Keywords

2.1 What Nurses Need to Know

2.1.1 Introduction

Haematopoietic stem cell transplantation (HSCT) is a therapeutic option for several malignant and non-malignant diseases including acute and chronic leukaemia, lymphoma and multiple myeloma, some of the inherited disorders such as severe combined immunodeficiency and thalassemia and other inborn errors of metabolism and autoimmune diseases (Maziarz and Slater 2021).

HSCT involves the use of autologous, patient’s own, haematopoietic stem cells (HSC) or allogeneic HSCT where the donor cells come from a family-related or an unrelated donor, and the source of HSC may be obtained from the bone marrow (BM) or peripheral blood (PBSC) or cord blood (CB).

The collected HSC are infused into a recipient (Gratwohl 2018). Before the infusion, the recipient is treated with a conditioning regimen (see Chap. 6), involving the use of different types and dosages of chemo and/or radiotherapy and/or immunosuppressant drugs (such as anti-thymocyte globulin) (Copelan 2006).

2.1.2 Aims of HSCT

  • In the autologous setting, patients with chemosensitive malignant diseases are offered high-dose chemotherapy in order to destroy or further reduce the malignant disease, ablating the marrow with this aggressive therapy. In this case, the stem cell infusion is intended to treat the prolonged chemotherapy-induced hypoplasia and not the disease itself (Michel and Berry 2016; Maziarz and Slater 2021).

  • In the allogeneic setting:

    • In malignant haematological disease, donor HSCs replace the immune system and help to eradicate malignancy (Michel and Berry 2016; Maziarz and Slater 2021).

    • In non-malignant diseases, where the cause is dysfunction of the haematopoietic stem cell (HSC), the HSCT procedure replaces the inefficient patient immune system with the donor one (Michel and Berry 2016).

2.1.3 Outcomes

Patient selection influences outcomes. Patients with better overall functional performance status, limited comorbidities and underlying organ damage have more favourable outcomes (Maziarz and Slater 2021). Outcomes vary according to:

  • The stage of the disease.

  • The age of the patients.

  • The lapse of time from diagnosis to transplant.

  • The histocompatibility between donor and recipient.

  • The donor/recipient sex combination (the overall survival decreases for male recipients having a female donor) (Sureda et al. 2015a).

  • Advances in immunogenetics and immunobiology.

  • Stem cell source and graft manipulation.

  • Conditioning regimens.

  • Disease characterization and risk stratification.

  • Immunosuppression.

  • Immune reconstitution (poor or delayed) may have an important impact on infectious morbidity, relapse of haematological disease and overall survival (Elfeky et al. 2019).

  • Antimicrobials.

  • Other pathologies and/or complications.

  • Other types of supportive care.

All these factors contribute to improvements in disease control and overall survival (Maziarz and Slater 2021).

2.1.4 Nursing Considerations

Patients require specific care to overcome the physical and emotional problems resulting from this treatment. Usually after myeloablative conditioning, HSCT recipients typically experience a period of profound pancytopenia lasting days to weeks depending on the donor source. The rapidity of neutrophil recovery varies with the type of graft: approximate recovery time is 2 weeks with G-CSF-mobilized PBSC, 3 weeks with BM and can be as long as 4 weeks with CB. However, re-establishment of immune system takes at least several months due to prolonged lymphocyte recovery process, and some patients continue to show immune deficits for several years after HSCT (Mosaad 2014). During this period, the patient has a high risk of developing complications; thus, HSCT units require multidisciplinary teams of physicians, nurses, pharmacists, social workers, nurse practitioners, physician assistants, nutrition experts and occupational and physical therapists, in addition to a specialized facility and technical resources (Maziarz and Slater 2021).

Nurses who work in HSCT units have a key role in treatment management and require specific training to:

  • Understand, prevent and manage the early and late effects of HSCT.

  • Care for high-risk patients.

  • Inform and educate patients and their caregivers.

  • Safely administer drugs, blood products and cell products.

  • Manage the central venous catheters (CVCs).

  • Give emotional support.

These topics will be covered in later chapters.

2.2 Different Types of HSCT

HSCs may be obtained from autologous, syngeneic or allogeneic related (HLA-matched) or unrelated donors (matched unrelated donor MUD). There are also partially matched HLA donors defined by a single-locus mismatch and/or missing HLA data known as mismatched alternative donors (MMAD). This includes mismatched unrelated donor MMUD (partially matched 7/8, 9/10 loci), unrelated CB and haploidentical donors (see Chap. 3) (Duarte et al. 2019). HSCs may be harvested from peripheral blood (PBSC), bone marrow (BM) or cord blood (CB) source.

2.2.1 Autologous Stem Cell Transplantation

Autologous HSCT is defined as “a high dose chemotherapy followed by the reinfusion of the patient’s own HSC” (cit. NCI Dictionary). After mobilization (see Chap. 5), the patient’s HSCs are collected and cryopreserved. Auto-HSCT facilitates the prompt reconstitution of a significantly depleted or ablated marrow following very aggressive chemotherapy intended to eradicate haematologic and non-haematologic malignancies (Maedler-Kron et al. 2016).

Graft failure can occur rarely, and some trials demonstrate how relapse remains an issue for the majority of patients with multiple myeloma (Michel and Berry 2016; Poirel et al. 2019).

2.2.2 Allogeneic Stem Cell Transplantation

In allogeneic HSCT, the recipient receives HSCs from a related or unrelated donor who can be fully or partially human leukocyte antigen (HLA)-matched (Fig. 2.1); related donors are family members; unrelated donors are identified through a donor registry or a cord blood bank. In allogeneic HSCT, the major histocompatibility complex includes HLA class I and II molecules located on chromosome 6 play an important role (Maziarz and Slater 2021). (See Chap. 3 for HLA typing and donor selection.)

Fig. 2.1
A chart of H S C T phases. It divides into mobilization and harvesting, conditioning regimen, reinfusion, neutropenic phase, engraftment and recovery, and follow-up. Mobilization divides into P B S C, bone marrow, and cord blood collections.

The diagram explains the principal transplantation phases and the number of the chapter in which you can have more information about

Full size image

In allogeneic HSCT, the aim of conditioning is to:

  • Kill tumour cells (in malignant diseases).

  • Eradicate existing bone marrow tissue in order to provide space for engraftment of transplanted donor stem cells.

  • Suppress the patient’s immune response and minimize the risk of graft rejection of the donor HSC (Maziarz and Slater 2021).

Allogeneic HSCT has been subject to several improvements during recent years.

Reduced intensity conditioning regimens, alternative donor transplants have increased the accessibility and availability, especially for older patients who have poor tolerance of the high toxicity of the treatment. These improvements have resulted in reduced transplant-related mortality, although relapse remains an issue (Michel and Berry 2016; Maedler-Kron et al. 2016).

2.2.2.1 Allogeneic Transplantation from HLA-Matched Related Donor (MRD)

The ideal donor is an HLA-identical sibling-matched sibling donor. Patients have a 25% chance of each sibling being fully HLA-matched, because siblings inherit 50% haplotype from each parent (see Chap. 3).

If the donor is an identical twin, they are referred to as syngeneic (see Sect. 2.2.2.5).

2.2.2.2 Allogeneic from Unrelated Donor (MUD, MMUD)

If recipient has no sibling or the blood tests confirm that there is no HLA compatibility with the sibling, then a search of “World Marrow Donor Association” registry database (WMDA) is activated (Carreras et al. 2019).

If the donor histocompatibility is fully matched with the recipient (Duarte et al. 2019), the donor is called a matched unrelated donor (MUD); if there is a partial incompatibility, the donor is called a mismatched unrelated donor (MMUD).

The time between the activation of the unrelated donor search and the beginning of transplantation procedure is fundamental. The more time spent in the search phase, the greater is the risk that the high-risk patient’s disease will worsen or they may even die (Carreras et al. 2019) (see Chap. 3).

2.2.2.3 Cord Blood Transplantation

Umbilical cord blood transplantation (CBT) provides an alternative donor option for patients who lack a conventional MRD and MUD. Advantages of CBT include the capacity to tolerate greater degrees of HLA mismatch than is possible using MUD (Bashey and Solomon 2014; Ballen 2017).

Disadvantages are due to limitations of cell dose, although there is active research in expanding CB progenitor cells (Fitzhugh et al. 2017). However, delayed engraftment, slow immune reconstitution and acquisition and storage costs remain important challenges (Bashey and Solomon 2014; Ballen 2017).

Even if CBT is still an option, especially for non-malignant diseases in paediatric centres (Passweg et al. 2017), in the past few years the use of CB is decreasing due to increasing safety in the use of haploidentical donors (Duarte et al. 2019) (see Chap. 5).

2.2.2.4 Haploidentical Transplantation

In the case of patients with high-risk haematological malignancies lacking a fully matched HLA-identical sibling, or unrelated donor and who requires HSCT urgently, it is possible to transplant with an available haploidentical donor (compatibility of 50%) (Bertaina et al. 2017; Aversa et al. 2019) (see HLA Chap. 3).

The donor may be a parent, child, brother, sister or other relative that matches for one haplotype and fully mismatched for the other who can immediately serve as an HSC donor (Bertaina et al. 2017). An haploidentical donor may be found more quickly with a potentially reduced overall cost (Gagelmann et al. 2019).

The most important criterion for an haploidentical transplant is the urgency of the transplant in order to avoid early relapse or progression of the disease or the lack of HLA-identical matched donor (Aversa et al. 2019; Gagelmann et al. 2019). The advantages of the haploidentical transplantation are:

  • Easy family donor availability (if patients are not fostered or orphans without other relatives).

  • Appropriate timing for HSCT.

  • Faster graft acquisition.

  • Easy access to donor-derived cellular therapies after transplantation (Aversa et al. 2019; Gagelmann et al. 2019).

The use of one single haplotype donor historically developed two main problems: a lethal GvHD and graft rejection. But for some patients this kind of transplant maybe the only chance. So during the last 20 years were developed conditioning regimens associated to different immunosuppressive therapies who gave these high-risk patient the best opportunity to be treated, with a reduced risk of TRM and develops GvHD than in the past.

There are two main approaches to haploidentical transplantation:

  • Haploidentical HSC T-replete transplantation with cyclophosphamide in immediate post-transplant phase making haplo-HSCT feasible; it appears to have overcome many of the obstacles historically associated with haploidentical donor transplantation, disadvantages such as high rates of graft rejection, transplant-related mortality, post-transplant infections (Bashey and Solomon 2014; Fitzhugh et al. 2017), promotes a graft versus leukaemia (GVL) therapeutic benefit with improved survival (Maziarz and Slater 2021; Sano et al. 2021), even if remains a higher risk of acute and chronic GvHD and there is a need for prolonged GvHD prophylaxis (Bertaina et al. 2017).

  • Haploidentical transplantation with depletion of T-lymphocytes exists in aggressive and severe immune depleting conditioning regimen followed by infusion of mega-doses of highly purified PBSC, so there is no need for any further post-transplant immune suppressive treatment, but there is a prolonged T-cell recovery and require dedicated laboratories and higher costs than conventional unmanipulated HSCT (Bashey and Solomon 2014; Bertaina et al. 2017; Aversa et al. 2019,).

2.2.2.5 Syngeneic Transplantation

Syngeneic is a type of transplantation where the donor is the recipient’s monochorionic twin and who is genetically identical to the patient. There is no immunological conflict such as GvHD (graft vs. host disease) (see Chap. 12) but at the same time no beneficial GVL (graft vs. Leukaemia) effect (Mackall et al. 2009).

(See Chaps. 10 and 12 for HSCT complications.)

2.3 The Stem Cell Sources

HSC can be isolated from the BM, PBSC after mobilization and umbilical CB (Maziarz and Slater 2021).

HSC are capable of repopulating all hematopoietic and lymphocytic populations while maintaining capacity for self-regeneration, assuring long-term immunologic and hematopoietic viability (Carreras et al. 2019; Maziarz and Slater 2021).

The choice of stem cell depends on accessibility to the donor, disease diagnosis, urgency for the transplant, and centre preference (Elfeky et al. 2019).

2.3.1 Peripheral Blood Stem Cells

PBSCs have been increasingly used in both auto- and allo-HSCT. Mobilization of haematopoietic stem cells to the peripheral blood can be achieved by the administration of growth factors such as G-CSF and/or myelosuppressive chemotherapy (Carreras et al. 2019).

An advantage HSCT performed with PBSC is a relatively rapid recovery of haematopoiesis compared to BM and increases the disease-free survival and overall survival in high-risk haematological malignancies. The disadvantage is an increased risk of chronic GvHD in the allogenic HSCT because of an increased number of T cells circulating (Maziarz 2015).

2.3.2 Bone Marrow

BM is traditionally harvested from the posterior iliac crests under general or epidural anaesthesia in a surgical room where trained haematologists or surgeons collect stem cells and blood directly from the bone marrow cavity in the bilateral posterior iliac crest region using aspiration needles.

HSCT performed with BM leads to less cGvHD compared to PBSC source, but has the disadvantage of a slower neutrophil and platelet engraftment (Maziarz 2015). BM is the most used source on children.

2.3.3 Umbilical Cord Blood

CB cells are collected and cryopreserved from the umbilical cord immediately after birth, but generally before the placenta has been delivered in order to avoid clots (Demiriz et al. 2012). They have been used both in related and unrelated HLA-matched and HLA-mismatched allogeneic transplants in children and in adults (Demiriz et al. 2012; Carreras et al. 2019). The advantage is a lower criteria for a match (4/6 match is acceptable) increasing the chance of identifying a suitable cord unit or cord units in a matter of days. Less GvHD is often observed. A key disadvantage is often slower engraftment compared to BM and PBSC and increased infection complications due to slow rate of haematopoietic recovery (Maziarz and Slater 2021) (see Chaps. 3 and 5).

2.3.4 HSCT Phases

2.3.4.1 Neutropenic Phase

Neutropenia occurs when the absolute neutrophil count is <500 cells/mm3. After the chemotherapy, the blood count decreases and the duration of neutropenic phase varies according to several factors, such as source of cells, type of transplantation, conditioning regimen, and will influence both short-term and long-term immune reconstitution (Carreras et al. 2019). Neutrophil recovery occurs faster among PBSCs (12–19 days) and BM (15–23 days) than single-CB (20–30 days) (see Chap. 14).

During this period, several complications may occur such as:

Increased risk of infections due to a not effective immune system. Infection following HSCT is associated with significant morbidity and mortality, so prevention is critical to improve outcomes (Duarte et al. 2019) (see Chap. 10).

  • Bleeding because of thrombocytopenia (platelets have a slow recovery after transplantation).

  • Tiredness caused by the decreasing of haemoglobin levels.

  • Pain because of mucositis.

    Nutrition. Oral intake is usually severely reduced because of, on one side, the oral mucositis that many patients develop and, on the other side, the prolonged post conditioning nausea. When oral intake is reduced and the body mass index decrease, total enteral/parenteral nutrition may be provided especially for children (see Chaps. 10 and 11).

2.4 Indications for HSC Transplant

The use of reduced-toxicity conditioning regimens, better infection monitoring and management, more sensitive, molecular-based, tissue typing techniques and advances in supportive care have enhanced the safety and efficacy of HSCT. As the outcome of HSCT improved, the number of non-malignant conditions treated by HSCT has continued to grow (Bertaina et al. 2017).

The patient assessment for a transplant procedure is complex and includes several factors such as the patient’s overall health and performance status, comorbidities, disease risk/status (e.g. remission state and responsiveness to treatment), graft and donor source. For example, autologous transplantation is not useful for diseases in which normal HSCs cannot be collected as in CML or myelodysplasia (Rowley 2013).

The indications for transplant are based on best available evidence from clinical trials or, where clinical trials are not available, registry, multicentre or single centre observational studies from each centre’s research priorities local expertise, cost considerations and easiness of access to particular transplant modalities (Majhail et al. 2015; Duarte et al. 2019). The HSCT specialist determines if transplant should be considered as an option for disease consolidation, but the final decision will be made in conjunction with the patient (Maziarz and Slater 2021).

There have been major changes in indications, such as the rise and fall of autologous HSCT for some solid tumours or of allogeneic HSCT for chronic myeloid leukaemia (CML), and in technology, as illustrated by the change from the bone marrow to peripheral blood, the rapid increase in use of unrelated donors and the introduction of reduced intensity conditioning. It is clear how some guidance is warranted, for transplant teams, hospital administrators, health-care providers and also patients (Apperley et al. 2012).

The HSCT indications are not the same in children and in adults (Table 2.1).

Table 2.1 Indication for transplant: Standard of care (S); Clinical option (CO); Developmental (D); MMAD-mismatched alternative donors, MSD-matched sibling donor, MUD well-matched unrelated donor
Full size table

Table 2.1 is a scheme of the main indications for autologous and allogeneic transplantation that combine the recommendations for MMAD, including CB, haploidentical and MMUD, in a single category separate from well-matched related and unrelated donors (Duarte et al. 2019).

2.4.1 Indications for Autologous HSCT

Most autologous transplantations are performed for newly diagnosed multiple myeloma and non-Hodgkin lymphomas. Auto-HSCT remains the standard of care for patients with Hodgkin lymphoma with chemosensitive relapse at first autologous, while in chemosensitive relapse after failure of a prior autograft, allo-HSCT should be considered, and in chemosensitive relapse DLBCL after first-line therapy.

Auto-HSCT is the standard of care for newly diagnosed multiple myeloma (MM) patients, but age and general health should be considered; double autograft has been shown to be superior to one single autologous HSCT, immunomodulatory drugs and bortezomib before transplantation has led to their use as consolidation and maintenance therapies after autologous HSCT and may be an alternative option for these patients; recently also allogeneic HSCT with post-transplant cyclophosphamide has been shown to be a possible treatment in MM, but relapse is still a problem.

Autologous is also consolidation treatment for FL with chemosensitive high-grade transformation.

There is an increased evidence base for autologous HSCT in some indications, including multiple sclerosis (MS), systemic sclerosis (SS), Crohn’s disease and systemic lupus erythematosus (SLE), while allogeneic HSCT has been used in the paediatric setting .

Among solid tumours autologous HSCT is the gold standard for adult patients with refractory primary germ cell tumour and for high-risk neuroblastoma in paediatric setting (Duarte et al. 2019). Neuroblastoma is the most common extra-cranial solid tumour of childhood and the most common in the first year of life (Tolbert and Matthay 2018). In children with high-risk neuroblastoma consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy (Meaghan Granger et al. 2021).

High dose therapy with Autologous stem cell transplant can be regarded as a potential clinical option in selected patients with Ewing’s sarcoma and medulloblastoma (Duarte et al. 2019). For further information on HSCT in non-malignant paediatric indication, see Sect. 2.5.

2.4.2 Indications for Allogeneic HSCT

A vast majority of allogeneic transplants are performed for malignant haematologic diseases (Epperla et al. 2018).

Adult patients with acute myeloid leukaemia (AML), Hodgkin lymphoma (HL) and T cell lymphomas should always be considered for allo- or auto-HSCT depending on risk category, complete remission (CR), previous treatments and measurable residual disease (MRD). Allogeneic transplant is not recommended for AML favourable-risk patients, while is the preferred option in AML in CR2 and beyond.

Allo-HSCT is the standard of care in high-risk acute lymphoblastic leukaemia (ALL) even if the use of CAR-T programs are revolutionizing the treatment of advanced forms of ALL. HSCT remains the standard-of-care treatment for children with CR1 ALL carrying high-risk features predicting leukaemia recurrence and for those experiencing high-risk first relapse or multiple recurrences (Merli et al. 2019).

It cannot be recommended as first-line treatment for chronic myeloid leukaemia (CML) and chronic lymphocytic leukaemia (CLL) because of the efficacy of the first-line therapy with tyrosine kinase inhibitors (TKI) such as dasatinib, nilotinib or ibrutinib.

Allo-HSCT at the moment is the only potential curative option for patients with myeloproliferative disorders and is considered the treatment of choice for adult patients with myelodysplastic syndromes (MDS) especially before progression to AML, thanks to MUD, MMAD and reduced intensity conditioning (RIC). In paediatric AML the current practice restricts the use of HSCT in CR1 only to those AML patients with high-risk (HR) features as well as secondary AML or AML evolving form MDS. There is general consensus that standard-risk patients should not be transplanted in CR1 but only after the first relapse and achievement of a second complete remission. In relapsed AML allogeneic HSCT offers the best chance of cure, ideally after the achievement of second CR (Algeri et al. 2021).

Allogeneic HSCT is indicated in several different types of lymphomas such as diffuse large B cell lymphoma (DLBCL) with relapse after autologous HSCT or in case of chemorefractory disease.

Allo-HSCT following the failure of ibrutinib treatment may be an option in mantle cell lymphoma (MCL) and in follicular lymphoma (FL) with chemosensitive relapse after autologous HSCT.

In non-malignant diseases allo-HSCT from an HLA-identical sibling is the standard of care for adult patients, while MUD is considered as first-line choice for young patients (<18) with acquired severe aplastic anaemia (SAA). MMAD may be considered after failure to respond to immunosuppressive therapy in young patients up to 20 years of age in the absence of MSD or MUD, and is the only treatment for constitutional SAA as Fanconi anaemia.

Allogeneic HSCT has completely revolutionized the natural history of several life-threatening or debilitating non-malignant disorders, including primary immune deficiencies (PIDs), bone marrow failure syndromes and hemoglobinopathies (Duarte et al. 2019; Epperla et al. 2018).

2.5 Indications for Transplant in Non-malignant Diseases (in Children)

More than 20% of allogeneic HSCT are performed in patients below 20 years. However, at least one third of HSCTs in children are performed for rare indications (Sureda et al. 2015b). Allogeneic HSCT can cure several non-malignant disorders in children.

2.5.1 Transplant in Inborn Errors of Immunity

Inborn errors of immunity (IEI) are a group of rare heterogeneous genetic disorders (Lankester et al. 2021) characterized by defective or impaired innate or adaptive immunity. Of these, severe combined immunodeficiencies (SCIDs) are the most severe, leading to death in infancy or early childhood unless treated appropriately (Sureda et al. 2015b).

2.5.2 Severe Combined Immunodeficiencies

Severe combined immunodeficiencies (SCIDs) are a genetically heterogeneous group of rare inherited defects characterized by severe abnormalities of immune system development and function (Gaspar et al. 2013; Gennery 2015) with impaired T-lymphocyte differentiation (Lankester et al. 2021). Most of the genetic defects responsible for SCID are inherited in an autosomal recessive fashion and therefore are more common in infants born to consanguineous parents (Rivers and Gaspar 2015). The incidence of SCID varies according to ethnicity (Booth et al. 2016). The different forms of SCID can have different patterns of lymphocyte development. Nearly all SCIDs have absent T cells but are then further divided by the presence or absence of B and NK cells (Rivers and Gaspar 2015; Booth et al. 2016). If not detected in a neonatal screening program or with an informative family history (Lankester et al. 2021), patients with SCID usually present in early infancy with recurrent, severe or opportunistic infections. Multiple pathogens may coexist, and opportunistic infection, for example, with Pneumocystis jiroveci, is common (Gennery 2015). This can also be accompanied by failure to thrive with persistent diarrhoea and persistent oral thrush. Infants that present with lymphopenia should be further evaluated (Rivers and Gaspar 2015).

The severity of the clinical and immunologic situation requires prompt intervention, and for most patients, the only curative treatment is allogeneic HSCT (Gaspar et al. 2013; Gennery 2015). Gene therapy and enzyme replacement therapy are available for some specific genetic subtypes (Gennery 2015). The objective of HSCT in patients with SCID is to provide normal haematopoiesis, facilitating correction of the immune defect. Therefore, it is critical to minimize potential long-term effects of treatment but to establish effective long-term immune function (Gennery 2015). Once the diagnosis of SCID is made, there is an urgency of finding a suitable donor (Gaspar et al. 2013) and proceeding to transplant. Factors that influence the prognosis include the age, the type of SCID and the clinical state at the time of diagnosis, in particular the presence of infection and the degree of HLA matching with the donor (Sureda et al. 2015b).

2.5.3 Non-SCID Inborn Errors of Immunity

The three of the more common non-SCID IEI disorders are as follows:

  1. 1.

    Chronic granulomatous disease (CGD) patients with CGD have a reduced ability of phagocytes (particularly neutrophils) to kill bacterial and fungal pathogens.

  2. 2.

    Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency caused by mutations in the WAS gene, presenting with thrombocytopenia, eczema and immunodeficiency.

  3. 3.

    Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease of severe hyper inflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages (Booth et al. 2016).

2.5.3.1 Conditioning

There is a debate about the best approach of treatment. Different centres are using a wide variety of conditioning regimes (Booth et al. 2016). The EBMT/ESID (European Society for Immunodeficiencies) have published in 2021 updated guidelines for HSCT for IEI. They recommend, whenever possible, that individual transplant protocol should follow these guidelines (Lankester et al. 2021). In the presence of an HLA-identical family donor, HSCT can be performed in certain types of SCID (particularly those with an absence of NK cells) without any conditioning regimen. These patients can have donor T-cell (and occasionally B-cell) reconstitution, thereby potentially sparing short- and long-term toxicities (Dvorak et al. 2014; Gennery 2015; Sureda et al. 2015b). Overall conditioning increases the likelihood of myeloid engraftment, thymic output and independence from Ig in SCID patients. Therefore conditioning is recommended as a default position in most cases. If patient condition can’t tolerate chemotherapy, an unconditioned rescue infusion may be performed, with a risk of absent B cell reconstitution, a decline in thymopoiesis overtime, and high risk of graft failure in T-B-NK+ SCID. In these cases the patient might need a second transplant with conditioning when they recover and don’t have evidence of durable immune reconstitution (Lankester et al. 2021).

In contrast to SCID disorders, HSCT in non-SCID IEI always requires conditioning therapy. Over the years, the use of reduced intensity conditioning approaches has been explored in order to reduce acute and late effects (Booth et al. 2016; Lankester et al. 2021).

2.5.3.2 Outcome

In recent years, the outcome of HSCT has improved considerably with overall survival rates now approaching 90% in optimal circumstances (Gennery 2015). This is most likely due to earlier diagnosis; improved supportive care, including the initiation of bacterial and fungal prophylaxis; and early referral for HSCT (Booth et al. 2016). For many patients with IEI, partial donor chimaerism is sufficient to induce cure if the affected recipient cell lineage is replaced completely or partially by donor cells, although complete donor chimaerism is best in some diseases (Gennery 2015). Pai et al. reported the results of 240 infants who received a transplant for SCID, at 25 centres in the USA between January 2000 and December 2009. The overall survival rate at 5 years was 74%; most deaths were within the first year after transplant and were due to infections (39%) or pulmonary complications (37%). Mortality was increased for patients who had active infection at the time of transplantation.

2.5.4 Newborn Screening

Newborn screening (NBS) for SCID was first introduced in the United States. Programmes have now been rolled out in a number of countries around the world, including a growing number of European countries (Elliman and Gennery 2021). NBS tests enable identification of infants with life-threating disorders, which require early intervention shortly after birth (Giżewska et al. 2020). This will significantly improve the outcome for SCID patients, allowing a rapid move to curative therapy before symptoms and infections accrue (Gaspar et al. 2013; Booth et al. 2016). Detection of SCID at birth allows immediate protection with prophylactic Immunoglobulin substitution and antibiotics, thus keeping children free from infection until a definitive procedure can be undertaken (Gaspar et al. 2013). Screening is based on a qPCR assay for T-cell receptor excision circles (TRECs) which can be performed on the dried blood spot tests—Guthrie already taken as part of universal newborn screening for other inherited conditions. TRECs are essentially a marker of thymic output and their levels are severely reduced in SCID and in a number of other conditions. If low TREC levels are detected, then assay is repeated before the patient is called for further immunological evaluation (Booth et al. 2016).

The optimal way to approach transplant in those infants identified through NBS programs has yet to be determined (Booth et al. 2016). Once diagnosis of SCID has been made there is an urgent need to identify a suitable donor. The use of chemotherapy in pre-symptomatic children with SCID is difficult for physicians and families to accept (Booth et al. 2016) and the challenge is the assessment of the best conditioning regimen at a young age, in order to reduce the chemotherapy-induced toxicity (Haddad and Hoenig 2019).

2.5.5 Inherited Bone Marrow Failure

The inherited bone marrow failure (BMF) syndromes are a rare group of syndromes characterized by impaired haematopoiesis and cancer predisposition. Most inherited BMF syndromes are also associated with a range of congenital anomalies (Mehta et al. 2010). Patients with inherited BMF syndromes are usually identified when they develop haematologic complications such as severe bone marrow failure, myelodysplastic syndrome or acute myeloid leukaemia (Alter 2017).

Fanconi anaemia (FA) is the most common inherited BMF syndrome (Alter 2017; Dufour 2017). It is an autosomal recessive disorder characterized by a wide variety of congenital abnormalities, defective haematopoiesis and a high risk of developing acute myeloid leukaemia and certain solid tumours. The indication for HSCT in FA is the development of bone marrow failure (Tischkowitz and Hodgson 2003). Virtually all patients with FA will require treatment with allogeneic HSCT (Mehta et al. 2010).

Diamond-Blackfan anaemia (DBA) is characterized by erythroid defect, the presence of congenital anomalies and cancer predisposition. The classic presentation of DBA usually includes anaemia with essentially normal neutrophil and platelet counts, in a child younger than 1 year (Vlachos and Muir 2010). HSCT is currently the only option for cure and must be considered early for children with transfusion-dependency (Da Costa et al. 2019).

Dyskeratosis congenita (DC) is a multisystem disorder, with a disruption in telomere biology leading to very short telomeres underpinning its pathophysiology. Bone marrow failure is a key feature in DC and is the leading cause of mortality (Barbaro and Vedi 2016). Many patients are diagnosed during childhood because of thrombocytopenia or aplastic anaemia (Alter 2017). DC is genetically heterogeneous with X-linked, autosomal dominant and autosomal recessive subtypes. The clinical features include cutaneous manifestations of abnormal skin pigmentation, nail dystrophy, mucosal leukoplakia and BMF, pulmonary fibrosis and predisposition to malignancy (Mehta et al. 2010; Alter 2017).

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive disorder characterized by severe thrombocytopenia at birth due to ineffective megakaryocytopoiesis and progression towards aplastic anaemia during the first years of life (Germeshausen and Ballmaier 2021). HSCT remains the only known curative treatment for CAMT (Mehta et al. 2010; Germeshausen and Ballmaier 2021).

2.5.6 Inherited Diseases: Inborn Errors of Metabolism

Most of the metabolic diseases considered for HSCT are lysosomal storage diseases that rely on transfer of enzyme from donor-derived blood cells to the reticuloendothelial system and solid organs (Sureda et al. 2015b). This group of rare diseases includes mucopolysaccharidosis (MPS) as Hurler’s syndrome and leukodystrophy as X-linked adrenoleukodystrophy (X-ALD) and infantile Krabbe disease. The success of SCT in metabolic diseases is determined particularly by the degree of tissue damage present by the time of transplantation and the rate of progression of the disease (Steward and Jarisch 2005). Patients who are transplanted early or in their presymptomatic phase achieve better results as opposed to children with advanced disease (Chiesa et al. 2016). If damage to the central nervous system is present, it is irreversible and therefore a contraindication for transplant (Boelens et al. 2008).

2.5.7 Haemoglobinopathies

Increasingly, paediatric patients with transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD) have been transplanted in the past years (Passweg et al. 2014). Both diseases are autosomal recessive diseases of the haemoglobin. Early detection of the diseases by newborn screening provides the possibility of starting early with prophylactic therapy, preventing organ damage, and reducing morbidity and mortality (Lees et al. 2000; Peters et al. 2012). In TDT, a β-globin defect leads to anaemia and therefore patients need frequent blood transfusion. Chronic blood transfusion includes the risks of iron overload and allo-immunization, both requiring strict monitoring. Adherence to chelation therapy is important, because of the risks of iron overload, such as cardiomyopathy and liver cirrhosis (Peters et al. 2012). SCD is characterized by the sickling red blood cell, causing vascular occlusion and premature breakdown. Patients can face complications such as anaemia, painful vaso-occlusive crises, acute chest syndrome and organ damage. Supportive care for SCD includes strict adherence to medication, lifestyle recommendations, monitoring and it could also include frequent blood tranfusions or blood exchange (Houwing et al. 2019). Despite improved supportive care, both TDT and SCD are diseases majorly affecting the quality of life and life expectancy; an HSCT offers an established curative option for these haemoglobinopathies. For TDT patients with an available HLA-identical sibling, HSCT should be offered early to prevent iron overload and complications (Angelucci et al. 2014). In case no HLA-identical donor is available, a MUD donor can be considered. With adjustments in preconditioning and reduced-toxicity conditioning, the outcomes post-HSCT have improved. Also, the use of haplo donors in TDT with post cyclofosfamide has increasingly been used and provides the possibility of cure with easy access to a donor if an HLA-identical or MUD donor is lacking (Oikonomopoulou and Goussetis 2021). An HSCT also provides a curative option for SCD patients. Outcomes are excellent in young children transplanted with an HLA-identical donor. It is recommended to transplant young symptomatic SCD patients who have an HLA-identical donor as early as possible (Angelucci et al. 2014). When an HLA-identical donor is lacking and in case of severe disease symptoms according to internationally respected specific criteria (Walters et al. 1996), alternate donor sources can be considered (Angelucci et al. 2014). The safety of haploidentical transplantations in SCD has been improved by adjustments in preconditioning, conditioning, post-HSCT T-cell depletion, and supportive care; nevertheless, graft failure remains a concern (Aydin et al. 2021; Iqbal et al. 2021). HSCT was until a few years ago rarely performed in adults with haemoglobinopathies; recently, adult SCD patients with SCD complications are offered a non-myeloablative HSCT when an HLA-identical donor is available (Hsieh et al. 2009). As future perspective, gene therapy should be listed, providing the opportunity to treat the patients with genetically modified autologous stem cells, not needing a donor and eliminating the risks of GvHD. Especially for TDT, trials are promising (Thompson et al. 2018).