Haematopoietic stem cell transplantation

• Haematopoietic stem cell transplantation (HSCT) replaces a patient's blood-forming system with healthy stem cells, collected from the patient (autologous) or from a donor (allogeneic).
• An autologous transplant uses the patient's own cells collected before high-dose therapy; an allogeneic transplant uses donor cells and brings a new immune system.
• The main allogeneic complications are graft-versus-host disease (GVHD), infection, and regimen-related toxicity such as sinusoidal obstruction syndrome (SOS, also called VOD).
• Choosing a donor follows a stepwise order: an HLA-matched sibling, then a matched unrelated donor, then other alternatives such as haploidentical, mismatched unrelated and cord blood donors.
• The intensity of the preparative conditioning regimen is chosen from myeloablative conditioning (MAC) through reduced-intensity (RIC) to non-myeloablative (NMA) conditioning, by age, fitness and disease status.

By the end of this page you should be able to:

1. Distinguish autologous from allogeneic transplantation and state the aim of each.
2. Explain HLA matching, donor selection order, and why donor age and timing now matter as much as HLA.
3. Compare bone marrow, peripheral blood and umbilical cord blood as stem cell sources.
4. Classify conditioning regimens as MAC, RIC or NMA, and name the common protocols.
5. Recognise acute and chronic GVHD, SOS/VOD, infection, and other complications, and outline first-line treatment.
6. Plan early post-transplant care and long-term follow-up, including vaccination and GVHD monitoring.
7. Adapt donor selection and follow-up for children, non-malignant disease and low-resource settings.

HSCT is a potentially curative treatment for many malignant and non-malignant disorders of blood and marrow, immune and metabolic diseases. It is not a single procedure but a whole treatment platform: patient selection, donor identification, stem cell harvest, preparative conditioning, infusion, supportive care, and long-term follow-up. The cells are infused intravenously and home to the bone marrow; HSCT is not an operation.

Transplant medicine has changed rapidly. HLA matching remains important, but newer GVHD prophylaxis, better typing and donor selection by age and availability have made transplants from mismatched donors far safer than in the past. ^[11]

Indications are disease-specific and change with new drugs and trials; the hospital team decides in each case. A transplant may be advised for:

• High-risk or relapsed acute leukaemias and some lymphomas when standard treatment is insufficient.
• Multiple myeloma, where autologous transplant remains standard after induction.
• Severe aplastic anaemia and some inherited marrow failure syndromes.
• Thalassaemia major, sickle cell disease and some inborn errors of metabolism and immunodeficiency when a matched donor is available.
• Some solid tumours in selected paediatric protocols.

The decision also takes into account age, comorbidity, disease stage and measurable residual disease. Risk tools combine these rather than any single variable: the EBMT risk score, the disease risk index and the HCT-specific comorbidity index are examples. ^[1] A high risk of non-relapse mortality pushes the team towards a reduced-intensity regimen. ^[1]

Pregnancy is an absolute contraindication. Relative contraindications include uncontrolled infection, severe or chronic liver disease, and severe impairment of heart, lung or kidney function (for example FEV1 or DLCO under 40%, or creatinine clearance under 30 ml/min). ^[1] Age alone is not a contraindication; fitness and comorbidity matter more. ^[1]

In an autologous transplant the patient's own stem cells are collected, stored, and reinfused after high-dose therapy. It restores haematopoiesis after dose-intensive treatment but gives no new immune system and no graft-versus-leukaemia (GVL) effect. In an allogeneic transplant, cells come from a donor and establish a new immune system; that donor immunity can attack residual disease (GVL) but can also attack the patient (GVHD).

Autologous transplant is common for myeloma and relapsed lymphoma. Allogeneic transplant is used when the marrow itself is diseased, failed, or the goal is immune replacement.

Human leukocyte antigen (HLA) matching is the cornerstone. In most European practice the classical set is HLA-A, -B, -C, -DRB1 and -DQB1 (10/10), with DPB1 also considered. ^[11] The traditional order is:

1. HLA-matched sibling donor (MSD).
2. HLA-matched unrelated donor (MUD), high-resolution 10/10.
3. Alternative donors when no full match exists: haploidentical relative, mismatched unrelated donor (MMUD), or umbilical cord blood.

Several things have changed this order. A young unrelated donor can give better overall and event-free survival than an older matched sibling, especially in the non-post-transplant cyclophosphamide (PTCy) setting. ^[11] With PTCy, a young fully matched unrelated donor also improves event-free survival and lowers relapse in certain situations. ^[11] Timely transplantation from an alternative donor gives survival and acute GVHD rates similar to an 8/8 matched unrelated transplant. ^[11] Donor age should therefore be counted alongside HLA. ^[11] Every candidate should have HLA typing at diagnosis and an early unrelated-donor search. ^[11]

For non-malignant disease and paediatric patients, HLA matching takes even greater priority: an MSD first, then a 10/10 MUD, with partially mismatched donors reserved for experienced centres. ^[11]

Donor age is the best studied extra factor: younger donors improve outcome with matched, mismatched and haploidentical transplants. ^[11] Stem cell source, donor sex, cytomegalovirus (CMV) serostatus and ABO compatibility have more mixed evidence and should carry lower priority in modern algorithms. ^[11] Using bone marrow reduces acute and chronic GVHD compared with peripheral blood, without a clear survival difference. ^[11]

About three times more CD34-positive cells are present in peripheral blood than in bone marrow for the same recipient weight, and roughly fifteen times more CD3 T cells. ^[2] Neutrophil engraftment is faster with peripheral blood (about 14 versus 21 days in sibling transplants, p less than 0.001), but chronic GVHD is commoner (about 73% versus 56%). ^[2] Peripheral blood is now used in more than 80% of adult allogeneic transplants worldwide, while bone marrow remains preferred in children. ^[2]

Cord blood is an attractive option when no adult donor is available: it is already typed and cryopreserved, tolerates greater HLA mismatch with low chronic GVHD, and has strong antileukaemic activity. Its disadvantages are slower engraftment, higher non-relapse mortality, limited cell dose (especially in adults), delayed immune reconstitution and the inability to obtain donor lymphocyte infusions later. Cord blood use has fallen as haploidentical transplant with PTCy has risen; two randomised trials showed haploidentical transplant superior. ^[1][3]

GVHD prophylaxis for cord blood transplants is usually a calcineurin inhibitor for 6-9 months plus mycophenolate for 2-6 months; methotrexate is usually avoided because of its effect on neutrophil recovery. ^[3] Antithymocyte globulin (ATG) can reduce GVHD but delays T-cell recovery and raises mortality in haematological malignancy, so it is generally not recommended in that setting. ^[3] Cord blood outcomes by disease risk in adults at 2 years are roughly 55% survival for low-risk disease and 19% for very high-risk disease. ^[3]

Donor-specific anti-HLA antibodies (DSA) raise the risk of primary graft failure in any HLA-mismatched transplant. All candidates for a haploidentical, mismatched unrelated or cord blood transplant must be screened, at referral and again at least one month before conditioning, because antibodies can be acquired after pregnancy or transfusion. ^[11] Flow-cytometric and single-antigen bead testing guide decisions; desensitisation may be attempted if no antibody-negative donor is available. ^[11]

Candidate evaluation follows a written plan. It covers medical history and examination, disease and remission status, routine blood tests, serology for viruses (CMV, EBV, herpes, toxoplasma, hepatitis B and C, HIV with local variation), chest imaging, lung and heart tests, dental and gynaecological review, and nutrition. ^[1] Most studies must be done within 30 days of transplant; disease re-evaluation within 7-15 days and a pregnancy test within 7 days. ^[1] Pre-transplant HLA typing is rechecked. ^[1]

Counselling is a formal step, not an afterthought. The patient is told what the transplant aims to achieve, the alternatives, the chance of relapse, and the early and late complications: graft failure, mucositis, SOS/VOD, GVHD, infections, infertility, endocrine problems and later cancers. ^[1] Matched unrelated donors can be found through the international registries, which now hold over 40 million donors; the chance of finding a compatible donor is 50-80%, depending on ethnic background. ^[1] Cord blood and haploidentical routes are explained when no full match exists. ^[1]

If possible the patient is asked to store sperm or oocytes before conditioning; infertility is common after myeloablative treatment. An advance directive and a named decision-maker should be discussed. Patients with functioning ovaries can consider ovarian suppression during conditioning, depending on local practice.

Stem cells are collected in one of three ways:

• Bone marrow harvest from the posterior iliac crests under general anaesthesia.
• Peripheral blood stem cell collection by apheresis after mobilisation with G-CSF (and sometimes chemotherapy).
• Cord blood collected at delivery and cryopreserved in a bank.

Apheresis products normally contain very few red cells, so ABO depletion is rarely needed. Bone marrow may need red cell depletion when donor and recipient are ABO incompatible. ^[2] Cell products are counted (CD34-positive cells per kilogram), quality-controlled and either infused fresh or cryopreserved. ^[2] The transplant itself is an intravenous infusion through a central line: HSCT resembles a blood transfusion, not surgery. ^[1]

Conditioning (the preparative regimen) is given before infusion. It has two jobs: to make space for donor cells in the bone marrow, and to suppress the recipient's immune system so the graft is not rejected. In cancer it also aims to eradicate malignant cells. ^[4]

A regimen has a myelodepletive and a lymphodepletive part. Classically:

• Myeloablative conditioning (MAC) causes irreversible marrow failure and must be followed by stem cell rescue. It was limited to younger, fitter patients (typically up to about 55 years) because of organ toxicity. ^[4]
• Reduced-intensity conditioning (RIC) causes profound but potentially reversible cytopenia and allows transplant in older or less fit patients. ^[4]
• Non-myeloablative (NMA) conditioning causes minimal cytopenia and aims mainly at immunosuppression and engraftment. ^[4]

Total body irradiation (TBI) is a cornerstone of many MAC regimens. TBI of at least 5 Gy in one fraction or 8 Gy in fractionated doses is considered MAC. ^[4] A classic schedule is 12 Gy in six fractions. ^[4] Intravenous busulfan replaced oral busulfan because its pharmacokinetics are more predictable, with less sinusoidal obstruction syndrome and treatment-related mortality. ^[4]

Common regimens:

• Allogeneic MAC: CY/TBI (cyclophosphamide 60 mg/kg for 2 days then TBI 12 Gy) or BU/CY; many centres now use fludarabine with busulfan 4 (FLU/BU4) or fludarabine with treosulfan. ^[4]
• RIC: FLU/BU2 (half-dose busulfan) or FLU/MEL (fludarabine plus melphalan). ^[4]
• Alternative donors: post-transplant cyclophosphamide (PTCy) regimens (Baltimore approach) classically use fludarabine, low-dose cyclophosphamide and low-dose TBI before transplant, with PTCy, tacrolimus and mycophenolate after; thiotepa-busulfan-fludarabine (TBF) is popular for haploidentical and cord blood grafts. ^[4]
• Autologous: BEAM for lymphoma; high-dose melphalan for myeloma; some centres add bortezomib or busulfan. ^[4]

TBI has major short- and long-term toxicities: mucositis, haemorrhagic cystitis, cataracts, infertility, growth retardation in children, interstitial pneumonitis, SOS/VOD and second malignancies. ^[4] Conditioning choice is individualised by age, comorbidity, disease type, donor type and disease status including measurable residual disease. ^[4]

Prophylaxis is chosen with the donor type, conditioning and recipient in mind. Standard prophylaxis is a calcineurin inhibitor (ciclosporin or tacrolimus) plus methotrexate or mycophenolate. In an unrelated or haploidentical setting ATG, PTCy or abatacept may be added. ^[5] Tacrolimus with methotrexate reduced grade II-IV acute GVHD to about 32% in sibling transplants and 56% in unrelated transplants, compared with 44% and 74% with ciclosporin and methotrexate in two randomised phase III trials. ^[5] PTCy has reduced GVHD risk and improved GVHD-free, relapse-free survival in both matched and mismatched transplantation, compared with calcineurin-based prophylaxis plus methotrexate. ^[11] ATG limits the effect of a single HLA mismatch to results close to a 10/10 match, but it is less effective in 8/10 mismatched transplants and is generally avoided in cord blood transplants because it delays immune reconstitution. ^[11] Abatacept plus a calcineurin inhibitor and methotrexate lowers acute GVHD in 7/8 mismatched unrelated transplants. ^[11]

Engraftment is the recovery of neutrophils and platelets from donor cells, usually taking a few weeks. Protective immune reconstitution takes months and sometimes years. Early care concentrates on:

• Infection prevention in a protective environment with high-efficiency particulate air (HEPA) filtration (at least 12 air exchanges per hour, positive pressure of about 2.5 Pa or more) and standard food-safety practices. ^[9]
• Hand hygiene, which is the single most effective measure, plus transmission-based precautions for suspected infections. ^[9]
• Prophylaxis against CMV, mould-active fungi, Pneumocystis and other infections according to local and international guidelines. ^[3]
• Watching for regimen-related toxicity, neutropenic fever and infusion reactions.
• Supportive care: red cell and platelet transfusion, antiemetics, mucositis care, nutrition and pain control.

Patients are followed two to three times a week as outpatients until about day 100 and should stay within about one hour of the transplant centre for the first 3 months. ^[1] Full recovery commonly takes about a year. ^[1]

Acute GVHD (aGVHD) is the main early allogeneic complication. It occurs in roughly 40% of recipients, with intensity depending on donor type and prophylaxis. ^[5] Without effective prophylaxis it is almost inevitable with unrelated or mismatched grafts. ^[5] It is driven by donor T cells responding to recipient tissues; risk rises with HLA disparity, older recipients, female donors for male recipients and more intense conditioning. ^[5]

It affects skin, liver, upper and lower intestine (a typical presentation is diarrhoea). Diagnosis is clinical and ideally confirmed by biopsy. Severity is staged by organ and graded I-IV; higher grades carry worse prognosis. ^[5] First-line treatment is high-dose corticosteroids at about 2 mg/kg/day of methylprednisolone (or equivalent) for 7-14 days, then taper. ^[5] About 40-50% respond. ^[5] Steroid-refractory disease can be treated with ruxolitinib, which achieved a 62% response rate against 39% with investigator's choice in a randomised phase 3 trial. ^[5] Refractory disease carries roughly 80% mortality, particularly with lower gut involvement. ^[5] Mesenchymal stromal cells have shown response rates above 50%. ^[5]

Chronic GVHD (cGVHD) is the most important cause of late non-relapse morbidity and mortality after allo-HSCT, contributing to about 25% of deaths. ^[6] It develops in about 50% of patients, between 3 months and 2 years after transplant; children have 6-40%, rising to 60% with increasing age. ^[6] Risk factors mirror those of aGVHD (PB stem cells rather than bone marrow, older donors or patients, female donor into male recipient, unrelated or mismatched donor, prior acute GVHD). ^[6] It may affect skin (scleroderma-like changes), mouth, eyes, liver, gut, lungs (bronchiolitis obliterans) and joints.

cGVHD has a protective side: patients with mild cGVHD have lower relapse from their original cancer and better survival than patients without cGVHD; even moderate cGVHD does not reduce overall survival, whereas severe cGVHD carries a long-term mortality of about 50%. ^[6]

First-line treatment is corticosteroids, with topical treatment for mild disease; initial doses are 1 mg/kg/day of prednisone or methylprednisolone, often with a calcineurin inhibitor; topical agents are used to limit steroid exposure, especially in children. ^[6] First-line therapy produces complete remission in about 20% of adults and 50% of children. ^[6] Response should not be judged before 8 weeks (3-6 months if there is deep skin sclerosis). ^[6] cGVHD increases infection risk, so patients with IgG under 400 mg/dL or recurrent infections may receive intravenous immunoglobulin, and only inactivated vaccines are used during active disease. ^[6]

Infection remains the leading cause of death in the first 100 days. Preventive work focuses on environment and air handling (HEPA filters), hand hygiene, isolation, and food safety. ^[9] Antimicrobial stewardship and surveillance for multidrug-resistant bacteria are recommended in every transplant centre. ^[9] Local protocols add prophylaxis against CMV (for example letermovir in cord blood transplants), mould-active azoles, co-trimoxazole for Pneumocystis and toxoplasmosis, and regular viral monitoring, guided by international consensus guidelines. ^[3]

SOS, also called veno-occlusive disease, is a life-threatening endothelial complication of conditioning affecting the small hepatic vessels. It occurs in about 5-15% of adults and about twice that in children, more with high-risk regimens. ^[7] Presentation is hepatomegaly, right upper quadrant pain, weight gain and ascites, jaundice and transfusion-refractory thrombocytopenia; severe disease has mortality above 80%. ^[7] Diagnosis uses the EBMT criteria (bilirubin, painful hepatomegaly, weight gain over 5%, ascites, ultrasound or elastography), with a separate probable category for early diagnosis before all criteria are met. ^[7] A hepatic venous pressure gradient over 10 mmHg is highly specific. ^[7]

Defibrotide is the only licensed treatment, at 25 mg/kg/day for a minimum of 21 days until resolution, and should be started promptly at diagnosis. ^[7] Ursodeoxycholic acid from the start of conditioning to day 90 is recommended prophylaxis in adults; in children defibrotide prophylaxis has shown benefit in a randomised trial despite negative results in an adult-inclusive trial. ^[7] A bilirubin above 2 mg/dL at any age predicts poor day-100 survival. ^[7]

Hepatotropic viruses (hepatitis B, C and E) need screening of donor and recipient; hepatitis B is managed with tenofovir or entecavir prophylaxis starting before conditioning, continued at least 1 year, and hepatitis C is usually cured with direct-acting antivirals before transplant where possible. ^[7]

Pulmonary dysfunction occurs in 25-55% of recipients. ^[8] Acute non-infectious problems include fluid overload (up to 60% early on), idiopathic pneumonia syndrome (IPS, less than 10% after myeloablative transplant; 7% with TBI of at least 12 Gy, 2% after reduced-intensity conditioning), and diffuse alveolar haemorrhage (2-14%). ^[8] Late non-infectious pulmonary complications occur in up to 20% of allogeneic recipients and include bronchiolitis obliterans syndrome (BOS) and interstitial lung disease. ^[8] All need rapid assessment with imaging, bronchoscopy and lavage, because infection and immune injury can coexist. ^[8] BOS is diagnosed on lung function and is treated cautiously: inhaled budesonide/formoterol has shown benefit in new-onset moderate-to-severe disease. ^[8]

Haemorrhagic cystitis (HC) occurs in two forms. Early-onset HC is chemical or radiation damage during or soon after conditioning and is rare. Late-onset HC occurs around engraftment and is usually viral, mainly BK polyomavirus, with overt disease in about 20% of patients; BK viruria is present in more than 50% of allogeneic recipients. ^[10] Diagnosis requires macrohaematuria with cystitis symptoms and BK viruria over 10^7 copies/mL; BK viremia over 10^3 copies/mL is associated with disease. ^[10] Prophylaxis for high-dose cyclophosphamide is hyperhydration with mesna; fluoroquinolones are not recommended. ^[10] Treatment includes cidofovir (intravenous, often with probenecid, or intravesical), hyperbaric oxygen, and bladder-directed measures; virus-specific T cells and mesenchymal cells are experimental. ^[10]

Acute kidney injury occurs in 27-66% of allogeneic recipients, mainly in the first 100 days, and is less common after autologous transplant. ^[10] It is graded by creatinine and urine output and raises the risk of chronic kidney disease, non-relapse and overall mortality. ^[10]

Transplant also carries risks of venous thrombosis and bleeding, sinusoidal and capillary leak syndromes, engraftment syndrome, post-transplant lymphoproliferative disease, iron overload, gonadal failure and infertility, endocrine dysfunction, osteoporosis, growth impairment in children, and second malignancies. Many of these have disease-specific chapters; the team's follow-up plan covers screening for them.

After discharge, HSCT is a form of long-term immunotherapy. Patients need weeks to months of immunosuppression for GVHD prophylaxis and monitoring for CMV, EBV, other viruses, and liver, lung and skin changes. Inactivated vaccines are reintroduced after immune recovery, once GVHD is controlled; live vaccines are avoided until immune reconstitution is adequate. ^[1][6] Late complications such as chronic GVHD and pulmonary disease need surveillance for years. ^[8]

Visit frequency eases from two or three times a week early on to less frequent as recovery proceeds; long-term follow-up is often lifelong. ^[1] Bone density, endocrine and growth checks apply, especially for children and adolescents. Long-term monitoring for chronic GVHD uses organ-specific grading; function (lung volumes, eye, mouth and skin) is tracked at intervals. ^[6]

Children. Bone marrow is still preferred in paediatrics to reduce chronic GVHD, and adult donors are preferred over child donors where possible, with adolescents before younger children. ^[11] Haploidentical transplant in children is usually performed with ex-vivo T-cell-depleted grafts; unmanipulated haploidentical transplant with PTCy is growing but should be used in trials. ^[11] Cord blood is a valuable option, with better outcomes when HLA mismatch is limited (6/8 or better at high resolution) and cell dose is high. ^[11] SOS/VOD and haemorrhagic cystitis are commoner in children. ^[10]

Non-malignant disease. Here the goal is durable engraftment with minimal toxicity and GVHD, because there is no benefit to graft-versus-tumour activity. An MSD is preferred, then a 10/10 MUD, with mismatched donors only in experienced centres. ^[11] Bone marrow is favoured as the graft source to limit chronic GVHD. ^[11] Heavily transfused patients (for example thalassaemia) must be screened early and repeatedly for anti-HLA antibodies and iron overload. ^[11]

Older adults. Age alone is not a barrier; reduced-intensity conditioning extends transplant to older and less fit patients. ^[4] Comorbidity and disease risk tools guide selection. ^[1]

• A single-procedure transplant (autologous for myeloma or lymphoma) can be run with limited infrastructure where there is a trained team, but allogeneic transplant needs HEPA-filtered rooms, blood bank support, infection diagnostics and intensive care, none of which should be compromised.
• Where no matched donor is available, cord blood may be an option if a banked unit can be imported and cell dose is adequate; haploidentical transplant lowers the donor barrier.
• Prolonged follow-up is the hardest part. Patients must be able to return to the centre frequently during the first months.
• Prevention of reactivation disease (CMV, hepatotropic viruses) and good infection control often matter more than expensive technology.

• HSCT replaces the blood-forming system using the patient's own (autologous) or donor (allogeneic) stem cells.
• Autologous transplant restores haematopoiesis after high-dose therapy; allogeneic adds a new immune system with GVL and GVHD.
• Donor selection now balances HLA, donor age, availability and timing, not HLA alone.
• Bone marrow lowers chronic GVHD; peripheral blood speeds engraftment and adds GVL; cord blood expands access but delays engraftment.
• Conditioning ranges from MAC (up to about age 55, usually with TBI or high-dose alkylators) to RIC and NMA for older or less fit patients.
• Acute GVHD affects about 40% of recipients; first-line treatment is methylprednisolone at about 2 mg/kg/day, with ruxolitinib for steroid-refractory disease.
• Chronic GVHD occurs in about 50% of patients and causes about a quarter of long-term deaths; first-line treatment is prednisone at 1 mg/kg/day. ^[6]
• SOS/VOD occurs in 5-15% (adults) and about 15-30% (children); defibrotide at 25 mg/kg/day is the licensed treatment.
• Pulmonary dysfunction occurs in 25-55% of recipients; late complications in up to 20%.
• Haemorrhagic cystitis occurs in 7-25% late after transplant, usually from BK virus; acute kidney injury in 27-66%.
• Aftercare is long-term and close to the transplant centre during the first months.

• Transplant rejection (immune principles shared with solid-organ rejection)
• Graft-versus-host disease (acute and chronic)
• Aplastic anaemia
• Acute leukaemias
• Multiple myeloma
• Chronic myeloid leukaemia
• Infection control and neutropenic sepsis
• Vaccination in immunocompromised patients
• Chronic kidney disease and dialysis (post-transplant renal dysfunction)