0884 Siltuximab -Sylvant- (1) (1)
Transcript of 0884 Siltuximab -Sylvant- (1) (1)
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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
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▪ 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
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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
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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.
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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;
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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
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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
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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
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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
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cancer, pancreatic cancer, prostate cancer, and renal cancer).
However, its effectiveness for these indications has not been
established.
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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.
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Breast Cancer
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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
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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
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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
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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
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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.
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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,
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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
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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.
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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
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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)
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▪ 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
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Code Code Description
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.
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C90.00 -
C90.32
Multiple myeloma
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Code Code Description
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
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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).
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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
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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.
Siltuximab (Sylvant) - Medical Clinical Policy Bulletins | Aetna Page 27 of 26
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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