PNH Famous Doctors Lecture Session 6 Professor Guangsheng He: PNH Treatment-Transplantation

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell gene mutation caused by erythrocyte membrane defects.
The root cause of the disease is to restore normal hematopoietic tissue function and eliminate abnormal hematopoietic stem/progenitor cells.
Allogeneic hematopoietic stem cell transplantation is the only way to cure the disease
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In this issue of "PNH Famous Doctors Lecture", Yimaitong invited Professor He Guangsheng from Jiangsu Provincial People's Hospital to share on the status and application of allogeneic hematopoietic stem cell transplantation in PNH! Professor Feng He Guangsheng, Chief Physician, Associate Professor, Master's Tutor, Deputy Director, Department of Hematology, Jiangsu Provincial People's Hospital, Chief Expert, Department of Hematology, Second Affiliated Hospital of Xuzhou Medical University Member of the Standing Committee of the Treatment Professional Committee Chairman of the Anemia Branch of the Jiangsu Research Hospital Association Chief Expert of the Department of Hematology, Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine.
The status of allogeneic hematopoietic stem cell transplantation in PNH treatment.
For erythrocyte membrane defects, mutations in hematopoietic stem cell genes will first cause excessive activation of the complement system in the patient’s body, manifested by massive destruction of red blood cells in blood vessels, intravascular hemolysis, and then a series of clinical symptoms.
Sleeping hemoglobinuria is PNH The most typical clinical symptoms, therefore, the disease is named paroxysmal nocturnal hemoglobinuria
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Since the disease is a clonal disease caused by genetic mutations, the only way to cure the disease is allogeneic hematopoietic stem cell transplantation, and other treatment measures can only delay or control the onset and development of the disease
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However, the implementation of allogeneic hematopoietic stem cell transplantation also has a series of challenges
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The first is the source of the donor: allogeneic hematopoietic stem cell transplantation requires the sex, age of the donor, and the relationship with the patient
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From the perspective of kinship with the patient, sibling donors are the most suitable.
However, due to China’s previous one-child policy, it is difficult for PNH patients to obtain donors who are relatively young and have no other contraindications for transplantation, even if they have siblings.
The probability that the HLA match is only 25%, which also limits the application of allogeneic hematopoietic stem cell transplantation in PNH patients
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Moreover, alternative donors still have certain challenges and risks in transplantation technology
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Alternative donors have many sources, such as blood-related haplotype allogeneic hematopoietic stem cell transplantation, unrelated allogeneic hematopoietic stem cell bank donors and cord blood stem cell bank, but the challenges and risks brought by transplantation technology are objective Exist
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Before transplantation, it is necessary to choose intravenous marlilan or whole body radiotherapy (TBI) as the pretreatment plan.
However, female patients who use marlilan may have ovarian failure and risk of menopausal-like manifestations.
For female patients with marriage and childbirth requirements, the use of marlilan is very important.
Difficult
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While TBI may greatly increase the risk of solid tumors, the challenge of using TBI in younger male patients is also objective
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 Secondly, the patients who need allogeneic hematopoietic stem cell transplantation are mostly severely ill or refractory patients, and this part has often received long-term large-scale red blood cell transfusion in the past.
The source of red blood cells in the body is very complex, rich in different types of white blood cells and HLA antigens.
The risk of HLA sensitization is very high, which will lead to failure or poor implantation of the patient's hematopoietic stem cells, which directly manifests as the difficulty or delay of the patient's hematopoietic reconstruction after transplantation, which will lead to a series of complications
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Moreover, HLA antigen sensitization can also lead to graft-versus-host disease (GVHD), in which acute GVHD will occur within 100 days after transplantation, and chronic GVHD will occur 100 days after transplantation
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For patients, both acute and chronic GVHD are huge challenges, which not only require a series of drug treatments, but also lead to prolonged hospitalization or frequent and repeated hospitalizations, as well as a heavy economic burden and subsequent recovery of organ function Difficult challenge
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 In addition, due to repeated blood transfusions, iron overload is also a common complication associated with PNH transplantation
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Iron is the most important trace element for hematopoiesis.
80% of the iron in the human body is stored in red blood cells
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Anemia patients need to absorb a large amount of iron, but the excretion of iron is limited
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Therefore, if the patient has severe anemia and has undergone a large number of red blood cell transfusions, the iron in the body is overloaded.
This iron will be deposited in some substantial organs such as the liver and heart, as well as important endocrines such as the pituitary gland, thyroid, and pancreas.
Of the glands, after transplantation, will cause iron overload-related transplant complications, which will increase the risk of death
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For example, hepatic vein occlusive syndrome, a complication with a very high mortality rate after transplantation, is fierce and has a very high mortality rate.
The occurrence of this disease is closely related to the accumulation of iron overload in the liver, which leads to liver fibrosis.
Related
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Therefore, the challenge of transplantation for severely ill patients with PNH is huge
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Allogeneic hematopoietic stem cell transplantation is suitable for PNH patient types.
Allogeneic hematopoietic stem cell transplantation is suitable for PNH patients: ①PNH with severe hematopoietic failure; ②PNH patients have repeated severe or life-threatening thrombotic events; ③Frequent severe attacks, Patients with refractory PNH who need a large number of red blood cell transfusions ④PNH patients who have relapsed or are refractory after intensive immunotherapy
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These patients can be treated with allogeneic hematopoietic stem cell transplantation
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The impact of C5 monoclonal antibody listing on the status of transplantation PNH is currently listed as a rare disease in China.
The state has provided a green channel for PNH projects for accelerated approval.
C5 monoclonal antibody is an orphan drug of PNH, and its marketing can be approved by green channel
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The listing of C5 monoclonal antibody may change the status of transplantation
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C5 monoclonal antibody is effective in the treatment of PNH patients with repeated severe or life-threatening thrombotic events and PNH patients with repeated hemolytic episodes.
After the C5 monoclonal antibody is marketed, these two types of patients can be exempted from allogeneic hematopoietic stem cell transplantation
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 Since complement is an important part of the human immune system, whether C5 monoclonal antibody treatment will affect allogeneic hematopoietic stem cell transplantation is still unknown
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In 2018, it was reported in the literature that 8 cases of PNH patients were successfully treated with C5 monoclonal antibody for bridging allogeneic hematopoietic stem cell transplantation
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The risk of allogeneic hematopoietic stem cell transplantation for PNH patients is related to blood transfusion and iron overload.
The use of C5 monoclonal antibody treatment in PNH patients can control excessive complement activation, reduce hemolysis, improve anemia, greatly reduce red blood cell transfusion, and the iron utilization and circulation in the body tend to Normally, the functions of the patient's heart, lungs, kidneys and other important organs can be significantly improved
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The tolerance of patients undergoing allogeneic hematopoietic stem cell transplantation after the improvement of organ function will be significantly improved, the risk of transplantation-related complications will be greatly reduced, and the survival rate will also be improved
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Therefore, bridging allogeneic hematopoietic stem cell transplantation after treatment with C5 monoclonal antibody may be a treatment option for severely ill patients with refractory disease
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About PNH paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell gene mutation caused by erythrocyte membrane defects.
The 10-year survival rate of domestic patients is about 70%
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The clinical manifestations are mainly intravascular hemolytic anemia, which may be accompanied by symptoms such as thrombosis, renal insufficiency, and pulmonary hypertension
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Typical patients have characteristic intermittent nocturnal hemoglobinuria
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There are more male patients than females in China, and the peak age of onset is 20-40 years old
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The patient suffers from pain and suffering for a long time, and the quality of life is low
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Many patients are in the golden age of their lives.
As the backbone of their families, they have lost their labor force due to illness, causing a great social burden
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Reference materials: 1.
Rare disease diagnosis and treatment guidelines (2019 edition) 2.
Journal of Hematology & Oncology (2018) 11:33.
PNH diagnosis and treatment Chinese expert consensus.
The small test RECOMMEND recommended reading 1.
PNH lecture hall 1 Issue | Professor Fu Rong: The pathogenesis and treatment mechanism of PNH 2.
PNH Famous Doctors Lecture Phase 2 | Professor Zhang Fengkui: PNH Status and Diagnosis Essentials 3.
PNH Famous Doctors Lecture Phase 3 | Professor Zhang Fengkui: PNH Treatment and Follow-up 4.
PNH Famous Doctors Lecture 4th | Professor Han Bing: PNH Treatment-Complications 5.
PNH Famous Doctors Lecture 5 | Professor Han Bing: PNH Treatment-Complications "Read the original text", we make progress together