Hematopoietic stem cell transplantation in children
The unit you supervise was opened in 2017. How many hematopoietic stem cell transplantation procedures have you performed in children so far?
Indeed, we have already been operating for 8 years. The launch of the unit had been preceded by obtaining the approval of the Minister of Health to perform procedures involving the collection and transplantation of hematopoietic cells – initially autologous ones, i.e., involving the patient's own cells. We performed such procedures for the first five years. Then, we also obtained the approval to perform allogeneic transplants, i.e., ones with the use of donor cells. Thus, we perform a wide range of procedures related to hematopoietic stem cell transplantation in children. And we have already performed over 100 transplantations.
In what situations is it necessary to transplant hematopoietic stem cells in children?
About 55% of indications are due to cancerous and 45% are due to non-cancerous causes. The group of neoplastic diseases includes leukemias, myelodysplastic syndromes, some lymphomas and solid tumors (mainly neuroblastoma). However, when it comes to non-cancerous diseases – these are primarily congenital and acquired bone marrow failure syndromes, inborn errors of metabolism, primary immunodeficiencies. All these diseases are rare. Even the most common cancers in children, i.e., leukemias, are rare. In Poland, we have over 7 million children, and leukemia is diagnosed in 250-300 cases per year. The previously mentioned non-cancerous diseases are even less common – they may occur at a frequency of one in several dozen or several hundred thousand births.
When we talk about the indications, I need to strongly emphasize that not all children with the above-mentioned diseases will require the transplantation of hematopoietic stem cells. The procedure is only performed if it is the only effective method. If we can use effective drugs, or gene therapy or immunotherapy is available, we obviously do not carry out transplantations in such cases.
How old are your patients?
The most transplants were performed in young children between 2 and 6 years of age. In terms of size, older adolescents between 15 and 18 years of age constituted the second largest group. We also happened to treat several-month-old infants in the unit.
Tell us more about the procedure. You mentioned that you started with autogenous transplantations. What do they involve and when are they performed?
Autologous transplants are those in which the hematopoietic cells come from the patient – they are his own cells. We use them mainly for solid tumors (such as neuroblastoma) and lymphomas (e.g., Hodgkin lymphoma). We also use them in some tumors of the central nervous system and in the recurrence of other solid tumors.
Suppose we have a child diagnosed with high-risk neuroblastoma. What course of treatment may we expect?
If the disease is advanced and bone marrow involvement has occurred, treatment begins with chemotherapy. Then, we collect hematopoietic stem cells from the patient's peripheral blood (blood circulating in the vessels). We freeze them and the treatment is continued, e.g., surgery is performed. The next stage involves the transplantation of previously collected patient's own hematopoietic stem cells. They are administered to enable and accelerate the restoration of hematopoiesis.
And what are allogeneic transplantations and in which patients are they carried out?
Allogeneic transplantations require donor hematopoietic stem cells collected from the peripheral blood or bone marrow, or cells from the umbilical cord blood. In such a case, compared to autotransplantation, we additionally gain the immune effect. Implanted donor-derived cells differ from the patient's own cells, and these genetic and antigenic differences result in the transplantation further helping to combat the underlying disease. The immune effect is essential, especially in the treatment of such aggressive cancers as leukemias or myelodysplastic syndromes. Allogeneic transplantations are also used in severe aplastic anemia, primary immunodeficiencies and some inborn metabolic disorders or bone marrow diseases.
How does such an allogeneic transplantation look in practice, for example in a child with leukemia?
Actually, we are performing this type of procedure today. The day of transplantation is "day zero". Earlier, for seven days, the patient receives aggressive chemotherapy to destroy his own diseased bone marrow. This is called conditioning. During this time, the child is completely vulnerable. So the patient must stay under special conditions, in a room that ensures high sanitary standards with HEPA filters. The medical staff also follow special precautions. Only one of the parents may stay with the child. The parent, just like the child, does not leave the isolation room. On "day zero", we perform the transplantation, i.e., the patient receives donor hematopoietic stem cells. After about two weeks a new hematopoietic process will initiate the production of lymphocytes, red blood cells, platelets, and granulocytes. After "day zero", the little patient is hospitalized for at least 28 more days. This period is associated with the risk of various complications. Therefore, the child constantly receives immunosuppressive treatment and prophylaxis of infections. Such management aims to prevent transplant rejection and graft-versus-host disease, as well as to prevent viral or fungal infections. If there are no complications, the child is discharged after four weeks and continues treatment at home. During this time, the patient presents for follow-up visits once or twice a week.
Does this post-transplantation period look the same in the case of autologous transplantations? Is there a need for prophylaxis, since there is no risk of graft-versus-host disease?
Indeed, there is no risk of graft-versus-host disease in this group of patients, but there is a risk of many other serious complications. Although the risk of infectious complications is lower than in the case of allogeneic transplantation, patients also stay in isolation rooms with one caregiver. They also receive prophylactic antifungal and antiviral drugs, although the prophylaxis is shorter than in patients who undergo allotransplantations.
With organ transplants, the majority of patients require immunosuppressive medication for the rest of their lives. Is it also the case after hematopoietic stem cell transplantation?
No, there's no need for such management. If everything is fine, immunosuppression reduction may be initiated after three months (i.e., on the hundredth day, counting from "day zero"). It may be completely discontinued six months after transplantation.
The healthy immune system is restored from the transplanted hematopoietic stem cells. Subsequently, after several months, a course of vaccinations is initiated and the child slowly returns to normal functioning. Attending school is usually possible two years after the transplantation. Afterwards, the child should present to a transplant clinic for follow-up visits. This is what a positive scenario looks like.
What is the prognosis in children after hematopoietic stem cell transplantation?
Over the past 50 years, the prognosis has significantly improved. At the moment, we can say that the probability of long-term survival in children after hematopoietic stem cell transplantation performed due to non-oncological indications reaches 80%. As regards oncological indications, it is 60%. However, it is worth remembering that hematopoietic stem cell transplantation is used for a variety of diseases. Various diseases are also associated with the risk of various types of complications. That is why we cannot put an equal sign here. Therefore, it can be said that patients after hematopoietic stem cell transplantations are still likely to live for several decades. And when it comes to children, the chance of long-term survival is higher than in adults.
Allogeneic transplantations would not be possible without donors. Are they hard to find?
As regards donors for allogeneic transplants, we always start by looking for a family donor. However, only 17-20% of allogeneic transplants in children in Poland are actually performed using hematopoietic stem cells obtained from family donors, most often from siblings. Therefore, for most recipients, we need a matched unrelated donor. Looking from the perspective of our department – we report our demand to the Department of Immunogenetics. They search Polish and foreign registers. The Polish registry contains over 2 million donors, and, for example, the German one – 8 million. There is also a global donor network – Bone Marrow Donors Worldwide (BMDW).
Does it take a long time to wait for a compatible donor?
Currently, most pediatric patients awaiting hematopoietic stem cell transplantation can be donor matched within a few weeks. However, the Department of Immunogenetics reserves the right to search for a donor for three months. It's not just a matter of finding the right person in the database. There is still a lot of additional testing to be done to make sure that the person may become a donor for our recipient.
Anybody can register in the Polish database of potential bone marrow and stem cell donors. A cheek swab is enough for the registration. We donate hematopoietic stem cells only when it turns out that we are the right donor for someone. Many people associate this with a very painful and unpleasant procedure. Is it true?
It doesn't hurt. A lot of procedures are performed worldwide and they are considered safe. Hematopoietic stem cells are collected from the peripheral blood or bone marrow. First, the donor is examined and qualified – it is checked whether he is healthy and whether he can donate hematopoietic stem cells. In the case of peripheral blood collection, the mobilization procedure must be performed first. The donor receives the so-called growth factor, thanks to which he produces more hematopoietic stem cells. The cells are then collected on the fourth or fifth day of mobilization. It is worth emphasizing that only the excess of hematopoietic stem cells is collected, so the donor does not lose anything. The collection takes about two hours. The donor is discharged on the same day. Do any undesirable effects occur afterwards? Flu-like symptoms related to the action of growth factor may appear, but they are usually not severe.
However, in the case of transplantation in children, we usually collect bone marrow from donors and the procedure for bone marrow collection is different. At the beginning, we also perform an examination and qualification, but no mobilization is carried out. In such a case, several per cent of the marrow is lost but it regenerates very quickly. The procedure is carried out in a bone marrow collection center under general anesthesia in the operating room. All principles of asepsis are observed. It lasts from an hour to an hour and a half. As for the consequences for the donor, there may be tenderness at the puncture site.
It seems that hematopoietic stem cell transplants are procedures that require the cooperation of numerous specialists in various fields.
That's true. We cooperate with many centers of the University Clinical Center of the Medical University of Warsaw. In addition to the aforementioned Department of Immunogenetics, we also cooperate with the Department of Hematology, Transplantology and Internal Diseases, where hematopoietic stem cells are collected from related adult donors, with the Hematopoietic Stem Cell Bank, the Department of Laboratory Diagnostics and Clinical Immunology. In addition, we are supported by specialists from the departments of our hospital, because our patients often require consultations with nephrologists, anesthesiologists, pulmonologists, gastrologists, endocrinologists, ENT specialists, surgeons, and psychiatrists. We have really great facilities here.
Interview by: Iwona Kołakowska
Photo: Tomasz Świętoniowski
Communication and Promotion Office