Understanding Castleman disease (CD) and its subtypes
CD is a heterogeneous group of rare disorders1
The two primary types of CD are unicentric and multicentric, which include a wide range of etiologies, presentations, treatments, and outcomes.2,3
Unicentric Castleman disease (UCD)
UCD involves a single group of enlarged lymph nodes and can be treated by surgically removing the affected lymph node.4,5
35% of all CD cases6,a
Multicentric Castleman disease (MCD)
MCD has lymphadenopathy in multiple lymph node sites and may require ongoing treatment to keep the symptoms under control.4
64.6% of all CD cases6,a
aStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 327.2 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for the incidence and prevalence of disease7:
- Of the 30.7 million patients eligible for inclusion in the analysis, 442 patients were diagnosed with Castleman disease (CD) according to ICD-9/ICD-10 codes, and 254 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.7
- The incidence of iMCD likely reflects individuals with a new diagnosis, and the prevalence of iMCD likely reflects individuals with a diagnosis currently listed in their medical record. Patients with claims associated with the ICD-9 code before 2017 were not included in incidence calculations.7
- Statistical methods included a Welch’s unequal variance t-test for continuous data and a 2-proportion test for discrete data to understand baseline characteristics between non-iMCD patients and patients with iMCD.7
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.7
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.7
- Administrative claims data are subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2), the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, and CPT-4 codes, whichever was diagnosed first between 2006 and 2020. iMCD incidence as a proportion of total patients with CD may be underestimated.7
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals; therefore, results cannot be generalized to the full patient population in the US.7
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Rabecka Martin was employed by EUSA Pharma at the time this research was conducted. She participated in the analysis and interpretation of data and provided editorial support to the authors.7
Idiopathic multicentric Castleman disease (iMCD)
is the most prevalent subtype of Castleman disease7,a
There are 3 known subtypes of MCD. Their classifications are based on the clinical and pathophysiological presentation of enlarged lymph nodes and the presence or absence of human herpesvirus-8 (HHV-8) or the polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome criteria.2,3
iMCD
A cytokine-driven disorder of ≥2 lymph node groups throughout the body.2 People who have iMCD are HIV negative and HHV-8 negative.4
POEMS-associated MCD
POEMS–associated MCD is defined by the presence of either bone lesions or a λ-restricted plasma cell disorder.2
HHV-8–positive MCD
This subtype of MCD is caused by HHV-8, also known as Kaposi sarcoma–associated herpesvirus, and is characterized by lesions on the skin, mouth, throat, and other parts of the body, in addition to lymph node involvement.2,8,9
aStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 327.2 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for the incidence and prevalence of disease7:
- Of the 30.7 million patients eligible for inclusion in the analysis, 442 patients were diagnosed with Castleman disease (CD) according to ICD-9/ICD-10 codes, and 254 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.7
- The incidence of iMCD likely reflects individuals with a new diagnosis, and the prevalence of iMCD likely reflects individuals with a diagnosis currently listed in their medical record. Patients with claims associated with the ICD-9 code before 2017 were not included in incidence calculations.7
- Statistical methods included a Welch’s unequal variance t-test for continuous data and a 2-proportion test for discrete data to understand baseline characteristics between non-iMCD patients and patients with iMCD.7
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.7
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.7
- Administrative claims data are subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2), the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, and CPT-4 codes, whichever was diagnosed first between 2006 and 2020. iMCD incidence as a proportion of total patients with CD may be underestimated.7
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals; therefore, results cannot be generalized to the full patient population in the US.7
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Rabecka Martin was employed by EUSA Pharma at the time this research was conducted. She participated in the analysis and interpretation of data and provided editorial support to the authors.7
iMCD affects more than 1000 people per year in the United States alone.7,a It accounts for 33%-58% of published MCD cases2
CD CLASSIFICATION
OVERVIEW PDF
Interleukin-6 (IL-6) is an important driver of the signs and symptoms of iMCD10
Overproduction of IL-6 is a common pathological driver of iMCD10
IL-6 plays an important homeostatic role as part of the body’s immune system by regulating B cells and T cells11
IL-6 is a cytokine that is typically produced during infection, inflammation, or cancer11
IL-6 is overproduced in the germinal centers within the lymph nodes12
iMCD presentation can vary from mild constitutional symptoms to a potentially life-threatening cytokine storm10
Generalized lymphadenopathy2,13: Enlargement seen across multiple groups of lymph nodes
of patients with iMCD have lymphadenopathy13,b
Flu-like symptoms2,13: Fevers, night sweats, fatigue, and weight loss
of patients with iMCD have flu-like symptoms7,a
Fluid accumulation2,13: Edema, ascites, and/or other symptoms of fluid overload
of patients with iMCD have fluid accumulation7,a
Organomegaly2,13: Enlarged liver or spleen
of patients with iMCD have organomegaly7,a
aStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 327.2 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for the incidence and prevalence of disease7:
- Of the 30.7 million patients eligible for inclusion in the analysis, 442 patients were diagnosed with Castleman disease (CD) according to ICD-9/ICD-10 codes, and 254 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.7
- The incidence of iMCD likely reflects individuals with a new diagnosis, and the prevalence of iMCD likely reflects individuals with a diagnosis currently listed in their medical record. Patients with claims associated with the ICD-9 code before 2017 were not included in incidence calculations.7
- Statistical methods included a Welch’s unequal variance t-test for continuous data and a 2-proportion test for discrete data to understand baseline characteristics between non-iMCD patients and patients with iMCD.7
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.7
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.7
- Administrative claims data are subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2), the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, and CPT-4 codes, whichever was diagnosed first between 2006 and 2020. iMCD incidence as a proportion of total patients with CD may be underestimated.7
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals; therefore, results cannot be generalized to the full patient population in the US.7
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Rabecka Martin was employed by EUSA Pharma at the time this research was conducted. She participated in the analysis and interpretation of data and provided editorial support to the authors.7
iMCD is not an indolent disease14,c
iMCD is associated with increased rates of morbidity14,c
© Springer Inc. Adapted from: Mukherjee et al. Leukemia. 2022;36(10):2539-2543. Reprinted with permission.
- Malignancy, organ dysfunction, and thrombotic events are all significantly more prevalent in the iMCD population14,c
- Organ dysfunction is the most prevalent of all morbidities, with kidneys and lungs the most likely affected organs (approximately 1 in 4 iMCD patients)14,c
cStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 235 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for morbidity patterns and healthcare utilization14:
- Of the 30.7 million patients eligible for inclusion in the analysis, 487 patients were diagnosed with Castleman disease according to ICD-9/ICD-10 codes, and 271 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.14
- To prevent confounding, iMCD patients were matched with non-iMCD controls (frequency, 1:50) to analyze key morbidities and healthcare metrics (e.g., ER visits, length of hospital stays).14
- Statistical methods (e.g., Mutual Information (MI) Analysis, Welch’s Unequal Variance t-Test) were used to identify relevant features and test to understand prevalence and morbidities in patients with iMCD.
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.14
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.14
- Administrative claims data is subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2) and the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, whichever was diagnosed first between 2006 and 2020. iMCD mimics or CD subtypes other than iMCD may have been inadvertently included in this study.14
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals, therefore results cannot be generalized to the full patient population in the US.14
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Karan Kanhai, Francis Shupo, and Rabecka Martin were employed by EUSA Pharma at the time this research was conducted. They participated in the analysis and interpretation of data and provided editorial support to the authors.14
iMCD has a worse prognosis than many cancers, and the 5 year overall survival rate is between 74% and 84%1,15,16
Emerging results demonstrate significantly higher rates of morbidity in patients with iMCD compared to a control population17,c
| Morbidity | MCD patients (n=271) | Control (n=12,894) | |
|---|---|---|---|
| Organ dysfunction (all) | 50.6% (137) | 12.9% (1667) | |
| Renal | 27.7% (75) | 5.7% (735) | |
| Respiratory | 24.4% (66) | 5.0% (642) | |
| Cardiovascular | 14.0% (38) | 3.9% (496) | |
| Metabolic | 12.2% (33) | 3.2% (407) | |
| Liver disease | 5.9% (16) | 0.7% (92) | |
| Thrombotic events (all) | 27.3% (74) | 7.8% (1007) | |
| Peripheral arterial disease | 11.8% (32) | 4.1% (523) | |
| Deep vein thrombosis of extremities | 8.1% (22) | 1.4% (180) | |
| Stroke, CV events, or transient ischemic attack | 7.4% (20) | 2.9% (372) | |
| Pulmonary embolism | 6.3% (17) | 0.7% (89) | |
| Myeloid malignancies (all) | 10.0% (27) | 0.6% (72) | |
| Myeloproliferative neoplasm | 5.2% (14) | 0.2% (31) | |
| Myelodysplastic syndrome | 5.2% (14) | 0.3% (36) | |
| CML | 0.7% (2) | 0.1% (8) | |
| Solid malignancies (all) | 18.1% (49) | 7.4% (954) | |
| Lung cancer | 5.2% (14) | 0.6% (71) | |
| Carcinoma of unknown primary | 4.8% (13) | 0.1% (18) | |
| Thyroid cancer | 2.6% (7) | 0.4% (56) | |
| Colon cancer | 2.2% (6) | 0.7% (92) |
cStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 235 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for morbidity patterns and healthcare utilization14:
- Of the 30.7 million patients eligible for inclusion in the analysis, 487 patients were diagnosed with Castleman disease according to ICD-9/ICD-10 codes, and 271 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.14
- To prevent confounding, iMCD patients were matched with non-iMCD controls (frequency, 1:50) to analyze key morbidities and healthcare metrics (e.g., ER visits, length of hospital stays).14
- Statistical methods (e.g., Mutual Information (MI) Analysis, Welch’s Unequal Variance t-Test) were used to identify relevant features and test to understand prevalence and morbidities in patients with iMCD.14
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.14
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.14
- Administrative claims data is subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2) and the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, whichever was diagnosed first between 2006 and 2020. iMCD mimics or CD subtypes other than iMCD may have been inadvertently included in this study.14
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals, therefore results cannot be generalized to the full patient population in the US.14
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Karan Kanhai, Francis Shupo, and Rabecka Martin were employed by EUSA Pharma at the time this research was conducted. They participated in the analysis and interpretation of data and provided editorial support to the authors.14
aStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 327.2 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for the incidence and prevalence of disease7:
- Of the 30.7 million patients eligible for inclusion in the analysis, 442 patients were diagnosed with Castleman disease (CD) according to ICD-9/ICD-10 codes, and 254 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.7
- The incidence of iMCD likely reflects individuals with a new diagnosis, and the prevalence of iMCD likely reflects individuals with a diagnosis currently listed in their medical record. Patients with claims associated with the ICD-9 code before 2017 were not included in incidence calculations.7
- Statistical methods included a Welch’s unequal variance t-test for continuous data and a 2-proportion test for discrete data to understand baseline characteristics between non-iMCD patients and patients with iMCD.7
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.7
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.7
- Administrative claims data is subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2), the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, and CPT-4 codes, whichever was diagnosed first between 2006 and 2020. iMCD incidence as a proportion of total patients with CD may be underestimated.7
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals, therefore results cannot be generalized to the full patient population in the US.7
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Rabecka Martin was employed by EUSA Pharma at the time this research was conducted. She participated in the analysis and interpretation of data and provided editorial support to the authors.7
cStudy Methodology
- The burden of the illness was evaluated using the Truven MarketScan® database that included 235 million US patients between 2006-2020. The following algorithm was used to identify patients to evaluate for morbidity patterns and healthcare utilization14:
- Of the 30.7 million patients eligible for inclusion in the analysis, 487 patients were diagnosed with Castleman disease according to ICD-9/ICD-10 codes, and 271 patients were identified as having iMCD if they also had ≥2 minor diagnostic and lab criteria based on the international diagnostic criteria for iMCD.14
- To prevent confounding, iMCD patients were matched with non-iMCD controls (frequency, 1:50) to analyze key morbidities and healthcare metrics (e.g., ER visits, length of hospital stays).14
- Statistical methods (e.g., Mutual Information (MI) Analysis, Welch’s Unequal Variance t-Test) were used to identify relevant features and test to understand prevalence and morbidities in patients with iMCD.14
Limitations
- Findings should be interpreted cautiously due to limitations inherent to using health claims datasets, which do not require histopathology confirmation or detailed clinical documentation as required.14
- These data are from a retrospective chart review. Results should be considered as hypothesis generating. Further confirmatory studies are required to draw any conclusions from these data.14
- Administrative claims data is subject to coding and data entry errors, which may limit the accuracy of the data. CD patients were identified based on the new diagnosis code for CD (ICD-10; D47.Z2) and the non-specific general code for enlargement of lymph nodes (ICD-9; 785.6) previously used for CD, whichever was diagnosed first between 2006 and 2020. iMCD mimics or CD subtypes other than iMCD may have been inadvertently included in this study.14
- The Truven MarketScan® database includes an overweighted sample of privately insured individuals, therefore results cannot be generalized to the full patient population in the US.14
- This research was sponsored by EUSA Pharma, now owned by Recordati Rare Diseases Inc. Karan Kanhai, Francis Shupo, and Rabecka Martin were employed by EUSA Pharma at the time this research was conducted. They participated in the analysis and interpretation of data and provided editorial support to the authors.14
CD, Castleman disease; CV, cardiovascular; HHV-8, human herpesvirus-8; IL-6, Interleukin-6; iMCD, idiopathic multicentric Castleman disease; MCD, multicentric Castleman disease; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; UCD, Unicentric Castleman disease.
References: 1. Liu W, Cai Q, Yu T, et al. Clinical characteristics and outcomes of Castleman disease: a multicenter Consortium study of 428 patients with 15-year follow-up. Am J Cancer Res. 2022;12(9):4227-4240. 2. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-1657. 3. Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135(16):1353-1364. 4. Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330. 5. Ehsan N, Zahra F. Castleman Disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. 6. Mukherjee S, Martin R, Sande B, Paige JS, Fajgenbaum DC. Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6 directed therapy. Blood Adv. 2022;6(suppl 2):1-6. 7. Mukherjee S, Martin R, Sande B, Paige JS, Fajgenbaum DC. Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6 directed therapy. Blood Adv. 2022;6(2):359-367. 8. Kaposi sarcoma. National Cancer Institute. Accessed May 6, 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/kaposi-sarcoma. 9. Kaposi sarcoma-associated herpesvirus. National Cancer Institute. Accessed May 6, 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ kaposi-sarcoma-associated-herpesvirus. 10. van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018;132(20):2115-2124. 11. Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018;17(6):395-412. 12. Choy EH, De Benedetti F, Takeuchi T, Hashizume M, John MR, Kishimoto T. Translating IL-6 biology into effective treatments. Nat Rev Rheumatol. 2020;16(6):335-345. 13. Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 2016:3(4):e163-e175. 14. Mukherjee S, Kanhai K, Kauffman D, et al. Organ dysfunction, thrombotic events and malignancies inpatients with idiopathic multicentric Castleman disease: a population-level US health claims analysis. Leukemia. 2022;36(10):2539-2543. 15. van Rhee F, Rosenthal A, Kanhai K, et al. Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease. Blood Adv. 2022;6(16):4773-4781. 16. Cohen A, Estevez M, Kelly J, et al. Clinical characteristics, treatment trends, and outcomes of patients with HHV-8-negative/idiopathic multicentric Castleman disease treated with siltuximab in a machine learning-selected real-world cohort. Blood. 2023;142 (Suppl1):907. 17. Mukherjee S, Kanhai K, Kauffman D, et al. Non-hematological malignancies in idiopathic multicentric Castleman disease patients: a matched cohort analysis using a health claims-based dataset. Poster presented at: European Hematology Association (EHA) Congress; June 9-12, 2022; Vienna, Austria. Poster P1733.