Bone marrow hematopoietic stem cell transplantation

Transplantation of hematopoietic stem cells (HSCT) of bone marrow, peripheral or umbilical cord blood is an effective and sometimes the only method of treating a number of dangerous pathologies of oncological, hematological, immunological profile. During the treatment, the patient receives healthy stem cells to replace those destroyed as a result of the disease or high doses of chemotherapy and/or radiation therapy.

Along with other traditional methods of treating oncohematological and immunological diseases, HSCT has been actively used to combat tumor conditions for over 40 years [ 1 ]. As transplantation methods and supportive therapy have developed, this procedure has become safer, and patient survival rates continue to improve.

This procedure shows positive results in patients with various types of oncohematological diseases and other pathologies associated with immune system dysfunction. Transplantation involves taking a certain number of stem cells that are normally present in the bone marrow and peripheral blood, filtering them, and transplanting them to the recipient.

Types of transplantation

Depending on who the stem cell donor is, there are different types of transplant:

1. Autologous. In this case, the patient himself acts as the donor of stem cells. Stem cells are prepared by multiple bone marrow punctures or through peripheral blood apheresis. The stem cells are then frozen under special conditions and stored until the patient completes a course of intensive treatment (high-dose chemotherapy, radiation therapy, etc.).
2. Allogeneic. The donor is another person. And depending on the family ties of the donor and recipient, as well as the degree of genetic compatibility, the following types of allogeneic transplants are distinguished:
3. A matched related donor (MRD) transplant is a transplant in which the recipient’s fully compatible sibling (brother or sister from the same parents) acts as the stem cell donor.
4. A matched unrelated donor (MUD) transplant is a transplant where the donor is a genetically compatible person who is not related by blood to the recipient.
5. A partially incompatible unrelated donor (MMUD) transplant is a transplant where the donor is not fully compatible with the recipient.
6. Haploidentical transplantation (haplo) is a type of related transplantation where the donor is a blood relative (parent or sibling, less commonly an uncle or aunt) who is partially compatible with the recipient.

Our center successfully performs all types of hematopoietic stem cell transplants.

Sources of stem cells (SC)

The source of stem cells can be:

1. peripheral blood,
2. umbilical cord blood,
3. bone marrow.

Stem cells from any of these sources can be used as a transplant. The choice of source is determined individually in each specific case and depends on the physical (age, weight) and clinical (diagnosis, toxicity, previous treatment) characteristics of the patient, as well as on the characteristics of the donor (weight, age, medical clearance, personal preferences, etc.).

Basic principles of donor selection

The stem cell donor can be the patient himself (autologous transplant) or another person (allogeneic stem cell transplant).

For successful HSCT, in case of using a transplant from a donor or a relative, it is extremely important to perform testing of the histocompatibility complex genes (HLA typing). For this, a blood test is performed, which shows how much the donor tissue type matches the patient’s tissue type. The more similar the HLA genes are in the donor and recipient, the higher the chance of successful engraftment of the bone marrow stem cell transplant and the success of the procedure. With low compatibility of the HLA genes, there is a high probability of complications, in which the donor cells attack the healthy cells of the patient. Full compatibility of the donor and recipient for the HLA genes is possible only in identical twins, so there are acceptable norms of differences that specialists are guided by when selecting a donor.

HLA typing is mandatory for the recipient and all potential donors. The following markers are assessed for match/mismatch: HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1. Each marker is present in two copies in the human body, so a donor that matches the recipient for 10 alleles out of 10 possible is considered compatible. A donor that matches the recipient for 8 or 9 alleles out of 10 is considered partially incompatible.

A person inherits half of their HLA proteins from their mother and half from their father, so the ideal donor is often a patient’s brother or sister from the same parents who inherited the same HLA markers, but only about 30% of patients have such a donor. At the same time, the parents themselves (in rare cases, half-siblings, as well as siblings of the parents) have a compatibility of 5 markers out of 10 with the recipient and are potential haplo-donors.

Where do we look for an unrelated donor?

For those patients who do not have a suitable compatible (10/10) related donor, there is the option to initiate a search for an unrelated donor in the following donor banks:

1. Central Registry of Hematopoietic Stem Cell Donors (Republic of Belarus)
2. Donor banks of the Russian Federation and the Republic of Kazakhstan
3. Donor Bank DKMS Registry
4. The largest international donor bank World Marrow Donor Association (WMDA)

For what diseases is it advisable to perform hematopoietic stem cell transplantation (HSCT)?

Allogeneic hematopoietic stem cell transplantation is performed in the following cases:

1. acute leukemia (myeloblastic, lymphoblastic, biphenotypic);
   chronic leukemia (myeloblastic, lymphoblastic);
2. anaplastic large cell lymphomas;
3. myelodysplastic syndrome;
4. congenital and acquired forms of aplastic anemia ;
5. congenital immune defects (Wiskott-Aldrich syndrome, severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), hemophagocytic lymphohistiocytosis, X-linked lymphoproliferative syndrome, Nijmegen syndrome, leukocyte adhesion deficiency (LAD), etc.).

Autologous hematopoietic stem cell transplantation has proven to be effective in treating diseases such as:

1. Neuroblastoma
2. Germ cell tumors (germinoma, seminoma, immature ovarian teratoma, yolk sac tumor, etc.)
3. CNS tumors (medulloblastoma, ependymoma, astrocytoma)
4. Lymphoma (Hodgkin’s lymphoma, non-Hodgkin’s lymphomas)
5. Nephroblastoma

How is hematopoietic stem cell transplantation (HSCT) performed?

A few days before the transplant, the patient undergoes immunosuppression. This procedure is aimed at suppressing the recipient’s own bone marrow and preparing it for colonization with donor cells.

Stem cells are prepared in advance, filtered, and then introduced into the recipient’s body under the constant supervision of transplant doctors.

However, it should be understood that the actual procedure of infusing stem cells into the recipient is only the first stage of a long and dangerous journey. Engraftment of the transplant, restoration of hematological parameters and possible side effects are the main factors of success or failure in HSCT.

Stages of stem cell transplantation

1. Determining the indications for transplantation. In each individual case, the indications for transplantation are determined at a medical consultation. Making a positive decision regarding the need for transplantation starts the further process: HLA typing of the patient and selection of the best possible donor.
2. The donor is selected based on priority. Siblings are considered first, if any. If they are absent, the donor search coordinator initiates a search for a suitable donor in stem cell banks (first in the Republic of Belarus, and then beyond).

Unfortunately, finding and organizing the collection of stem cells from an unrelated donor can take a long time, or a compatible unrelated donor may not be found. In this case, or if an urgent transplant is needed, it is possible to involve a haploidentical donor due to his availability.

3. Preparation. This stage is carried out by the patient’s attending physician. If HSCT is a necessary procedure, the attending physician performs a full and comprehensive examination of the patient according to the approved protocol in order to identify possible contraindications, assess the general condition and readiness for the procedure, and reduce the risks of side effects. At this stage, the patient signs consent for the operation.
4. Preparatory immunosuppressive treatment (conditioning). Immediately before the HSCT procedure, the patient undergoes a course of treatment aimed at suppressing the existing immune system. Chemotherapy or combined chemoradiation therapy is administered as indicated.

This is done with the aim of:

• elimination of mutated pathological cells that may remain after completion of the main treatment;
• freeing up space for new donor cells;
• weakening the immune system to reduce the risk of rejection of donor cells.

Depending on the underlying diagnosis and treatment protocol, as well as the individual characteristics of the patient, two types of conditioning can be used:

• myeloablative (more intense),
• non-myeloablative (less intense).

5. Introduction of the transplant

When the time for the surgery is set, the patient is injected with donor stem cells through a tunneled catheter. The stem cells are transported from a syringe or transfusion bag, similar to a blood transfusion procedure. All manipulations are performed in a hospital room under sterile conditions. Sedation can be performed if necessary.

6. Engraftment stage

Engraftment begins immediately after the stem cells enter the recipient’s body and travel through the bloodstream to the bone marrow, where new cells begin to divide and differentiate.

On average, the engraftment process takes 14-21 days, which is determined by the source of stem cells and the patient’s condition, his previous treatment. At this stage, additional injections of colony-stimulating agents are administered to stimulate the process. In addition, a blood transfusion may be required.

Possible side effects

Transplantation is a serious procedure, after which there is a high probability of developing certain complications and side effects.

From the beginning of conditioning until the moment of engraftment, the patient experiences suppression of the main functions of the bone marrow (aplasia), which is why there is a high risk of developing infectious processes of various origins (viral, fungal, bacterial). This period can last 3-4 weeks and is dangerous due to the development of serious infectious diseases [ 3 ].

Therefore, prevention of severe infections is one of the main tasks for successful HSCT. Activities include:

• placing the patient in a ward with increased sterility and carrying out mandatory sanitary measures – sanitization, sterilization, thorough hygiene;
• destruction of pathogenic microflora with antibiotics and antifungal agents;
• If necessary, transfusion of red blood cells and platelet mass is performed.

Complications caused by the graft-versus-host reaction (GVHD) may also develop. Acute (up to +100 days after HSCT) or chronic (after +100 days after HSCT) damage to the skin, mucous membrane, gastrointestinal tract, liver, eyes, and musculoskeletal system may lead to severe complications and require long-term treatment involving a multidisciplinary team of specialists.

Hematopoietic stem cell transplantation at the Center for Children’s Oncology, Hematology and Immunology

The Center for Children’s Oncology, Hematology and Immunology has a well-deserved reputation as a leader in the field of hematopoietic stem cell transplantation for children and young adults under 30 in Belarus. Not only does it meet the country’s needs for this type of high-tech medical care, but it also exports the service abroad.

From 1998 to 2023, the Center performed more than 1,150 transplants, of which more than 50% were allogeneic.

Our results

Survival rates after transplantation:

• More than 70% – in acute lymphoblastic leukemia
• More than 95% – with primary immunodeficiencies
• More than 90% – with acquired aplastic anemia

Price

The Center performs all types of hematopoietic stem cell transplants (autologous, allogeneic, haplo and co-transplantation of mesenchymal stem cells).

1. Cost of the examination
	quantity	price, US dollars	total, US dollars
Consultation	2	50	100
Doctor’s appointment (initial), including specialists	4	30	120
Doctor’s appointment (repeat)	3	17	51
Laboratory diagnostic tests			4665
Consumables			64
total			5000
2. Cost of autologous hematopoietic stem cell transplantation (including pre-transplantation period)
	number of days	price, US dollars	total, US dollars
Staying in treatment
in the transplant department	20	200	4,000
in the inpatient department	20	100	2,000
in the day care department	20	25	500
Laboratory diagnostic tests			1,500
Medicines			11 600
Consumables			400
total			20,000
3. Cost of related hematopoietic stem cell transplantation (including pre-transplantation period)
	number of days	price, US dollars	total, US dollars
Staying in treatment
in the bone marrow transplant department	40	200	8,000
in the inpatient department	30	100	3,000
in the day care department	50	25	1 250
Laboratory diagnostic tests			22 700
Medicines			32 450
Consumables			2 600
total			70,000
4. Cost of performing unrelated hematopoietic stem cell transplantation (including pre-transplantation period)
	number of days	price, US dollars	total, US dollars
Staying in treatment
in the transplant department	40	200	8,000
in the inpatient department	30	100	3,000
in the day care department	50	25	1 250
Laboratory diagnostic tests			22 700
Medicines			32 450
Consumables			2 600
Transplant search and delivery			20,000
total			90,000

* If necessary, further treatment and observation after the transplantation at the Center for more than four months requires additional payment. The approximate cost of this treatment is from 55,000.0 US dollars.

The cost of treatment is not fixed and may change during the course of treatment. The cost is determined by the number of days spent in hospital, the scope of the necessary examination, the medications used to prevent and treat complications, and the patient’s weight.

In case of reduction of the cost of treatment, the Center guarantees a refund.

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Sources of information

1. Carreras E., Dufour C., Mohty M. The 2019 revised edition of the EBMT-ESH Handbook on Haemopoietic Stem Cell Transplantation. https://doi.org/10.1007/978-3-030-02278-5_1
2. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/bone-marrow-transplantation
3. Protocols for transplantation of allogeneic hematopoietic stem cells. Edited by Savchenko V.G. Moscow. 2020. –P. 319