Wong and colleagues (2013) evaluated the safety and

effectiveness of siltuximab in patients with symptomatic,

measurable, HIV-negative and HHV-8-negative MCD.

Patients could be newly diagnosed/pre-treated and on stable,

low-dose corticosteroids. Patients were randomly assigned

2:1 to siltuximab 11 mg/kg or placebo given by 1-hr

intravenous (IV) infusion q3w. All patients also received best

supportive care (BSC) to manage MCD symptoms. Patients

received study agent until protocol-defined treatment failure,

after which patients randomized to placebo could cross-over to

unblinded siltuximab. Primary analysis occurred after the last

treated patient completed assessments at 48 wks. Primary end

point was durable tumor and symptomatic response defined as

PR or CR (Cheson criteria) by independent review and

improvement/stabilization in MCD-related symptoms for greater

than or equal to 18 wks. Secondary end-points included

additional pre-defined efficacy measures and safety. A total of

79 patients were randomized and treated with siltuximab (n =

53) or placebo (n = 26) from February 2010 to February 2013.

Treatment arms were well-balanced. Median age was 48 yrs, 48

% were Asian, 39 % were white, 66 % were male, 30 % were

on corticosteroids, and 58 % had prior systemic therapy.

Patients had mixed (44 %), hyaline vascular (33 %), or

plasmacytic (23 %) histologic subtypes by pre- randomization

central pathology review. Baseline MCD symptoms included

fatigue (86 %), malaise (61 %), night sweats (52 %), peripheral

sensory neuropathy (38 %), anorexia and pruritus (37 % each).

Median treatment duration





was 375 versus 152 days with siltuximab versus placebo, with

64 % versus 27 % completing 48 wks of treatment. A higher

percentage of durable tumor and symptomatic response was

observed with siltuximab compared with placebo (34 % (1 CR,

17 PR) versus 0 %; p = 0.0012). Median duration of tumor

and symptomatic response in siltuximab-treated patients of

340 days indicated prolonged disease control. Tumor

response rate by central radiology review was 38 % versus 4

% (p = 0.0022). Median time to treatment failure was not

reached versus 134 days (p = 0.0084). Median time to next

treatment was not reached versus 280 days (p = 0.0013).

Durable symptomatic response rate was 57 % versus 19 % (p

= 0.0018), including complete symptom resolution in 25 %

versus 0 % (p = 0.0037). Hemoglobin improvement by greater

than or equal to 15 g/L at wk 13 was seen in 61 % versus 0 %

anemic patients (p = 0.0002). Sustained decreases in CRP,

erythrocyte sedimentation rate, and fibrinogen, and increase in

albumin were seen with siltuximab; 13 of 26 patients on

placebo crossed-over to siltuximab. The safety profile as

defined by frequencies of treatment-emergent AEs was similar

between siltuximab and placebo despite the greater than 2x

longer treatment duration with siltuximab: Grade greater than

or equal to 3 AEs 47 % versus 54 %, serious AEs 23 % versus

19 %, AEs leading to discontinuation 23 % versus 38 %

(mostly due to progressive disease [PD]), AEs leading to

treatment interruption 28 % versus 19 %. Infusion reactions

with siltuximab were infrequent (8 %) and low-grade, except

for 1 anaphylactic reaction that led to treatment

discontinuation. Grade greater than or equal to 3 AEs

frequently reported with siltuximab were fatigue (9 %); night

sweats (8 %); and hyperkalemia, hyperuricemia, localized

edema, hyperhidrosis, neutropenia, thrombocytopenia,

hypertension, and weight gain (4 % each). Grade greater than

or equal to 3 AEs reasonably related to siltuximab reported in

more than 1 patient were neutropenia and thrombocytopenia

(4 % each); 3 (6 %) patients had serious AEs reasonably

related to siltuximab; 2 (4 %) patients in siltuximab died due to

PD after treatment discontinuation; 4 (15 %) non-crossover





patients in placebo died (1 AE, 3 PD). The authors concluded

that this was the first randomized study in MCD. The

effectiveness of siltuximab in MCD patients was demonstrated

by durable tumor and symptom response, and clinical benefit

was confirmed by marked improvement of time to treatment

failure, MCD-related symptoms, hemoglobin levels, and

sustained reduction in inflammatory markers. They stated that

in conjunction with the tolerable safety profile in this

population, this study provided compelling evidence that

siltuximab should be considered a new treatment of choice for

MCD patients.

Sylvant (siltuximab) binds human IL‐6 and prevents the

binding of IL‐6 to both soluble and membrane bound IL‐6

receptors IL‐6 has been shown to be involved in diverse

normal physiologic processes such as induction of

immunoglobulin secretion. Overproduction of IL‐6 has been

linked to systemic manifestations in patients with multicentric

Castleman’ disease.

On April 23, 2014, the Food and Drug Administration (FDA)

approved siltuximab (Sylvant) to treat patients with MCD. The

FDA reviewed Sylvant under its priority review program, which

provides an expedited review for drugs that demonstrate the

potential to be a significant improvement in safety or

effectiveness in the treatment of a serious condition. Sylvant

was also granted orphan product designation because it is

intended to treat a rare disease or condition. Sylvant’s safety

and effectiveness were evaluated in a clinical trial of 79

participants with MCD who were HIV and HHV-8 negative.

Participants were randomly assigned to receive a combination

of Sylvant and BSC, or placebo and BSC. Results showed 34

% of participants treated with Sylvant and BSC experienced

tumor response, while no participant treated with placebo and

BSC did. Common side effects associated with the use of

siltuximab include hyperuricemia, pruritis, rash, weight gain,

and upper respiratory tract infection. Siltuximab is

administered as an 11 mg/kg dose given over 1 hour by





intravenous infusion every 3 weeks until treatment failure.

Sylvant was not studied in patients with MCD who are HIV

positive or HHV-8 positive because siltuximab did not bind to

virally produced IL-6 in a non-clinical study.

Warnings and Precautions

▪ Concurrent Active Severe Infections: Do not administer

Sylvant to patients with severe infections, monitor for

infections, institute prompt treatment, and interrupt

Sylvant until resolution of infection.

▪ Vaccinations: Do not administer live vaccines because

IL-6 inhibition may interfere with the normal immune

response to new antigens.

▪ Infusion Related Reactions: Administer Sylvant in a

setting that provides resuscitation equipment,

medication, and personnel trained to provide

resuscitation.

▪ Gastrointestinal (GI) perforation: Promptly evaluate

patients presenting with symptoms that may be

associated or suggestive of GI perforation.

An UpToDate review on "Multicentric Castleman's

disease" (Astor et al, 2014) states that "Where available,

immunotherapy with monoclonal antibodies directed at IL-6

(siltuximab) or the IL-6 receptor (tocilizumab) is our preferred

therapy for most symptomatic, HIV/HHV-8 negative patients

without evidence of organ failure. This approach has resulted

in two-year overall and relapse-free survival rates of 94 to 95

percent and 79 to 85 percent, respectively".

Siltuximab for Other Indications

Siltuximab, either as a single agent or in combination with

other chemotherapeutic agents, has also been shown to have

potential benefits in treating different types of cancers (e.g.,

colorectal cancer, head and neck cancer, multiple myeloma,

non-Hodgkin lymphoma, non-small cell lung cancer, ovarian




cancer, pancreatic cancer, prostate cancer, and renal cancer).

However, its effectiveness for these indications has not been

established.


In a phase I/II study, Angevin et al (2014) evaluated safety,

effectiveness, and pharmacokinetics of escalating, multiple

doses of siltuximab in patients with advanced/refractory solid

tumors. In the phase I dose-escalation cohorts, a total of 20

patients with advanced/refractory solid tumors received

siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg

every 3 weeks intravenously. In the phase I expansion (n =

24) and phase II cohorts (n = 40), patients with Kirsten rat

sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-

EGF receptor refractory/resistant non-small cell lung cancer

(NSCLC), colorectal, or head and neck cancer received 15

mg/kg every 3 weeks. The phase II primary efficacy end-point

was CR, PR, or SD greater than 6 weeks. A total of 84

patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other)

received a median of 3 (range of 1 to 45) cycles. One DLT

occurred at 5.5 mg/kg. Grade greater than or equal to 3 AEs

were hepatic function abnormalities (15 %), physical health

deterioration (12 %), and fatigue (11 %). Ten percent of

patients had siltuximab-related grade greater than or equal to

3 AEs. Neutropenia (4 %) was the only possibly related AE

grade greater than or equal to 3 reported in more than 1

patient. Serious AEs were reported in 42 %; most were

related to underlying disease. The pharmacokinetic profile of

CHO-derived siltuximab appeared similar to the previous cell

line. No objective responses occurred; 5 of 84 patients (6 %)

had SD greater than 6 weeks. Hemoglobin increased greater

than or equal to 1.5 g/dL in 33 of 47 patients (70 %). At 11

and 15 mg/kg, completely sustained CRP suppression was

observed. The authors concluded that siltuximab

monotherapy appeared to be well-tolerated but without clinical

activity in solid tumors, including ovarian and KRAS-mutant

cancers. The recommended phase II doses were 11 and 15

mg/kg every 3 weeks.




Breast Cancer


Casneuf and co-workers (2016) noted that IL-6 is an important

growth factor for estrogen receptor-α (ERα)-positive breast

cancer, and elevated serum IL-6 is associated with poor

prognosis. These researchers examined the role of the

phosphorylated signal transducer and activator of transcription

3 pathway in ERα-positive breast cancer. A panel of cell lines

was treated with exogenous IL-6. An IL-6 specific gene

signature was generated by profiling ten ERα-positive breast

cancer cell lines alone or following treatment with 10 ng/ml

recombinant IL-6 or human marrow stromal cell-conditioned

media, with or without siltuximab (a neutralizing anti-IL-6

antibody) and grown in 3-D tumor microenvironment-aligned

cultures for 4 days, 5 days, or 6 days. The established IL-6

signature was validated against 36 human ERα-positive breast

tumor samples with matched serum. A comparative MCF-7

xenograft murine model was utilized to determine the role of

IL-6 in estrogen-supplemented ERα-positive breast cancer to

assess the efficacy of anti-IL-6 therapy in-vivo. In 8 of 9 ERα-

positive breast cancer cell lines, recombinant IL-6 increased

phosphorylation of tyrosine 705 of STAT3. Differential gene

expression analysis identified 17 genes that could be used to

determine IL-6 pathway activation by combining their

expression intensity into a pathway activation score. The gene

signature included a variety of genes involved in immune cell

function and migration, cell growth and apoptosis, and the

tumor microenvironment. Validation of the IL-6 gene signature

in 36 matched human serum and ERα-positive breast tumor

samples showed that patients with a high IL-6 pathway

activation score were also enriched for elevated serum IL-6

(greater than or equal to 10 pg/ml). When human IL-6 was

provided in-vivo, MCF-7 cells engrafted without the need for

estrogen supplementation, and addition of estrogen to IL-6 did

not further enhance engraftment. Subsequently, these

investigators prophylactically treated mice at MCF-7

engraftment with siltuximab, fulvestrant, or combination

therapy. Siltuximab alone was able to blunt MCF-7





engraftment. Similarly, siltuximab alone induced regressions

in 90 % (9/10) of tumors, which were established in the

presence of hMSC expressing human IL-6 and estrogen. The

authors concluded that given the established role for IL-6 in

ERα-positive breast cancer, these findings demonstrated the

potential for anti-IL-6 therapeutics in breast cancer.

Castration-resistant Prostate Cancer (CRPC)

In an open-label, 2-part, phase II trial, Fizazi et al (2012)

assessed mitoxantrone/prednisone (M/P) with and without

siltuximab for patients with metastatic castration-resistant

prostate cancer (CRPC) who received prior docetaxel-based

chemotherapy. Part 1 assessed the safety of bi-weekly

siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P.

Part 2 assessed safety and effectiveness of siltuximab plus

M/P versus M/P alone. The primary end-point was progression-

free survival (PFS). Progression was defined as progressive

disease per Response Evaluation Criteria in Solid Tumors

(RECIST), or greater than or equal to 3 new skeletal lesions

with clinical deterioration or without deterioration confirmed by

repeated bone scan. Rising prostate-specific antigen (PSA) was

not considered progression. Siltuximab plus M/P was well-

tolerated in Part 1 (n = 9). In Part 2, 48 and 49 patients received

siltuximab plus M/P or M/P alone, respectively. Enrolment was

prematurely terminated by the Independent Data Monitoring

Committee since an apparent imbalance in patient baseline

characteristics (favoring the M/P only arm) made it unlikely that

the study could achieve its primary efficacy end-point. Median

PFS was 97 days with siltuximab combination and 228 days

with M/P alone (hazard ratio [HR], 1.72; p = 0.043). Use of a

novel non-validated PFS definition may have contributed to this

result. Abnormal laboratory assessments were more frequent

with the combination. Infection and febrile neutropenia rates

were similar between groups. Greater CRP suppression was

achieved during siltuximab combination treatment compared





with M/P alone (p = 0.0003). The authors concluded that while

siltuximab plus M/P appeared well-tolerated, improvement in

outcomes was not demonstrated.

In an open-label, dose-escalation, multi-center, phase 1 study,

Hudes et al (2013) evaluated the safety and tolerability of

siltuximab in combination with docetaxel, the pharmacokinetics

of docetaxel alone and with siltuximab, and the effectiveness

and pharmacodynamics of siltuximab plus docetaxel for the

treatment of CRPC. Patients with metastatic, progressive

CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6

mg/kg q2w (n = 12), 9 mg/kg q3w (n = 12), or 12 mg/kg q3w (n

= 15). Dose-limiting toxicity, PSA, and radiologic response

according to WHO criteria were evaluated. Dose-limiting

toxicity was reported in 1 of 11 patients receiving 6 mg/kg, 1 of

12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg.

Grade greater than or equal to 3 AEs were neutropenia (73

%), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %),

and fatigue (14 %). Toxicities were not dose-dependent.

Siltuximab did not affect docetaxel pharmacokinetics. The

pharmacokinetic profile for siltuximab in combination was

similar to single-agent siltuximab pharmacokinetics. Twenty-

three (62 %; 95 % CI: 45 % to 78 %) of 37 combination-treated

patients achieved a confirmed greater than or equal to 50 %

PSA decline. Of 17 patients with measurable disease at

baseline, 2 confirmed and 2 unconfirmed radiologic PRs

ranging 190 to 193 days were achieved with 9- and 12-mg/kg

siltuximab. C-reactive protein concentrations were suppressed

throughout treatment in all patients. The authors concluded

that these results suggested that siltuximab in combination

with docetaxel was safe and showed preliminary efficacy in

patients with CRPC, although alternative siltuximab schedules

may be better tolerated for future studies.

Multiple Myeloma





In a phase II, multi-center study, Voorhees et al (2013)

evaluated the safety and effectiveness of siltuximab for

patients with relapsed or refractory MM who had greater than

or equal to 2 prior lines of therapy, one of which had to be

bortezomib-based. A total of 14 initial patients received

siltuximab alone, 10 of whom had dexamethasone added for

suboptimal response; 39 subsequent patients were treated

with concurrent siltuximab and dexamethasone. Patients

received a median of 4 prior lines of therapy, 83 % were

relapsed and refractory, and 70 % refractory to their last

dexamethasone-containing regimen. Suppression of serum

CRP levels was demonstrated. There were no responses to

siltuximab but combination therapy yielded a partial (17 %) +

minimal (6 %) response rate of 23 %, with responses seen in

dexamethasone-refractory disease. The median time to

progression, PFS and overall survival for combination therapy

was 4.4, 3.7 and 20.4 months, respectively. Hematological

toxicity was common but manageable. Infections occurred in

57 % of combination-treated patients, including greater than or

equal to grade 3 infections in 18 %. The authors concluded

that further study of siltuximab in modern corticosteroid-

containing myeloma regimens is needed, with special attention

to infection-related toxicity.

In a randomized, double-blind, placebo-controlled, multi-center

study, Brighton and colleagues (2019) examined blocking IL-6

with siltuximab to delay the transition from high-risk smoldering

MM (SMM) MM. A total of 85 patients with high-risk SMM

were randomized to 15 mg/kg siltuximab (43 patients) or

placebo (42 patients). The primary end-point was 1-year PFS

rate, based on IMWG CRAB criteria. Secondary end-points

included progressive disease indicator rate, PFS, and safety.

Median age was 62 years (range of 21 to 84); 57 % were men

and 87 % had a baseline Eastern Cooperative Oncology

Group (ECOG) score of 0. The 1-year PFS rate was 84.5 %

(siltuximab) and 74.4 % (placebo). After a median follow-up of

29.2 months, 32.6 % of PFS events occurred with siltuximab

and 42.9 % with placebo. Median PFS was not reached with


       

   




siltuximab but was 23.5 months with placebo [HR 0.50 (95 %

CI: 0.24 to 1.04); p = 0.0597]. The safety profile of siltuximab

was comparable with placebo. Most AEs observed in the

siltuximab group were grade 2/3; the most common serious

AEs were infections/infestations, and renal/urinary disorders.

Mortality was low in both groups (3 deaths in the siltuximab

group and 4 in the placebo group). The authors concluded

that although this study did not meet the pre-specified protocol

hypothesis criteria, these findings suggested that siltuximab

may delay the progression of high-risk SMM.

Myelodysplastic Syndrome

In a phase II, randomized, double-blind, multi-center study,

Garcia-Manero et al (2014) evaluated the safety and

effectiveness of siltuximab in patients with low- and

intermediate-1-risk myelodysplastic syndrome (MDS) who

require transfusions for MDS anemia. Patients were

randomized in a 2:1 ratio to siltuximab 15 mg kg (-1) every 4

weeks + best supportive care (BSC) or placebo + BSC for 12

weeks. The primary end-point was reduction in red blood cell

(RBC) transfusions to treat MDS anemia, defined as greater

than or equal to 50 % relative decrease and greater than or

equal to 2-unit absolute decrease in RBC transfusions; 50 and

26 patients were randomized to the siltuximab and placebo

groups, respectively. The study did not meet its pre-specified

hypothesis, with 6 (12 %) patients in the siltuximab group and

1 (3.8 %) in the placebo group having reductions in RBC

transfusions (p = 0.271). At the time of the planned futility

analysis, the pre-specified cut-off criteria were not met, and the

study was terminated early due to lack of efficacy. No

unexpected safety findings were observed. The authors

concluded that compared to placebo, treatment with siltuximab

did not reduce RBC transfusions in transfusion-dependent

patients with low- and intermediate-1-risk MDS. They stated

that future studies might explore siltuximab in patients with

less iron overload and with elevated IL-6 levels and/or using

higher doses for MDS.





Myeloma Bone Disease

Bolzoni and colleagues (2018) noted that bone destruction is

the hallmark of MM. About 80 % of MM patients at diagnosis

presents myeloma bone disease (MBD) leading to bone pain

and pathological fractures, significantly affecting patients'

quality of life (QOL). Bisphosphonates are the treatment of

choice for MBD, but osteolytic lesions remain a critical issue in

the current management of MM patients. Several studies

clarified the mechanisms involved in MM-induced osteoclast

formation and activation, leading to the identification of new

possible targets and the development of better bone-directed

therapies. These investigators summarized the latest

advances in the knowledge of the pathophysiology of the

osteoclast formation and activation induced by MM cells, and

the new therapeutic targets identified. Recently, neutralizing

antibodies (i.e., denosumab, siltuximab, daratumumab), as

well as recombinant fusion proteins, and receptor molecular

inhibitors, have been developed to block these targets.

Clinical trials testing their anti-MBD potential are ongoing. The

authors concluded that although further studies are needed to

arrive at a clinical approving, the basis for the development of

better bone-directed therapies has been established.

Non-Infectious Uveitis

Lin and colleagues (2015) noted that IL-6 is a pleiotropic

cytokine implicated in the pathogenesis of many immune-

mediated disorders including several types of non-infectious

uveitis. These uveitic conditions include Vogt-Koyanagi-

Harada syndrome, uveitis associated with Behcet disease, and

sarcoidosis. These investigators summarized the role of IL-6

in immunity, highlighting its effect on Th17, Th1, and

plasmablast differentiation. They reviewed the down-stream

mediators activated in the process of IL-6 binding to its

receptor complex. These researchers also summarized the

biologics targeting either IL-6 or the IL-6 receptor, including

tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab,





and siltuximab. The target, dosage, potential side effects, and

potential uses of these biologics were summarized based on

the existing literature. The authors concluded that anti-IL-6

therapy for non-infectious uveitis shows promise in terms of

efficacy and side effect profile.

Pancreatitis

Hao and associates (2017) stated that chronic pancreatitis

(CP) is a progressive inflammatory disease of the pancreas,

leading to its fibrotic destruction. There are currently no drugs

that can stop or slow the progression of the disease. The

etiology of the disease is multi-factorial, whereas recurrent

attacks of acute pancreatitis are thought to precede the

development of CP. A better understanding of the pathology

of CP is needed to facilitate improved diagnosis and treatment

strategies for this disease. These researchers developed a

mathematical model of CP based on a dynamic network that

includes macrophages, pancreatic stellate cells, and

prominent cytokines that are present at high levels in the CP

microenvironment. The model was represented by a system

of partial differential equations. The model was used to

explore in silico potential drugs that could slow the progression

of the disease (e.g., infliximab, tocilizumab and siltuximab).

Plasma Cell Cancers

Rossi and associates (2015) stated that human IL-6 is a

cytokine produced by many cell types that has pleiotropic

effects. Inhibitors of IL-6 reduce inflammation, hepatic acute

phase proteins, and anemia and have anti-angiogenic effects.

Blocking IL-6 has demonstrated therapeutic efficacy in

Castleman's disease without major toxicity. Interestingly, the

inhibition of CRP production is a trustworthy surrogate marker

of anti-IL-6 therapy efficacy. Clinically registered IL-6 inhibitors

include siltuximab and tocilizumab. In various cancers, in

particular plasma cell cancers, large randomized trials showed

no efficacy of IL-6 inhibitors, despite a full inhibition of CRP





production in treated patients, the numerous data showing an

involvement of IL-6 in these diseases, and initial short-term

treatments demonstrating a dramatic inhibition of cancer cell

proliferation in-vivo. A likely explanation is the plasticity of

cancer cells, with the presence of various subclones, making

the outgrowth of cancer subclones possible using growth

factors other than IL-6.

Renal Cell Carcinoma

In a 3-part, phase I/II study, Rossi et al (2010) evaluated the

effectiveness of siltuximab in patients with progressive

metastatic renal cell carcinoma (RCC). In part 1, 11 patients

received 1, 3, 6, or 12 mg/kg at weeks 1, 4 and q2w × 2

thereafter; in part 2, 37 patients randomly received 3 or 6

mg/kg q3w × 4; and in part 3, 20 low-risk patients received 6

mg/kg q2w × 6. Modified World Health Organization (WHO)

response criteria were assessed at weeks 7, 11, the 6-week

follow-up, and when clinically indicated. Siltuximab was well-

tolerated overall, with no maximum tolerated dose or immune

response observed. In all, 5 out of 11, 17 out of 37, and 9 out

of 20 patients in parts 1, 2, and 3, respectively, received

extended treatment beyond 4 to 6 initial infusions. In part 2,

stable disease (SD) (greater than or equal to 11 weeks) or

better was achieved by 11 out of 17 (65 %) 3 mg/kg treated

patients (1 PR at approximately 8 months, 10 SD) and 10 out

of 20 (50 %) 6 mg/kg treated patients (10 SD). In part 3,

documented CR or PR was not observed, but 13 out of 20 (65

%) patients achieved SD. The authors concluded that

siltuximab stabilized disease in more than 50 % of progressive

metastatic RCC patients; 1 PR was observed. The authors

concluded that given the favorable safety profile of siltuximab

and poor correlation of tumor shrinkage with clinical benefit

demonstrated for other non-cytotoxic therapies, further

evaluation of dose-escalation strategies and/or combination

therapy may be considered for patients with RCC.





Rheumatoid Arthritis

Kim et al (2015) stated that rheumatoid arthritis (RA) is a

chronic inflammatory disease characterized by polyarthritis.

Numerous agents with varying mechanisms are used in the

treatment of RA, including non-steroidal anti-inflammatory

drugs (NSAIDs), disease-modifying anti-rheumatic drugs

(DMARDs), and some biological agents. Studies to uncover

the cause of RA have recently ended up scrutinizing the

importance of pro-inflammatory cytokine such as tumor

necrosis factor-alpha (TNF-α) and IL-6 in the pathogenesis of

RA. Inhibitors of TNF-α are increasingly used to treat RA

patients who are non-responsive to conventional anti-arthritis

drugs. Despite its effectiveness in a large patient population,

up to 2/3 of RA patients are found to be partially responsive to

anti-TNF therapy. Therefore, agents targeting IL-6 such as

tocilizumab (TCZ) attracted significant attention as a promising

agent in RA treatment. The authors reviewed the mechanism

of anti-IL-6 in the treatment of RA, provided the key safety and

effectiveness data from clinical trials of approved anti-IL-6,

TCZ, as well as 6 candidate IL-6 blockers and their future

perspectives in the treatment of RA.

Rosai-Dorfman Disease

Lee and colleagues (2018) noted that Rosai-Dorfman disease

(RDD) is a rare, macrophage-related disorder of unknown

cause that presents as a localized or systemic disorder

involving lymph nodes and other organs. RDD is often self-

limiting, however, sometimes permanent or even fatal. The

rarity and unpredictability of RDD renders optimal timing and

modality of treatment difficult. Bone involvement is especially

rare, and predicts a chronic course with decreased likelihood

of spontaneous remission. These researchers presented a

case of refractory, disseminated RDD that achieved a CR with

siltuximab indicating a major role for IL-6 in this disease. The

treatment schedule of quarterly infusion appeared to have long

term benefit with minimal adverse effects. The authors





stated that the drawback of this single-case study was the lack

of measurement of IL-6; however, the clinical response

suggested cytokine dysregulation as part of the

pathophysiology and should be answered in future studies.

They stated that based on the excellent response in this case,

larger clinical trials with siltuximab should be considered.

Waldenstrom Macroglobulinemia

Ferrario and associates (2017) noted that the role of IL-6 in

tumorigenesis and in particular in hematological malignancies

is crucial. On the basis of the favorable results obtained in the

subset of MCD, siltuximab has been evaluated in

hematological malignancies such as MM, MDS and NHL.

These investigators discussed available data related to the

role of IL-6 as a therapeutic target, the characteristics of

siltuximab in term of pharmacokinetics and pharmacodynamics

properties and a detailed analysis of the studies involving

hematological malignancies with a peculiar focus on NHL.

The authors stated that the results obtained with siltuximab in

hematological malignancies and in particular with NHL are

inferior to those obtained in MCD. The complex interaction

between malignant clones, inflammatory background and host

response could justify this difference. These researchers

stated that new interesting areas of study are the role of

siltuximab in early phase of MM (smoldering MM) and if there

may be a possible future application in the treatment of

Waldenstrom macroglobulinemia.

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network Drugs and

Biologics Compendium (NCCN, 2020) provides the following

recommendations for siltuximab (Sylvant):

B-cell lymphomas

Castleman's Disease - (Category 2A)





▪ Single-agent therapy for active idiopathic multicentric

CD with no organ failure for patients with

plasmacytic/mixed histology who are human

immunodeficiency virus-negative and human

herpesvirus-8-negative

• as primary treatment (preferred)

• as alternate treatment for relapsed disease

• if no response to alternate primary treatment

▪ Second-line therapy as a single agent for relapsed or

refractory unicentric CD for patients with

plasmacytic/mixed histology who are human

immunodeficiency virus-negative and human

herpesvirus-8-negative.

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

Other CPT codes related to the CPB:

96365 Intravenous infusion, for therapy, prophylaxis,

or diagnosis (specify substance or drug); initial,

up to 1 hour

96413 Chemotherapy administration, intravenous

infusion technique; up to 1 hour, single or initial

substance/drug

HCPCS codes covered if selection criteria are met:

J2860 Injection, siltuximab, 10 mg

ICD-10 codes covered if selection criteria are met:

D47.Z2 Castleman's disease






ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

B10.89 Other human herpesvirus infection

B20 Human immunodeficiency virus disease [HIV]

B97.35 Human immunodeficiency virus, type 2 [HIV 2]

as the cause of diseases classified elsewhere

C00.0 -

C14

Malignant neoplasm of lip, oral cavity, and

pharynx

C18.0 -

C20

Malignant neoplasm of colon, rectosigmoid

junction or rectum

C25.0 -

C25.9

Malignant neoplasm of pancreas

C34.00 -

C34.92

Malignant neoplasm of bronchus and lung [non-

small cell lung cancer]

C50.011 -

C50.929

Malignant neoplasm of breast

C56.1 -

C56.9

Malignant neoplasm of ovary

C61 Malignant neoplasm of prostate

C64.1 -

C64.9

Malignant neoplasm of kidney, except pelvis

C76.0 Malignant neoplasm of head, face, and neck

C85.80 -

C85.99

Non-hodgkin lymphoma

C88.0 Waldenstrom macroglobulinemia.




C90.00 -

C90.32

Multiple myeloma







D46.0 -

D46.9

Myelodysplastic syndromes

D76.3 Other histiocytosis syndromes [Rosai-Dorfman

disease]

H20.00 -

H20.29,

H20.041 -

H20.9

Iridocyclitis other than secondary infectious

[non-infectious uveitis]

K85.0 -

K85.9

Acute pancreatitis

K86.1 Other chronic pancreatitis

M05.00 -

M06.9

Rheumatoid arthritis

The above policy is based on the following references:

1. Angevin E, Tabernero J, Elez E, et al. A phase I/II,

multiple-dose, dose-escalation study of siltuximab, an

anti-interleukin-6 monoclonal antibody, in patients

with advanced solid tumors. Clin Cancer Res. 2014;20

(8):2192-2204.

2. Aster JC, Brown JR, Munshi NC. Multicentric

Castleman's disease. UpToDate [online serial].

Waltham, MA: UpToDate; reviewed March 2014.

3. Bolzoni M, Toscani D, Storti P, et al. Possible targets to

treat myeloma-related osteoclastogenesis. Expert Rev

Hematol. 2018;11(4):325-336.

4. Brighton TA, Khot A, Harrison SJ, et al. Randomized,

double-blind, placebo-controlled, multicenter study of





siltuximab in high-risk smoldering multiple myeloma.

Clin Cancer Res. 2019;25(13):3772-3775.

5. Casneuf T, Axel AE, King P, et al. Interleukin-6 is a

potential therapeutic target in interleukin-6

dependent, estrogen receptor-α-positive breast

cancer. Breast Cancer (Dove Med Press). 2016;8:13-27.

6. Ferrario A, Merli M, Basilico C, et al. Siltuximab and

hematologic malignancies. A focus in non Hodgkin

lymphoma. Expert Opin Investig Drugs. 2017;26

(3):367-373.

7. Fizazi K, De Bono JS, Flechon A, et al. Randomised

phase II study of siltuximab (CNTO 328), an anti-IL-6

monoclonal antibody, in combination with

mitoxantrone/prednisone versus

mitoxantrone/prednisone alone in metastatic

castration-resistant prostate cancer. Eur J Cancer.

2012;48(1):85-93.

8. Garcia-Manero G, Gartenberg G, Steensma DP, et al. A

phase 2, randomized, double-blind, multicenter study

comparing siltuximab plus best supportive care (BSC)

with placebo plus BSC in anemic patients with

International Prognostic Scoring System low- or

intermediate-1-risk myelodysplastic syndrome. Am J

Hematol. 2014;89(9):E156-E162

9. Hao W, Komar HM, Hart PA, et al. Mathematical model

of chronic pancreatitis. Proc Natl Acad Sci U S A.

2017;114(19):5011-5016.

10. Hudes G, Tagawa ST, Whang YE, et al. A phase 1 study

of a chimeric monoclonal antibody against interleukin-

6, siltuximab, combined with docetaxel in patients with

metastatic castration-resistant prostate cancer. Invest

New Drugs. 2013;31(3):669-676.

11. Iftikhar A, Hassan H, Iftikhar N, et al. Investigational

monoclonal antibodies in the treatment of multiple

myeloma: A systematic review of agents under clinical

development. Antibodies (Basel). 2019;8(2).





12. Janssen Biotech, Inc. Sylvant (siltuximab) for Injection,

for intravenous infusion. Perscribing Information.

Horsham, PA: Janssen Biotech: April 2014.

13. Janssen Biotech, Inc. Sylvant (siltuximab) for Injection,

for intravenous infusion. Prescribing Information.

Horsham, PA: Janssen Biotech, revised May 2018.

14. Kampan NC, Xiang SD, McNally OM, et al.

Immunotherapeutic interleukin-6 or interleukin-6

receptor blockade in cancer: Challenges and

opportunities. Curr Med Chem. 2018;25(36):4785-

4806.

15. Kim GW, Lee NR, Pi RH, et al. IL-6 inhibitors for

treatment of rheumatoid arthritis: Past, present, and

future. Arch Pharm Res. 2015;38(5):575-584.

16. 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):3659-3670.

17. Lee H, King G, Garg K, et al. Successful treatment of

disseminated Rosai-Dorfman disease with siltuximab.

Haematologica. 2018;103(7):e325-e328.

18. Lin P. Targeting interleukin-6 for noninfectious uveitis.

Clin Ophthalmol. 2015;9:1697-1702

19. National Comprehensive Cancer Network (NCCN).

Non-Hodgkin's lymphomas. NCCN Clinical Practice

Guidelines in Oncology. Version 2.2015. Fort

Washington, PA: NCCN; 2015.

20. National Comprehensive Cancer Network (NCCN).

Siltuximab. NCCN Drugs and Biologics Compendium.

Fort Washington, PA: NCCN; 2020.

21. Rossi JF, Lu ZY, Jourdan M, Klein B. Interleukin-6 as a

therapeutic target. Clin Cancer Res. 2015;21(6):1248-

1257.

22. Rossi JF, Negrier S, James ND, et al. A phase I/II study of

siltuximab (CNTO 328), an anti-interleukin-6





monoclonal antibody, in metastatic renal cell cancer.

Br J Cancer. 2010;103(8):1154-1162.

23. Schmidt-Wolf IG, Straka C, Scheid C, et al. State of the

art treatment of progressive or refractory multiple

myeloma. Dtsch Med Wochenschr. 2014;139

(41):20912095

24. U. S. Food and Drug Administration (FDA). FDA

approves Sylvant for rare Castleman’s disease. FDA

News. Silver Spring, MD: FDA; April 23, 2014.

25. 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-

3708.

26. Varga C, Laubach JP, Anderson KC, Richardson PG.

Investigational agents in immunotherapy: A new

horizon for the treatment of multiple myeloma. Br J

Haematol. 2018;181(4):433-446.

27. 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):357-366.

28. Wong RS, Casper C, Munshi N, et al. A multicenter,

randomized, double-blind, placebo-controlled study of

the efficacy and safety Of siltuximab, An anti-

interleukin-6 monoclonal antibody, in patients with

multicentric Castleman’s disease. Blood. 2013;122

(21):505.



Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors

in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely

responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is

subject to change.

Copyright © 2001-2021 Aetna Inc.

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http://aetnet.aetna.com/mpa/cpb/800_899/0884.html 1/21/2021


AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0884 Siltuximab

(Sylvant)

For the Pennsylvania Medical Assistance plan NCCN category 1, 2A, and 2B recommendations will be reviewed for medical necessity on a case by case basis.

updated 11/06/2020

Proprietary

0884 Siltuximab -Sylvant- (1) (1)

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