Bone marrow transplantation (BMT) stands as a cure for numerous primary immunodeficiency (PID) conditions. Over the past two decades, significant strides have been made in enhancing success and survival rates, expanding the spectrum of treatable conditions through BMT.
What is Bone Marrow?
Bone marrow, located at the core of bones, is the soft, spongy tissue crucial for generating three vital blood cell types: red blood cells, white blood cells (integral to the immune system), and platelets. Stem cells, the initial form of these cells, undergo maturation within the bone marrow before being gradually released into the bloodstream. In a bone marrow or stem cell transplant, healthy cells from a compatible donor are harvested and introduced to the individual with a PID. Subsequently, these transplanted stem cells develop into fully functional white blood cells, actively combating infections and enhancing immune capabilities.
Understanding Bone Marrow Transplants
When individuals with Primary Immunodeficiency (PID) undergo a bone marrow transplant, various crucial steps are involved in this life-changing procedure. Below are the key components:
- Donor Selection: The patient receives bone marrow or stem cells, often sourced from umbilical cord blood, from a donor sharing the same tissue type. The two primary considerations are a perfectly matched related donor (typically a sibling) or a well-matched unrelated donor. Occasionally, a less well-matched donor might be explored.
- Matching Process: The donor is chosen based on tissue type compatibility.
- Conditioning Phase: To foster cell growth, patients undergo conditioning, where powerful chemotherapy medicines serve a dual purpose:
- Creating space for the new stem cells.
- Suppressing the immune system to enhance acceptance of the transplanted cells.
- Exception for SCID: Certain cases of SCID allow transplantation without the need for conditioning.
Duration of Bone Marrow Transplantation (BMT)
A Bone Marrow Transplant (BMT) entails an extended hospital stay, typically averaging 6–8 weeks, although this period may extend further. Patients are accommodated in isolation rooms on dedicated transplant wards, characterized by stricter visiting regulations, dietary restrictions, and enhanced hygiene protocols compared to general wards. These precautions are vital because the patient’s immune system is temporarily compromised during the transplant, necessitating additional safeguards against infections.
In recent years, there has been notable progress in BMT techniques, especially for Primary Immunodeficiency (PID) cases. Results indicate significant improvements, with survival and cure rates reaching 85–90% in specialized centers equipped for PID patient transplants. While BMT is generally better tolerated in childhood, advancements in transplantation techniques have extended successful outcomes to young people and adults. However, it’s crucial to acknowledge that BMT, despite its advancements, is not devoid of risks. Patients and medical teams carefully weigh the potential benefits against these inherent risks during the decision-making process.
Understanding the Risks of Bone Marrow Transplantation (BMT)
Bone Marrow Transplantation (BMT) comes with inherent risks, primarily centered around infection and graft-versus-host disease (GvHD). GvHD occurs when the new bone marrow from the donor perceives the patient’s cells as foreign, triggering a reaction that can affect the skin, liver, and bowels. Additionally, the initial post-BMT period renders the patient highly immunodeficient, elevating susceptibility to infections. The new immune system may take 4–6 months to mature and function adequately, requiring the use of prophylactic antibiotics and immunoglobulin during this period.
Here are the possible risks you get during BMT:
- Infection: Immediate susceptibility post-BMT necessitates ongoing prophylactic measures.
- Graft-Versus-Host Disease (GvHD): Potential complications affecting the skin, liver, and bowels.
General Recommendations for BMT in PIDs:
- Timing of Consideration: BMT should be considered promptly after a PID diagnosis, especially before the onset of serious infections or inflammatory issues. Siblings are tested for tissue compatibility, and if not a match, efforts to find a well-matched unrelated donor commence. Counseling is essential to guide individuals through this crucial decision-making process.
- Specialist Center Involvement: BMT should be performed in a specialized center with experience in PID transplants. Specialized doctors offer updated advice on risks and benefits specific to the PID condition.
- Personalized Discussions: Consult with healthcare professionals to assess suitability and individual risk factors for the patient and their family.
It’s crucial to acknowledge that while BMT can cure a person’s PID, the inheritance implications persist, necessitating consideration and discussion about passing the condition to future generations. Patients and their families should engage in thorough conversations with healthcare providers to make informed decisions aligned with their unique circumstances.
Primary Immunodeficiency Conditions Treatable by BMT
This list outlines the types of PID that may undergo BMT, covering common indications but not exhaustively, as other specific PIDs might be suitable for transplantation.
Severe combined immunodeficiency (SCID)
- CD3 antigen delta subunit deficiency (CD3D)
- CD3 antigen epsilon subunit deficiency (CD3E)
- CD3 antigen zeta subunit deficiency (CD3 Z)
- Coronin 1A
- IL2RG (Common Gamma Chain, X-linked)
Combined immunodeficiency (CID)
- Cernunnos deficiency
- CD3 antigen gamma subunit deficiency (CD3G)
- CD8 antigen deficiency
- CD40 ligand deficiency (CD154)
- DNA ligase IV deficiency
- ITK deficiency
- Omenn syndrome
- ORAI 1
- RAG 1 (leaky phenotypes)
- STIM 1
- ZAP70 deficiency
HLA class II deficiency
- Major histocompatibility complex class II transactivator (MHC2TA)
- Regulatory factor X 5 (RFX5)
- Regulatory factor X ankyrin-repeat containing (RFXANK)
- Regulatory factor X-associated protein (RFXAP)
Other T-cell deficiency
- DOCK8 deficiency
- STAT5b deficiency
Omenn syndrome (due to)
- DNA ligase IV deficiency
- Gamma C (X-linked)
Diseases of immune dysregulation
- Familial hemophagocytic lymphohistiocytosis syndrome (FHLH)
- Munc 13.4 deficiency (UNC 13D)
- Munc 18.2 deficiency (STXBP2)
- Perforin 1 deficiency (PRF1)
- Syntaxin 11 deficiency
Immunodeficiency with hypopigmentation
- Chediak–Higashi syndrome
- Griscelli syndrome
- Hermansky–Pudlak syndrome, type 2
- X-linked lymphoproliferative syndrome
- Foxp3 deficiency
Early-onset inflammatory bowel disease (IL10R deficiency)
- IL10R alpha
- IL10R beta
Other well-defined PIDs
Wiskott–Aldrich syndrome (WAS)
- Cartilage hair hypoplasia
- Chronic mucocutaneous candidiasis (CMC)
- Congenital dyskeratosis (some forms)
- Immunodeficiency centromeric instability facial anomalies syndrome (ICF)
- Schimke disease
Hyper IgE syndrome – autosomal dominant (STAT 3 deficiency)
Hyper IgE syndrome – autosomal recessive
- Chronic granulomatous disease (CGD)
- Leukocyte adhesion deficiency (LAD)
- Severe congenital neutropenia
- Shwachman–Diamond syndrome
Frequently Asked Questions
What to do if you don’t have a BMT match with your family?
After exploring the option of locating a related donor within the family, doctors initiate the search for a suitable match on national registries like the Anthony Nolan Registry and cord stem cell banks. This quest can extend globally through international registries. In cases where a well-matched donor is unavailable, alternatives such as the use of umbilical cord blood or haploidentical transplants are increasingly considered. As a last resort for patients without a matched donor, gene therapy has become a viable option, and the range of conditions eligible for this approach has expanded in recent years.
Are parents eligible for BMT and be a donor for their children?
BMT is most effective when there is a 100% or 90% match of crucial markers on cells between the donor and the recipient. Siblings, with a 25% chance of being a perfect match, are frequently chosen as donors. Parents, with a usual 50% match, were traditionally not always considered ideal donors, although some may, by chance, be better matches. With advancements in BMT techniques, “haplo” BMTs are increasingly performed when no other suitable donor is available. “Haploidentical” refers to half-identical matches, typically involving a parent. Stem cells or bone marrow for a haplo-BMT undergo special treatment to eliminate cells that could harm the patient. Although the immune system recovery time is longer, this approach provides an alternative in situations where none existed before.
Is BMT much more difficult for adults than children?
Yes. Typically, adults being evaluated for BMT have experienced prolonged issues like chronic lung and gut diseases. The gradual accumulation of tissue damage resulting from these chronic problems and infections can complicate the BMT process. Additionally, due to the inherent risks associated with BMT, determining whether it is the right course of action becomes more challenging for adults. Factors such as dependent relationships and the potential for financial hardship, particularly with the necessity for time off work, contribute to the complexity of decision-making in adult cases.
Is BMT only for children having PID?
No. Over the past few years, an increasing number of adults have been undergoing BMT, although the overall numbers remain relatively low. A notable recent breakthrough involves the introduction of ‘reduced-intensity conditioning,’ a gentler form of chemotherapy employed to ready the patient for the donor’s bone marrow. This approach has demonstrated success in BMT for certain adults with PID. It is anticipated that more adults with PID will undergo BMT in the coming years, thanks to advancements such as reduced-intensity conditioning.
Is BMT an ideal option for people having CVID?
The suitability for BMT in CVID cases varies based on factors such as the specific CVID type, its genetic origins, and the individual’s overall health history. CVID is likely an assortment of distinct genetic disorders sharing common features under the same diagnostic umbrella. Current knowledge indicates that certain immune deficiencies result from genetic alterations exclusively affecting the immune system, while in other cases, the genetic abnormality influencing symptoms may reside in non-immune cells. BMT might be considered when the disorder predominantly affects the immune system and exhibits severe symptoms. However, if the disorder has broader impacts on various tissues and organs or lacks clarity, the risks of BMT may not be outweighed by an improvement in overall clinical condition. In less severe cases, particularly those resembling combined immune deficiency (CID) or instances where a patient has CVID along with one or more lymphomas, the prevailing approach is typically to pursue a genetic diagnosis. In cases without a genetic diagnosis, non-BMT alternatives are often explored, except for very severe circumstances.
Is it required for children with CVID to undergo conditioning before getting BMT?
The outcome hinges on the specific type of SCID and the degree of tissue compatibility between the donor cells. In certain cases of SCID, children having a perfect tissue match from a sibling may not require conditioning with chemotherapy at all, particularly if the transplant is conducted early in life.
How often can people with PID undergo BMT?
Sometimes, a BMT may not be successful due to graft rejection. In such cases, the possibility of another transplant can be considered. However, this depends on the suitability of the original donor or the availability of another suitable donor. The patient’s medical condition must be robust enough to attempt a subsequent transplant. Additionally, there can be accumulated toxicity in the body from the chemicals used during the initial chemotherapy, complicating further BMT attempts. While second transplants have been successful for some PID patients, various factors need careful consideration before proceeding.