Overview 

A comprehensive review of medicine regarding haematopoietic stem cell transplantation (HSCT) to treat Fanconi anaemia (FA) is valuable in different ways. It informs patients and their families about the benefits and potential risks, helping them to make informed decisions on their healthcare. Furthermore, sharing this knowledge can raise public awareness about FA and the role of HSCT, which can encourage more individuals to become stem cell donors. Ultimately, such awareness builds greater community support for patients and their families. HSCT is considered to be the only established treatment which can cure FA – a rare inherited autosomal recessive disorder manifested by bone marrow failure, congenital defects and an increased cancer risk. In HSCT, the transfer of healthy donor stem cells to a person affected by FA is done by replacing the dysfunctional stem cells with intact blood cells to restore bone marrow cell composition and its ability to produce healthy blood cells, improving the overall prognosis.

Successful HSCT in FA depends on many factors, including the age of the recipient, the disease severity, donor availability, and compatibility.

Introduction

FA is a rare inherited bone marrow disorder that causes a decrease in blood cell production in bone marrow, congenital defects and increased cancer risk due to defective response in the DNA repair system, leading to genomic instability.^1,2 The majority of cases of inherited bone marrow failure or aplastic anaemia are due to FA.³

HSCT is a cellular therapy aimed at treating incurable genetic conditions by using healthy donor stem cells to replace dysfunctional stem cells to maintain healthy bone marrow cellularity and function. The clinical importance of HSCT comes from its potential to treat various conditions, such as haematological, oncological, immunological and hereditary conditions.⁴

Although HSCT is a promising treatment, there are many contrary indications and associated risks which should be accounted for and addressed carefully. Additionally, to maintain successful HSCT, other factors should be considered depending on each patient's condition.⁴

Background on fanconi anemia

Genetic basis 

Most cases of FA are caused by autosomal recessive genetic mutations, but there are also some X-linked and autosomal dominant cases. The mutations can take different forms, such as point mutations, duplications, deletions, or problems with messenger RNA (mRNA) splicing. The condition is linked to a group of genes called Fanconi anemia complementation (FANC) genes, which produce proteins that help repair damaged DNA.⁶

Pathophysiology 

FA is a condition of variable severity. Due to various genetic changes, the outcome is the production of cells with defects in DNA. Due to an unresponsive DNA repair pathway, cells become susceptible to cytotoxic effects and ultraviolet radiation; this results in cell death and subsequent pancytopenia. FA is the most common cause of inherited aplastic anaemia; patients show a decline in all blood cell lines. Moreover, patients are at high risk for cancer development, such as acute myeloid leukaemia and head and neck squamous cell carcinomas.⁵

Congenital defects occur in up to 75% of FA cases, including short stature, skin pigmentation and lesions, and abnormalities in extremities and the bone skeleton are observed.⁷ In addition to the clinical features due to pancytopenia, anaemia, skin bleeding, and recurrent infection are due to low counts of red blood cells, platelets and white blood cells, respectively.⁵

Diagnosis of fanconi anaemia 

• A complete blood count shows reduced numbers of red blood cells, white blood cells and platelets and an increase in mean cell volume of red blood cells
• Increased levels of foetal haemoglobin 
• High erythropoietin levels in response to the low red blood cell count 
• A bone marrow biopsy indicates bone marrow with low cellular levels, and the cells are replaced by fatty tissues. Indicates the absence of overall blood stem cell lines 
• The chromosomal breakage test is an indicator diagnostic test 
• A CT scan for skeletal abnormalities 
• MRI scan to detect neural defects
• Clinical features and structural abnormalities also play a role in diagnosis ⁸

Hematopoietic stem cell transplantation 

A therapeutic multi-step procedure, in which the collected stem cells from HLA gene-compatible donors are transferred to a recipient's bone marrow to replenish the cell line production and restore bone marrow function. HSCT can be autologous or allogeneic, based on the donor of the stem cells. Autologous stem cells are collected from the patient, this type is used in conditions such as before radiation therapy or chemotherapy. The cells are administered to the patient's bone marrow afterwards. This procedure claims to treat the cytotoxic effect of such treatments on the patient's bone marrow. In allogeneic stem cell transplantation, stem cells are obtained from compatible donors.⁹ 

Autologous transplantation is safer than allogeneic as it lowers the possibility of immune rejection, but it is not valuable in bone marrow conditions. In Fanconi anaemia, allogenic stem cells are the only curative treatment. The collection of stem cells can be carried out from different sources, from either peripheral blood, bone marrow or umbilical cord blood.⁹

Historical prospective

Over the previous 20 years, there has been an improvement in the HSCT outcome in patients with FA, resulting in significantly reduced deaths due to allogeneic transplantation and the long-term viability of transplanted stem cells. The usage of haematopoietic growth factors and attention to the pre-transfusion treatment improve the outcome of the transplantation. Minimising the chance of engraftment failure by using stem cells from matched sibling donors raised the success rate of the HSCT by at least 80%. Also, an improvement in HSCT from unrelated donors was noticed due to HLA matching techniques and advances in donor registries, but matched sibling donors were still the most successful in outcome.¹⁰

More recent prospective approaches have used gene therapy CRISPR/Cas9 technology in editing genetic defects in autologous haematopoietic stem cells to overcome the immune rejection risk.¹¹

Indications for stem cell transplantation in FA 

Patients are considered for HSCT according to the disease severity if the patient expresses progressive cytopenia, in cases of severe bone marrow failure, acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS), or poor prognosis genetic aberration.¹² 

Donor availability with identical HLA antigens is also considered an indication for HSCT. 

Studies showed that young patients in the first decade of life, before developing of any clonal disorders, represent a better response to HSCT.¹⁰ Otherwise, transplantation after 10 years old,  after clonal disorders, complications, graft versus host disease (GVHD), and stem cells obtained from peripheral blood – these factors individually are found to be associated with the risk for secondary malignancy.¹⁰

To lower the HSCT-associated risks, a pre-transplant consideration and evaluation must be addressed as:

• A thorough clinical evaluation, addressing the patient’s medical history, physical examination, and haematological parameters evaluation. This is important in accounting for the presence of infection, or previous drug use, and regular follow-up of blood cell count to evaluate the bone marrow status. Bone marrow biopsy is also important in screening for bone marrow cellularity, AML or MDS transformation 
• Organ function examination, to exclude organ damage as a disease complication 
• Infection screening: screening for the presence of infection, either bacterial, fungal or viral, is considered life-threatening in the post-transplantation period 
• Genetics and HLA typing, genetic testing to confirm the diagnosis and highlighting the exact gene mutation, HLA typing is important in patient compatibility. A matched donor sibling is the most favourable for a stem cell transplant. In the absence of such a choice, HLA matching with an unrelated donor or haploidentical donor is tested for donation¹²

The transplantation process 

Before the transplantation procedure, a lot of preparation is needed. After finding an HLA-matched donor, the next step is to collect the stem cells either from peripheral blood by venipuncture. Certain medications are introduced into the donor to increase the HSC count in peripheral blood or from bone marrow by fine needle aspiration of the interior or posterior iliac crest. This procedure is performed under anesthesia, either local or general. The next step is patient preparation; chemotherapy with or without irradiation is administered to the patient in order to eradicate bone marrow from dysfunctional or abnormal cells, introducing immunosuppressant drugs to facilitate stem cell engraftment and prevent any adverse immune rejection.⁹

After 1-3 weeks, bone marrow is ready for transplantation, and patients are placed in sterile isolation rooms to avoid infection risk. Before stem cell infusion, they must be counted to ensure their optimal count and characteristics, then transfused to the patient. It takes up to two hours to infuse stem cells; the cells are infused via the vein, and they subsequently home to the bone marrow.⁹

Post-transplantation care

Patients are kept in sterile, isolated rooms to avoid infection risk, as the patient's immune system is suppressed to avoid immune rejection. Prophylaxis, nutrients and antibiotics are administered to avoid infection and nutritional loss. Regular haematological tests and organ function tests are performed. Engraftment is evaluated by testing the patient's blood cell counts; successful transplantation is indicated by an increase in the patient's blood cell counts. 

Lifelong follow-ups to monitor the later effects of transplantation, encouraging patients to follow a healthy lifestyle.⁹

Complications and challenges 

Complications related to HSCT can be either acute or chronic: Acute complications occur within the first three months of transplantation and may include suppression of the myeloid series with low neutrophil count, anaemia or low platelet count. Also, infection and graft versus host disease (GVHD) may occur as a short-term reaction. Chronic or delayed complications include chronic GVHD or secondary malignancy.⁹

Summary 

Fanconi anaemia is an inherited genetic condition, usually autosomal recessive. The affected genes control the DNA repair pathway. Defects cause bone marrow failure, pancytopenia, and increased cancer risk. The cells become sensitive to the cytotoxic effect and cell death occurs, leading to a major reduction of stem cells and blood cell precursors in the bone marrow. 

HSCT is the only established curative treatment for FA, by replacing patients' dysfunctional cells with normal stem cells to restore bone marrow cellularity and improve overall prognosis. HSCT can be autologous or allogeneic, and the cells can be obtained from bone marrow, peripheral blood or umbilical cord blood. 

Transplantation is ideally performed before 10 years of age and as early as possible to avoid developing clonal complications. To ensure successful transplantation, patients undergo immunosuppression therapy to facilitate engraftment. After transplantation, patients are closely monitored to assess both immediate and long-term complications. Maintaining a healthy lifestyle is crucial for overall well-being and reducing the risk of adverse outcomes.