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As a rare disease in the blood field, Castleman disease was included in China's "First List of Rare Diseases" in 2018
.
Due to the lack of uniform and clear diagnostic criteria, the symptoms are diverse, and the differential diagnosis is difficult.
Patients with this disease are facing severe challenges in survival
.
Stuximab was approved by the National Medical Products Administration (NMPA) for the treatment of adult patients with human immunodeficiency virus (HIV)-negative, human herpesvirus-8 (HHV-8)-negative multicenter Castleman disease
.
On this occasion, Yimaitong specially invited Professor Wu Depei, director of the Department of Hematology of the First Affiliated Hospital of Soochow University, to systematically interpret the application of stuximab in Castleman's disease, so as to assist the clinical diagnosis and treatment of Castleman's disease
.
Yimaitong: Castleman disease is highly heterogeneous.
Could you please introduce, what are the classifications of Castleman disease? What are the characteristics? Professor Wu Depei Castleman disease can be divided into hyaline vascular type (HV type), plasma cell type (PC type) and mixed type (Mix type) according to histopathological characteristics of lymph nodes; according to the distribution of enlarged lymph nodes and the location of organ involvement, it can be divided into Unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD)
.
UCD only involves a single lymph node region, with a relatively high incidence and mild systemic symptoms.
The main treatment method is surgery, and the prognosis is good.
MCD involves multiple lymph node regions and has a relatively low incidence.
Cytopenia or even life-threatening organ dysfunction is associated with poor prognosis
.
Clinically, MCD can be further divided into HHV-8-related MCD, POEMS (polyperipheral neuropathy, organomegaly, endocrine abnormalities, M protein in serum, skin changes)-related MCD and idiopathic MCD (iMCD) according to the etiology.
)
.
iMCD is a general term for the types of MCD that are HHV-8-negative, HIV-negative and of unknown etiology, accounting for about 33-58% of MCD, and the average survival time is only 2.
57 years
.
The clinical manifestations of iMCD are diverse and can be further divided into iMCD-TAFRO (thrombocytopenia, severe edema, fever, myelofibrosis and organomegaly) and unspecified iMCD (iMCD-NOS) according to their characteristics
.
Yimaitong: At present, the etiology and pathogenesis of iMCD are still unclear.
Could you please introduce, what hypotheses are there for the pathogenesis of iMCD? What is the role of interleukin-6 (IL-6) in the pathogenesis of iMCD? Professor Wu Depei's previous research generally believed that iMCD lymph node enlargement is related to tumor cells that produce IL-6, and tumor cells can release a large amount of IL-6 to cause systemic inflammation and organ dysfunction
.
In recent years, with the deepening of research, a new view is that iMCD lymph node enlargement and corresponding pathological changes are reactive changes to the increase of IL-6 in cytokine storm
.
There are three major hypotheses about the causes of cytokine storm in iMCD, mainly including ① pathogen hypothesis: uncontrolled infection causes cytokine storm; ② autoimmunity/autoinflammation hypothesis: B cells or T cells mutate to produce autoantibodies or cause Auto-reaction, or germline gene mutation leads to auto-inflammation, which in turn causes cytokine storm; ③ Paraneoplastic syndrome hypothesis: excessive proliferation of cytokine-secreting monoclonal cells leads to cytokine storm
.
IL-6 is a pleiotropic agent that can be produced by a variety of cells, including mesothelial cells, monocytes, macrophages, lymphocytes, fibroblasts, endothelial cells, mesangial cells, and various tumor cells.
Sexual cytokines that play a central role in the pathophysiology of Castleman disease
.
Serum IL-6 levels are higher in patients with Castleman disease, and excess IL-6 leads to overgrowth of B lymphocytes, increased lymph node vascularity and inflammation, and can also lead to autoimmune phenomena
.
Studies have shown that the symptoms of patients with Castleman disease usually change with changes in serum IL-6 levels
.
Yi Mai Tong: Could you please talk about the IL-6 targeted drugs approved at home and abroad for the treatment of Castleman's disease? What's the difference? Professor Wu Depei currently has two drugs approved for the treatment of Castleman disease abroad: anti-IL-6 monoclonal antibody situximab (more than 40 countries in North America, EU, Canada, etc.
) and anti-IL-6 receptor (IL-6R) Monoclonal antibody tocilizumab (Japan)
.
In China, stuximab was recently approved for the treatment of HIV-negative, HHV-8-negative adult patients with multicenter Castleman disease
.
Stuximab is a human-mouse chimeric monoclonal antibody that was first approved in the United States in 2014 and has been approved in more than 40 countries and regions around the world.
List of Overseas New Drugs Urgently Needed in Clinical Practice
.
Stuximab and tocilizumab target different sites
.
The former binds to IL-6 with a higher affinity than IL-6 and IL-6R, and has a stronger antagonistic effect; while tocilizumab acts on IL-6R and has a lower affinity for IL-6R, which may be affected by in vivo IL-6R.
Competitive antagonism of IL-6
.
Yi Mai Tong: Could you please talk about how situximab is recommended in the domestic and international guidelines for Castleman disease? Professor Wu Depei clinically classified iMCD into non-severe and severe according to the iMCD disease severity stratification of Castleman Disease International Working Group (CDCN)
.
No matter for non-severe or severe iMCD, many authoritative guidelines consensus recommends seltuximab as the first-line treatment for iMCD
.
The 2018 edition of the International Evidence-Based Consensus Guidelines for iMCD recommends seltuximab as the first-line treatment for patients with non-severe iMCD (see Figure 1); and recommends stuximab combined with high-dose glucocorticoids as the first-line treatment for patients with severe iMCD
.
The 2021 edition of the Chinese Society of Clinical Oncology (CSCO) lymphoma guidelines lists stuximab as a class I recommendation for the treatment of iMCD
.
The 2021 edition of the National Comprehensive Cancer Network (NCCN) guidelines also recommends seltuximab as the first choice for iMCD patients
.
Figure 1 2018 International Evidence-Based Consensus Guidelines for the Treatment of iMCD It is gratifying that the Chinese expert consensus on diagnosis and treatment of Castleman disease (2021 edition) was officially released this year, which is of great significance to the diagnosis and treatment of Castleman disease in China
.
The consensus is based on evidence-based medical evidence including the only randomized double-blind controlled study in the current iMCD treatment field, and pointed out that for non-severe iMCD, stuximab ± prednisone is recommended as the first-line treatment for non-severe iMCD patients; For severe iMCD, stuximab combined with high-dose glucocorticoids is recommended first-line according to the patient's condition (see Figure 2)
.
Figure 2 Expert consensus on diagnosis and treatment of Castleman's disease in China (2021 version) MCD recommended treatment path Yimaitong: Recently, stuximab was approved by the NMPA, breaking the deadlock of no cure for Castleman's disease patients in China
.
Could you please introduce, what are the advantages of stuximab? What significance does this approval bring to the diagnosis and treatment of Castleman disease in my country? Prof.
Depei Wu has combined the current international clinical research on Castleman's disease and found that the comprehensive advantages of stuximab treatment are relatively significant
.
The results of a classic study published in Lancet in 2014 showed that the 18-week tumor and symptom sustained remission rate of iMCD patients after situximab treatment reached 34%, and the average C-reactive protein (CRP) decreased after 1 course of treatment.
to normal levels
.
In 2020, van Rhee F et al.
found that the 6-year disease control rate of iMCD patients treated with setuximab was as high as 97%, and the survival rate was 100%
.
The approval this time has brought a new dawn to China's Castleman disease patients to a certain extent, and it has also contributed to the treatment of rare diseases in China
.
Conclusion The launch of stuximab in China has filled the gap in the field of Castleman disease treatment to a certain extent and brought hope to Chinese Castleman disease patients
.
However, how to better apply situximab to the clinic and serve patients is inseparable from the concerted research of workers in related fields
.
The launch of stuximab is a good start, but there is still a long way to go in the treatment of Castleman's disease.
It is hoped that clinicians will actively accumulate clinical experience to help the treatment of Castleman's disease in China
.
Professor Wu Depei Chief Physician, Professor, Doctoral Supervisor Director of Hematology Department of the First Affiliated Hospital of Soochow University Executive Deputy Director of National Clinical Research Center for Hematological Diseases Deputy Director of Jiangsu Hematology Research Institute Deputy Director of Soochow University Clinical Medicine Research Institute of Soochow University Hematopoiesis Director of Stem Cell Transplantation Institute Member of the 13th National Committee of the Chinese People's Political Consultative Conference Chairman of the Chinese Medical Association Hematology Branch Standing Committee Member of the Chinese Medical Association Internal Medicine Branch Vice President of the Chinese Medical Doctor Association Hematologist Branch Click "read the original text", let's make progress together
.
Due to the lack of uniform and clear diagnostic criteria, the symptoms are diverse, and the differential diagnosis is difficult.
Patients with this disease are facing severe challenges in survival
.
Stuximab was approved by the National Medical Products Administration (NMPA) for the treatment of adult patients with human immunodeficiency virus (HIV)-negative, human herpesvirus-8 (HHV-8)-negative multicenter Castleman disease
.
On this occasion, Yimaitong specially invited Professor Wu Depei, director of the Department of Hematology of the First Affiliated Hospital of Soochow University, to systematically interpret the application of stuximab in Castleman's disease, so as to assist the clinical diagnosis and treatment of Castleman's disease
.
Yimaitong: Castleman disease is highly heterogeneous.
Could you please introduce, what are the classifications of Castleman disease? What are the characteristics? Professor Wu Depei Castleman disease can be divided into hyaline vascular type (HV type), plasma cell type (PC type) and mixed type (Mix type) according to histopathological characteristics of lymph nodes; according to the distribution of enlarged lymph nodes and the location of organ involvement, it can be divided into Unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD)
.
UCD only involves a single lymph node region, with a relatively high incidence and mild systemic symptoms.
The main treatment method is surgery, and the prognosis is good.
MCD involves multiple lymph node regions and has a relatively low incidence.
Cytopenia or even life-threatening organ dysfunction is associated with poor prognosis
.
Clinically, MCD can be further divided into HHV-8-related MCD, POEMS (polyperipheral neuropathy, organomegaly, endocrine abnormalities, M protein in serum, skin changes)-related MCD and idiopathic MCD (iMCD) according to the etiology.
)
.
iMCD is a general term for the types of MCD that are HHV-8-negative, HIV-negative and of unknown etiology, accounting for about 33-58% of MCD, and the average survival time is only 2.
57 years
.
The clinical manifestations of iMCD are diverse and can be further divided into iMCD-TAFRO (thrombocytopenia, severe edema, fever, myelofibrosis and organomegaly) and unspecified iMCD (iMCD-NOS) according to their characteristics
.
Yimaitong: At present, the etiology and pathogenesis of iMCD are still unclear.
Could you please introduce, what hypotheses are there for the pathogenesis of iMCD? What is the role of interleukin-6 (IL-6) in the pathogenesis of iMCD? Professor Wu Depei's previous research generally believed that iMCD lymph node enlargement is related to tumor cells that produce IL-6, and tumor cells can release a large amount of IL-6 to cause systemic inflammation and organ dysfunction
.
In recent years, with the deepening of research, a new view is that iMCD lymph node enlargement and corresponding pathological changes are reactive changes to the increase of IL-6 in cytokine storm
.
There are three major hypotheses about the causes of cytokine storm in iMCD, mainly including ① pathogen hypothesis: uncontrolled infection causes cytokine storm; ② autoimmunity/autoinflammation hypothesis: B cells or T cells mutate to produce autoantibodies or cause Auto-reaction, or germline gene mutation leads to auto-inflammation, which in turn causes cytokine storm; ③ Paraneoplastic syndrome hypothesis: excessive proliferation of cytokine-secreting monoclonal cells leads to cytokine storm
.
IL-6 is a pleiotropic agent that can be produced by a variety of cells, including mesothelial cells, monocytes, macrophages, lymphocytes, fibroblasts, endothelial cells, mesangial cells, and various tumor cells.
Sexual cytokines that play a central role in the pathophysiology of Castleman disease
.
Serum IL-6 levels are higher in patients with Castleman disease, and excess IL-6 leads to overgrowth of B lymphocytes, increased lymph node vascularity and inflammation, and can also lead to autoimmune phenomena
.
Studies have shown that the symptoms of patients with Castleman disease usually change with changes in serum IL-6 levels
.
Yi Mai Tong: Could you please talk about the IL-6 targeted drugs approved at home and abroad for the treatment of Castleman's disease? What's the difference? Professor Wu Depei currently has two drugs approved for the treatment of Castleman disease abroad: anti-IL-6 monoclonal antibody situximab (more than 40 countries in North America, EU, Canada, etc.
) and anti-IL-6 receptor (IL-6R) Monoclonal antibody tocilizumab (Japan)
.
In China, stuximab was recently approved for the treatment of HIV-negative, HHV-8-negative adult patients with multicenter Castleman disease
.
Stuximab is a human-mouse chimeric monoclonal antibody that was first approved in the United States in 2014 and has been approved in more than 40 countries and regions around the world.
List of Overseas New Drugs Urgently Needed in Clinical Practice
.
Stuximab and tocilizumab target different sites
.
The former binds to IL-6 with a higher affinity than IL-6 and IL-6R, and has a stronger antagonistic effect; while tocilizumab acts on IL-6R and has a lower affinity for IL-6R, which may be affected by in vivo IL-6R.
Competitive antagonism of IL-6
.
Yi Mai Tong: Could you please talk about how situximab is recommended in the domestic and international guidelines for Castleman disease? Professor Wu Depei clinically classified iMCD into non-severe and severe according to the iMCD disease severity stratification of Castleman Disease International Working Group (CDCN)
.
No matter for non-severe or severe iMCD, many authoritative guidelines consensus recommends seltuximab as the first-line treatment for iMCD
.
The 2018 edition of the International Evidence-Based Consensus Guidelines for iMCD recommends seltuximab as the first-line treatment for patients with non-severe iMCD (see Figure 1); and recommends stuximab combined with high-dose glucocorticoids as the first-line treatment for patients with severe iMCD
.
The 2021 edition of the Chinese Society of Clinical Oncology (CSCO) lymphoma guidelines lists stuximab as a class I recommendation for the treatment of iMCD
.
The 2021 edition of the National Comprehensive Cancer Network (NCCN) guidelines also recommends seltuximab as the first choice for iMCD patients
.
Figure 1 2018 International Evidence-Based Consensus Guidelines for the Treatment of iMCD It is gratifying that the Chinese expert consensus on diagnosis and treatment of Castleman disease (2021 edition) was officially released this year, which is of great significance to the diagnosis and treatment of Castleman disease in China
.
The consensus is based on evidence-based medical evidence including the only randomized double-blind controlled study in the current iMCD treatment field, and pointed out that for non-severe iMCD, stuximab ± prednisone is recommended as the first-line treatment for non-severe iMCD patients; For severe iMCD, stuximab combined with high-dose glucocorticoids is recommended first-line according to the patient's condition (see Figure 2)
.
Figure 2 Expert consensus on diagnosis and treatment of Castleman's disease in China (2021 version) MCD recommended treatment path Yimaitong: Recently, stuximab was approved by the NMPA, breaking the deadlock of no cure for Castleman's disease patients in China
.
Could you please introduce, what are the advantages of stuximab? What significance does this approval bring to the diagnosis and treatment of Castleman disease in my country? Prof.
Depei Wu has combined the current international clinical research on Castleman's disease and found that the comprehensive advantages of stuximab treatment are relatively significant
.
The results of a classic study published in Lancet in 2014 showed that the 18-week tumor and symptom sustained remission rate of iMCD patients after situximab treatment reached 34%, and the average C-reactive protein (CRP) decreased after 1 course of treatment.
to normal levels
.
In 2020, van Rhee F et al.
found that the 6-year disease control rate of iMCD patients treated with setuximab was as high as 97%, and the survival rate was 100%
.
The approval this time has brought a new dawn to China's Castleman disease patients to a certain extent, and it has also contributed to the treatment of rare diseases in China
.
Conclusion The launch of stuximab in China has filled the gap in the field of Castleman disease treatment to a certain extent and brought hope to Chinese Castleman disease patients
.
However, how to better apply situximab to the clinic and serve patients is inseparable from the concerted research of workers in related fields
.
The launch of stuximab is a good start, but there is still a long way to go in the treatment of Castleman's disease.
It is hoped that clinicians will actively accumulate clinical experience to help the treatment of Castleman's disease in China
.
Professor Wu Depei Chief Physician, Professor, Doctoral Supervisor Director of Hematology Department of the First Affiliated Hospital of Soochow University Executive Deputy Director of National Clinical Research Center for Hematological Diseases Deputy Director of Jiangsu Hematology Research Institute Deputy Director of Soochow University Clinical Medicine Research Institute of Soochow University Hematopoiesis Director of Stem Cell Transplantation Institute Member of the 13th National Committee of the Chinese People's Political Consultative Conference Chairman of the Chinese Medical Association Hematology Branch Standing Committee Member of the Chinese Medical Association Internal Medicine Branch Vice President of the Chinese Medical Doctor Association Hematologist Branch Click "read the original text", let's make progress together
