Source：National Local Laboratory for Adult Stem Cells

PART 1 What is hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation is to completely destroy the patient's hematopoietic and immune system through high-dose radiotherapy and chemotherapy, and then input normal hematopoietic stem cells to rebuild the patient's hematopoietic function and immune function, to achieve the purpose of treating certain diseases.

PART 2 Hematopoietic stem cell transplantation is suitable for diseases

01 Neoplastic disease

a)Hematological malignancies such as acute leukemia, chronic leukemia, malignant lymphoma, myelodysplastic syndrome, multiple myeloma, etc.

b)Certain solid tumors: small cell lung cancer, breast cancer, testicular cancer, neuroblastoma, ovarian cancer, melanoma, etc.

02 Non-neoplastic disease

a)Blood diseases such as aplastic anemia, some congenital hemolytic anemia such as Marine anemia;

b)Certain hereditary diseases such as hereditary bone marrow failure syndrome, hereditary immunodeficiency diseases, hereditary metabolic diseases;

c)Autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis, etc.

PART 3 Hematopoietic stem cell transplantation classification

01 Autotransplantation

Autologous transplantation using one's own stem cells is called autologous transplantation, also known as autologous hematopoietic stem cell salvage therapy.

First, the patient's own normal stem cells are extracted and stored, and then injected back into the patient after the patient receives a large dose of radiotherapy and chemotherapy to obtain hematopoietic reconstruction. The purpose is to increase the dose of radiotherapy and chemotherapy and enhance the efficacy.

Autologous transplantation is suitable for patients whose bone marrow has not been affected by the disease or has returned to normal after treatment. If the own bone marrow is violated, then the extracted bone marrow needs to be purified in vitro to remove cancer cells, and after the release and chemotherapy, these "clean" bone marrow will be imported back into the patient.

Different bone marrow transplant centers use different methods to perform extracorporeal purification.

Advantages of autologous transplantation:

Fewer complications, less transplant-related mortality, and lower costs.

Disadvantages of autologous transplantation:

It is easy to relapse, mainly applicable to lymphoma, myeloma, some moderate and low critical leukemia, solid tumor and autoimmune diseases.

02 Allograft

Allogeneic transplantation is a transplant using stem cells from another person.

If the donor is related to the patient, it is called a relative donor transplant; If the bone marrow is provided by another non-relative, it is called an unrelated transplant.

Allogeneic transplantation has a difference in the antigen of the donor recipient compared with autologous transplantation, so that the donor lymphocyte can attack the patient's own tissues and organs as a foreign body, resulting in graft-versus-host disease (GVHD).

All allogeneic transplants require human leukocyte antigen (HLA) testing, and the higher the degree of compatibility of the donor and recipient at the major HLA sites, the lower the chance of GVHD.

Allogeneic transplantation, due to the immune attack of the donor lymphocytes on the recipient tumor cells (also known as graft-versus-tumor effect), has the advantage of low recurrence rate and is the only means to cure some diseases.

However, the disadvantages are the high probability of GVHD and infection, the high transplant-related mortality, and the high cost.

03 Isotransplantation

The donor is an identical twin brother or sister with the exact same genotype as the patient. As with autologous transplantation, patients generally do not develop graft-versus-host disease.

Because the grafts are free of tumor cell contamination, the recurrence rate is lower than that of autologous transplantation, and there are fewer complications, less transplant-related mortality, and lower costs.

PART 4 Hematopoietic stem cell source

01 Bone marrow stem cell

Bone marrow is rich in hematopoietic stem cells, which can be obtained from multiple parts, and the corresponding transplantation is called bone marrow transplantation.

02Peripheral blood hematopoietic stem cell

The number of hematopoietic stem cells in normal peripheral blood is very small, which can not meet the needs of transplantation. Hematopoietic stem cells in bone marrow are mobilized into peripheral blood by injection of mobilizers, and blood components rich in hematopoietic stem cells can be collected by the machine for transplantation, which is called peripheral blood hematopoietic stem cell transplantation.

03 Cord blood stem cells

Neonatal cord blood is also rich in hematopoietic stem cells, which can also be used for hematopoietic stem cell transplantation. However, due to the small number of hematopoietic stem cells it contains, cord blood transplantation has been mainly limited to children.

In recent years, with the maturity of double cord blood transplantation technology, cord blood transplantation can also be used in adults. Collecting cord blood has no effect on the fetus or the mother.

PART 5 Classification of transplant donors

01 Full sib donor

A fully compatible sibling is the preferred source of allogeneic transplants, but the probability of two siblings being identical is only 25%.

02 A non-blood donor

Volunteers from a pool of non-blood donors.

China has established the hematopoietic stem cell Donor Database (CMDP). By the end of February 2024, China's bone marrow bank had more than 3.45 million registered donors, providing non-blood stem cells to more than 17,000 patients. It is followed by Taiwan Tzu Chi Bone Marrow Bank with more than 460,000 registered donors.

Because the probability of finding an HLA-matched non-blood donor varies according to bone marrow pool size, nationality and recipient HLA genotype, and the search for non-blood related volunteer donors takes a certain period, about 3-4 months on average, and some patients' conditions do not allow waiting, so it is only applicable to some patients.

03 Non-blood cord blood

It has the advantages of fast query, no waiting, and low HLA requirements.

The advantages of cord blood transplantation are the low incidence of GVHD, but the high implantation failure rate, slow implantation, high incidence of infection, and the inability to perform donor lymphocyte infusion after transplantation limit its use in patients with high risk of refractory recurrence.

04 Related HLA haploid match

Semi-identical transplants or haploid transplants are those in which the matches between relatives are only partially identical and the same site is located in one chromatid.

Almost all patients had at least one HLA haploid compatible relative donor, including parents, children, siblings, siblings of parents, and first Cousins.

The advantage of identical haploid transplantation is that there is a wide range of donor sources and no need to wait. The disadvantage is that due to the different HLA matching, the complications such as GVHD and infection after transplantation are higher, and the cost is higher than that of fully compatible transplantation. It is used for patients who must transplant but have no fully compatible donor or the primary disease cannot wait.

PART 6 Adaptation to disease and optimal timing of stem cell transplantation

01 Acute leukemia

Complete remission can be achieved through induction chemotherapy, and the first complete remission period is the best time for transplantation. After remission, direct transplantation or consolidation chemotherapy can be selected according to the condition, and the residual tumor cells in the body can be reduced after 2-4 courses of transplantation. Allogeneic transplantation is usually chosen.

02 Chronic myeloid leukemia

Due to the application of tyrosine kinase inhibitors, there is generally no need for transplantation in the chronic stage. If the disease accelerates or changes rapidly during the treatment process, it is best to control the disease again through drug-resistant gene mutation detection, select sensitive drugs to transplant after the chronic stage, and generally choose allogeneic transplantation.

03 Myelodysplastic syndrome

International prognostic index score of low-risk patients generally do not need transplantation, but transfusion-dependent patients, if there is a compatible donor, allogeneic transplantation is feasible; Patients with a high risk of international prognostic index score should undergo allogeneic transplantation as soon as possible as long as a suitable donor is available.

Generally, there is no need to receive chemotherapy before transplantation. Patients who convert to leukemia can be transplanted with demethylated drugs combined with low-dose chemotherapy to reduce tumor load.

04 Severe aplastic anemia

If the age is younger than 50 years, if there is a siB compatible donor, it is appropriate to perform allogeneic transplantation as soon as possible (50-60 years old, according to the patient's physical condition, organ function, comorbidities and patient's willingness to choose).

If no siB compatible donor is available, alternative donor transplantation such as non-consiglitic transplantation, cord blood transplantation, or haploid identical transplantation may be considered after immunosuppressive therapy has failed.

If the patient is predicted to have poor immunosuppressive effect, or the disease is too serious to wait until the onset time (such as young age, very severe type, combined with serious infection, and blood product infusion is ineffective), immunosuppressive therapy can not be directly performed by non-related or haploid identical transplantation.

05 Malignant lymphoma

The stage is 3-4, the prognosis score is high risk, high invasive type, can be considered autologous transplantation, generally after 3-5 courses of chemotherapy.

Patients with refractory recurrence may be treated with salvage autologous transplantation. Some highly aggressive types such as advanced NK/T cell type, some Burkitt lymphoma, lymphoblastic lymphoma, or high proliferative activity, or detection of some poor prognostic gene mutations such as MYC,BCL2/BCL6, or combined hemophagocytic syndrome, may be considered allogeneic transplantation.

06 Multiple myeloma

Generally, autologous transplantation is selected after chemotherapy achieves complete remission or near remission, and salvage autologous transplantation can be performed in refractory recurrent patients. Allogeneic transplantation may also be considered in young patients with very high risk or refractory recurrence.

07 Certain solid tumors

Such as lung cancer, breast cancer, testicular cancer, etc., generally require chemotherapy to achieve complete remission or near remission after transplantation, usually autologous transplantation.

08 Autoimmune disease

Some types, such as systemic lupus erythematosus, multiple sclerosis, mixed connective tissue disease, can be considered for autologous transplantation if conventional drugs are not well controlled.

09 Some hereditary diseases

Such as hereditary bone marrow failure syndrome, hereditary immunodeficiency disease, allogeneic transplantation as soon as possible after diagnosis.

PART 7 Hematopoietic stem cell transplantation costs

Autotransplantation	The cost of the first hospitalization is generally 50,000 to 100,000 yuan.
Full sib allogeneic transplantation	The cost of the first hospitalization is usually 100,000 to 200,000 yuan.
Non-consanguineous allogeneic transplantation	The cost of the first hospitalization is generally 200,000 to 300,000 yuan.
Cord blood transplant	The cost of the first hospitalization is generally 200,000 to 300,000 yuan.
Haploid homotransplantation	The cost of the first hospitalization is generally 200,000 to 300,000 yuan.

The above costs refer to the occurrence of complications such as severe infection and GVHD in the absence of these complications, which will increase the cost of transplantation, depending on the severity of the complications.

PART 8 Success rate of hematopoietic stem cell transplantation

Early implantation rate:

The implantation rate of general myeloablative transplantation was 97%-99%, and the implantation rate of non-myeloablative transplantation was about 90%.

Long-term survival rate:

Refers to completely free from the primary disease, and no life-threatening complications, the general assessment time limit is 5 years, that is, the five-year survival rate in medicine.

The long-term survival rate after transplantation is affected by a variety of factors, such as the degree of primary disease risk, remission status (remission period, recurrence period), pre-transplantation physical condition, donor and recipient matching, donor and recipient age and other factors.

In the early stage of leukemia, the long-term survival rate of total compatible transplantation is about 70-80%, while in the middle and late stages of the disease, the survival rate is greatly reduced, and if the transplant is advanced, the long-term survival rate is only 10-20%. Due to the higher transplant-related mortality, the long-term survival rate of incomplete transplantation is 10-20% lower than that of total transplantation.

For benign diseases such as aplastic anemia and early MDS, the long-term survival rate is 10-20% higher than that of leukemia due to the absence of primary disease relapse factors.

Therefore, in order to improve the survival rate, it is crucial to select the most appropriate time for transplantation and the best donor. To decide whether to transplant according to the risk at the early stage of the disease, perform HLA matching as soon as possible, transplant as soon as possible after disease remission for patients with fully compatible sibs, and apply for non-related donor enquiry at the China Bone Marrow Bank or Taiwan Bone Marrow Bank as soon as possible for patients without fully compatible sibs. Avoid delaying the optimal transplant time while waiting for a donor.

In high-risk patients, haploid identical donors can be selected even if there is no sib compatible donor or well-matched non-blood donor.

PART 9 Hematopoietic stem cell transplantation process

01 There are roughly three stages

Pretreatment:

Before the infusion of stem cells, the patient receives high-dose chemotherapy or chemotherapy combined with radiotherapy to kill the residual malignant cells in the body as much as possible, prepare "space" for the hematopoietic stem cells of the donor, and inhibit the immune system of both the donor and the patient to avoid rejection and reduce graft-versus-host disease.

Hematopoietic stem cell infusion:

Transfusion of donor hematopoietic stem cells.

The infusion is given intravenously from bone marrow, peripheral blood stem cells, or cord blood stem cells.

Management of post-transplant complications:

Transplantation of donor hematopoietic stem cells in patients and treatment of organ toxicity and infection, graft-versus-host disease, recurrence and other complications.

02 Treatment cycle

1. Pre-treatment is generally 5-10 days, and the program may be different depending on the disease.

2. Donor hematopoietic stem cells are transfused for 1-2 days, and cell counts vary depending on the transplantation method.

3. Donor cells are generally viable 2 to 3 weeks after cell infusion, after which the patient's condition is stable and can be discharged from the warehouse.

4. According to the different conditions of patients with different transplantation methods, most of them are hospitalized for observation for 1-2 months after discharge.

5. The patient was discharged after his condition was stable, and the outpatient clinic was followed up regularly after discharge.

6. Generally, most patients can return to normal life after 1-2 years of transplantation.