Bone Marrow Transplantation and Cellular Therapy

What is bone marrow transplantation?

Bone marrow transplantation is the replacement of a patient’s damaged or destroyed bone marrow with new bone marrow cells. Bone marrow transplantation can be a lifesaving method in acute leukemias and lymphomas, which are resistant to standard chemotherapy.

Types of transplantation

Stem cells may be collected from a person’s own body or that of another person. This other person is called a donor.

Autologous transplantation is the procedure of using the person’s own stem cells. This method of transplantation is mainly used in multiple myeloma and lymphoma patients.

Fully matched allogeneic transplantation is the procedure of using another person’s fully compatible stem cells. This is preferably a fully matched sibling of a patient.

Matched unrelated donor transplantation is performed for patients who do not have a fully matched sibling. A donor is found by searching national and international bone marrow banks.

Haploidentical transplantation is performed for patients who do not have a fully matched sibling and are in urgent need of transplantation. The donor is a half-matched sibling, parent, or child of the patient. This is a relatively new method and can be as effective as matched unrelated donor transplantation in experienced centers.

How is the donor determined in matched unrelated donor transplantation? 

• If the patient does not have a related donor, national and then international (DKMS and BMDW) databases are searched for an unrelated donor. A 10-parameter high-resolution HLA typing test will be performed to check donor registries.
• Once the patient’s HLA type is known, a preliminary search can be performed. The preliminary search is a computerized search designed to identify potential bone marrow donors that have similar HLA antigens.
• If the preliminary search is successful in identifying potential donors, a formal search is initiated. During this process, potential donors are contacted by the bank, and blood samples are obtained to confirm HLA typing and to perform other screening tests. These additional blood tests are specialized and designed to determine which donor is the best possible match.
• An unrelated donor search is a complex and time-consuming process. On average, it takes up to three months to complete the search process. Therefore, it is imperative to begin the unrelated search process as soon as possible.
• Once an adequate number of stem cells have been collected from the donor, they will be sent to Acıbadem Transplant Center for the transplant procedure.

What is haploidentical transplantation?

Haploidentical stem cell transplantation is a very special method of transplantation that is currently performed at only a few centers worldwide. This method is likely to eliminate the problem of finding a donor completely and is therefore considered the transplantation method of the future. A 10/10 tissue match is not considered essential in haploidentical transplantation, and the semi-compatible sibling, parent, or child of the patient can be a donor, even if there is only half compatibility.

Which diseases is bone marrow transplantation used for?

Bone marrow transplantation is performed for individuals who have diseases affecting the bone marrow, including leukemia, myelodysplastic syndrome, other hematological malignancies (such as lymphoma and multiple myeloma), and aplastic anemia, in which the bone marrow cannot provide adequate blood-forming cells. It can also be used in numerous chemotherapy-unresponsive cancers, such as testicular cancer, neuroblastoma, and medulloblastoma, and congenital disorders, such as thalassemia, sickle cell disease, porphyrias, and severe immunodeficiency disorders.

How long does the healing process take after transplantation?

High-dose chemotherapy leads to nausea, diarrhea, fever, hair loss, and the need for blood and platelet transfusion. Within two weeks after transplantation, the new cells find their places and start producing more cells. The patient’s general condition improves with elevating blood cell levels, and they reach a point where they can be discharged. From that point on, the patient returns for follow-up visits at regular intervals.

How long do follow-up visits continue?

The follow-up period after transplantation at Acıbadem Hospital ranges between three months and one year, depending on the progress of the patient, who is then followed up in their home country. Within the first year, the patient’s immune system needs to be protected, as it is affected by the therapy. Patients are advised to avoid crowded environments because even common upper respiratory tract infections may require inpatient treatment. Therefore, patients are advised to reorganize their lives. Provided that these warnings are not ignored, most patients can return to work within 3–6 months. Additionally, patients are advised to eat cooked meals and peeled fruits and vegetables for the first few months.

Does bone marrow transplantation affect fertility?

In some cases, fertility may be affected due to chemotherapy. Families who are planning to have children are sometimes able to do so using in vitro fertilization methods. If there is time before initiating treatment, freezing sperm or ova might be an option.

How exactly is the allogenic transplantation procedure performed?

1. In all types of allogeneic transplantation, both the patient and donor are analyzed via extensive pre-transplant tests, including routine blood, cardiological, respiratory, and dental tests. HLA tests are repeated to check compatibility.
2. In haploidentical transplantation, tests can predict whether donor cells have a high chance of rejection by the patient. If these tests are positive, then a new donor is requested.
3. These tests usually take 4–5 days, and if the donor is suitable, mobilization of stem cells from the donor is commenced. When the donor arrives at the hospital, a catheter is inserted into each arm, and stem cell collection is performed using an apheresis machine until enough cells are obtained for the patient. This usually takes about two days.
4. Once an adequate number of stem cells have been collected from the donor, it is time to start the transplant procedure. The donor may then return to their home country. The duration of the stay for the donor is approximately 10 days.
5. The patient is admitted to the hospital, and a central catheter is inserted into a neck vein. This catheter is used throughout the transplant procedure to provide chemotherapy and other medications, such as antibiotics, allow blood and platelet transfusion, and perform blood tests.
6. The duration of chemotherapy for full HLA-matched allogeneic transplants is six days, for matched unrelated donor transplants is seven days, and for haploidentical transplantation is nine days. Following a day of rest, the donor stem cells are infused through the catheter in the neck in a similar manner to transfusing blood.
7. Following chemotherapy and during the latter parts of the transplant, the patient usually has chemotherapy-induced loss of appetite and diarrhea. Therefore, there is a need for blood and platelet transfusion. Pyrexia is frequent and is treated with antibiotics administered through the catheter in the neck.
8. Stem cells start to engraft approximately 10 days after the transplant. The patient’s symptoms (loss of appetite, diarrhea, etc.) start to improve at this stage. However, the patient will only be ready to leave the hospital after another 5–7 days, as it is still necessary to stabilize blood counts and electrolytes and establish adequate oral feeding. Hence, the total duration of the hospital stay is approximately one month.
9. Once the patient is clinically stable, they are discharged from the hospital and looked after in approved apartment hotels where they can stay with their families. Transport is provided for clinic controls and follow-up blood tests. A translator is always present for both in-patient and out-patient purposes.
10. Bone marrow analysis is usually performed one month after the transplant to make sure that there is no disease and check that the cells indeed belong to the donor.
11. When the patient is determined to be in stable condition, they are transferred to their home country. The estimated time from the day of admission to the return date is approximately two to three months, but this may change if there are problems, such as ongoing infections or slow rising blood counts.
12. If there are complications such as infections that do not respond to standard treatments during their stay in their home country, the patient may return to Acıbadem for further care.

Why Acıbadem Hospital?

We provide services in a sterilized environment that conforms to international standards. Interdisciplinary work is important in bone marrow centers. When necessary, support is provided by all relevant branches, such as the intensive care unit, general surgery, cardiology, nephrology, and ear-nose-throat. Transplanted stem cells are prepared in our licensed GMP laboratory, and all cells are analyzed for vitality, count, and activity prior to the transplantation procedure.

• At Acibadem Hospital, we perform haploidentical transplants by alpha/beta T cell depletion to reduce the lethal complication of graft-versus-host disease and, hence, reduce patient loss as a result of this complication.
• CD19-positive cells are also depleted to avoid post-transplant lethal Epstein–Barr virus (EBV) infection. This also avoids EBV-related lethal lymphoproliferative disease.
• Mesenchymal stem cell support, which helps to reduce graft-versus-host disease, aid engraftment, and speed recovery of immune function, is provided for all allogeneic transplants, including full-matched, matched unrelated, and haploidentical transplantation.
• CD45Ra-depleted donor T cells are routinely infused into all haploidentical transplantation patients in order to boost antiviral immunity.
• Virus-specific T cells are routinely provided for resistant cytomegalovirus, EBV, BK virus, adenovirus, and herpes simplex virus activation in the patient. This procedure can be lifesaving at times.
• At Acıbadem Hospital, we utilize the latest transplant technologies, and with the aid of an experienced clinical transplant team, we provide patients with the best chance of survival.
• At Acıbadem Hospital, we present economical transplant packages to establishments that are highly competitive when compared with Western Europe and the USA.

CAR T-Cell Therapy at Acibadem Turkiye

CAR T-cell therapy is a new type of cancer treatment using immune cells to attack tumors. Acibadem is first in Turkiye and the region to apply the new treatment.

What is CAR T-Cell Therapy?

CAR T-cell treatment is a form of immunotherapy that modifies the targeting mechanism of the immune system to fight cancer. The therapy is customized for each patient, using T cells, the major component of our immune system.

How does CAR T-Cell Therapy Work?

In CAR T cell immunotherapy, T-cells are derived from the body and genetically engineered in laboratory settings to produce specific chimeric antigen receptors (CARs). When modified T-cells are infused back into the patient, the new receptors enable them to identify particular antigens of the cancer cells and destroy the tumor.

What Cancers Can be Treated with CAR T-Cell Therapy?

Up to date, CAR T-cell therapy is approved for refractory B-cell Acute Lymphoblastic Leukemia (B-ALL), B-cell Lymphoma, and Multiple Myeloma. At Acibadem, the CAR-T treatment carries the CD-19 receptor. It can be considered for patients with post-transplant relapsed or refractory B-cell Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma (NHL). Our product will be ready in the next 1 year for clinical trials on multiple myeloma.

For successful CAR T-cell therapy, the patient should be in good overall health, and the tumor load should be low. Therefore, our physicians will mostly prescribe bridging chemotherapy and/or radiotherapy before the procedure to increase treatment success.

What is the CAR T-Cell Procedure?

If you are found eligible for CAR T-cell therapy, your or your donor’s peripheral blood cells will be collected with a device by apheresis. This procedure lasts about 2 to 4 hours. Next, the genetic structure of these cells will be engineered, and they will be proliferated in laboratory settings. The final product will be frozen and stored for you until quality assurance tests are completed. Production and quality control processes of CAR-T cells will take approximately 21 days. 

Meanwhile, before the therapy starts, a dual-agent chemotherapy protocol for lymphodepletion will be maintained for 4 days to create room for modified CAR-T cells in your body. 48 hours should elapse to help the excretion of drugs from the body. Finally, personalized CAR T-cells will be intravenously administered within 30 minutes.

How Long does it Take to Recover from CAR T-Cell Therapy?

CAR-T cell therapy is an approximately 2-week treatment that includes the lymphodepletion and administration of CAR T-cells. After the procedure, side effects such as cytokine release syndrome, neurotoxicity, or infections can be managed by our physicians. The time that elapses from the administration of cells to discharge is usually shorter than 1 month. 

After CAR T-cell therapy, you will need IVIG (immunoglobulin) treatment for up to 1 year. The number of CAR T-cells will be counted, the probability of insidious disease will be checked, and the B-lymphocyte count will be analyzed at monthly intervals. If a negative result is obtained in one of these three follow-up parameters, your treatment will be completed with allogeneic stem cell transplantation. 

What is the Success Rate of CAR T-Cell Cancer treatment?

International trials demonstrate that total response can be >90% in Acute Lymphoblastic Leukemia and >80% in Non-Hodgkin Lymphoma patients. These figures are comparable to our data. Today, CAR T-Cell therapy is the most effective option available for patients with ALL and NHL resistant to second-line treatment. CAR-T immunotherapy provides these patients with the opportunity of a complete cure.