Aetna considers siltuximab (Sylvant) medically necessary for the treatment of individuals with unicentric or multicentric Castleman’s disease who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
Aetna considers siltuximab experimental and investigational for the treatment of the following cancers/tumors (not an all-inclusive list) because of insufficient evidence:
See also CPB 0799 - Tocilizumab (Actemra)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: (i) unicentric and (ii) 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.
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.
National Comprehensive Cancer Network guidelines on non-Hodgkin's lymphoma (NCCN, 2015) recommend the use of siltuximab for the following indications:
Single-agent therapy for active multicentric CD with no organ failure for patients who are human immunodeficiency virus-negative and human herpesvirus-8-negative
Second-line therapy as a single agent for relapsed or refractory unicentric CD for patients who are human immunodeficiency virus-negative and human herpesvirus-8-negative.
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, 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 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.
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.
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 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.
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.
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.
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.
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.
Dosing: Administer as an 11 mg/kg dose given over 1 hour by intravenous infusion every 3 weeks.
|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 "+":|
|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:|
|C9455||Injection, siltuximab, 10 mg|
|ICD-10 codes covered if selection criteria are met:|
|R59.0 - R59.9||Enlarged lymph nodes [individuals with unicentric and multicentric Castleman's disease who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative]|
|ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):|
|B10.89||Other human herpesvirus infection|
|B20||Human immunodeficiency virus [HIV] disease|
|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]|
|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|
|C90.00 - C90.32||Multiple myeloma|
|D46.0 - D46.9||Myelodysplastic syndromes|
|H20.00 - H20.29, H20.041 - H20.9||Iridocyclitis other than secondary infectious [non-infectious uveitis]|
|M05.00 - M06.9||Rheumatoid arthritis|