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The importance of haematopoietic stem cells (HSCs) in the formation of blood cellular components
Haematopoiesis is defined as "a continuous process of blood-cell production occurring through the orchestrated proliferation, self-renewal and differentiation of haematopoietic stem cells (HSCs)."1
Throughout life, all blood cell lineages derive solely from HSCs.1
The hierarchical system of normal haematopoiesis2
- HSC: haematopoietic stem cell.
- 1. Mendelson, A. and Frenette, PS., Nat Med. 2014; 20:833-46, 2. Adapted from Zhang, P. et al., Stem Cell Res Ther. 2019; 10:327.
What is haematopoietic stem cell transplantation (HSCT)?
HSCT, also referred to as bone marrow transplantation, is the infusion of HSCs to re-establish haematopoietic function in patients with a damaged or defective bone marrow or immune system.1,2
- Patients with malignant haematopoietic diseases require HSCT to rescue their bone marrow from the toxic effects of high-dose chemotherapy and exploit the graft-versus-leukaemia effect against residual disease.
- In non-malignant diseases, the goal of HSCT is to replace genetically defective stem cells or failing haematopoiesis.
Stem cells for HSCT are usually derived from bone marrow, peripheral blood or umbilical cord blood.1
Over 40,000 HSCTs are carried out in Europe each year.3
- HSC: haematopoietic stem cell; HSCT: haematopoietic stem cell transplantation
- 1. Saria, MG. and Gosselin-Acomb, T., Clin J Oncol Nurs. 2007; 11:53–63, 2. Mosaad, YM., Immunol Invest. 2014; 43:858–87, 3. Passweg, JR. et al., Bone Marrow Transplant. 2016; 51:786–92.
HSCT is categorised by the donor source
Autologous
From the patient’s own peripheral blood.
Allogeneic
From another person, related or unrelated, who has been selected based on HLA-matching and other factors.
- HLA: human leukocyte antigen; HSCT: haematopoietic stem cell transplantation.
- Saria, MG. and Gosselin-Acomb, T. Clin J Oncol Nurs. 2007; 11:53–63.
Immune reconstitution after HSCT
Immune reconstitution after HSCT is a critical process to prevent infections and malignancy relapse.1,2
It is a gradual process by which the patient's immune system regains its normal function over time.1
Immune reconstitution involves the recovery of neutrophils, monocytes, antigen-presenting cells, T cells, B cells, and NK cells.1,3,4
- HSCT: haematopoietic stem cell transplantation; NK: natural killer
- 1. Elfeky, R. et al., Exp Rev Clin Immunol. 2019; 15:735-51, 2. Servais, S. et al., Biol Blood Marrow Transplant. 2014; 20:507-17, 3. de Koning, C. et al., Biol Blood Marrow Transplant. 2019; 25:819-26, 4. Velardi, E. et al., Nat Rev Immunol. 2021; 21:277-91.
Factors affecting immune reconstitution
Autologous HSCT3
Immune reconstitution after autologous HSCT is not impaired by factors such as graft-rejection, immunosuppression and GvHD. A more rapid reconstitution results in a generally lower risk of infection.
- CMV: cytomegalovirus; GvHD: graft-versus-host disease; HLA: human leukocyte antigen; HSCT: haematopoietic stem cell transplantation; IgG: immunoglobulin G.
- 1. Stern, L. et al., Front Immunol. 2018; 9:1672, 2. Gaytán-Morales, JF. et al., Bol Med Hosp Infant Mex. 2021; 78:191-9, 3. Champlin, R., Selection of Autologous or Allogeneic Transplantation. In: Kufe, DW. et al., Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.
HSCT can lead to secondary immune deficiency (SID)
SID is defined as "the transient or persistent impairment of the cellular or humoral components of the immune system, caused by extrinsic factors, leading to increased risk of infection."1
Timely diagnosis, ongoing monitoring, and prophylactic therapy are needed for SID management.1
Aetiology of SID
- HSCT: haematopoietic stem cell transplantation; SID: secondary immune deficiency.
- 1. Cem Ar, M. et al., Leukemia Research. 2023; 133:107365, 2. Tuano, KS. et al., Ann Allergy Asthma Immunol. 2021 Dec;127(6):617-626, 3. Shah, N. et al., Crit Rev Oncol Hematol. 2023; 181:103896, 4. Heck, C. et al., Fronts Immunol. 2021; 12:736137.
Impaired B cell function and secondary antibody deficiency (SAD)
Allogeneic HSCT can result in significant impairment of B cell function, including reduced antibody production and impaired memory B cell generation.1
B cell impairment can lead to SID, particularly secondary antibody deficiency (SAD).2,3
GvHD* can further impair B cell function and exacerbate SAD, as it affects the bone marrow microenvironment, leading to a reduced number and function of B cells and plasma cells.3
Immunosuppressive therapy for GvHD* contributes to SAD.3
SAD can result in an increased risk of infections and the need for prophylactic antibiotics and immunoglobulin replacement therapy.
- * Only valid for allogeneic HSCT
- GvHD: graft-versus-host disease; HSCT: haematopoietic stem cell transplantation; SAD: secondary antibody deficiency; SID: secondary immune deficiency.
- 1. Van der Maas, NG. et al., Front Immunol. 2019; 10:782, 2. Barrow, M. et al., Front Immunol. 2022; 13:928062, 3. Patel, SY. et al., Front Immunol. 2019; 10:33.
Allogeneic HSCT is associated with multiple complications, mainly related to conditioning and immunosuppression
- GvHD: graft-versus-host disease; HSCT: haematopoietic stem cell transplantation; VOD: veno-occlusive disease.
- Adapted from Saria, MG. and Gosselin-Acomb, TK., Clin J Oncol Nurs. 2007; 11:53–63.
Infection remains a substantial cause of death after HSCT in adults
2018–2020
Autologous HSCT*
Total transplants: 29,748
Allogeneic HSCT*°
Total transplants: 19,042
- * As data is shown to 0 d.p. total percent may not equal 100%; ° Includes ≥2 HLA antigen mismatch donors; ‡ 3-year mortality. † % of total transplants in adults in the USA, 2018-2020. GvHD: graft-versus-host disease; HLA: human leukocyte antigen; HSCT: haematopoietic stem cell transplantation.
- Adapted from Bolon, YT. et al., Current use and outcome of hematopoietic stem cell transplantation in the USA: CIBMTR summary slides, 2022, available at: https://cibmtr.org/CIBMTR/Resources/Summary-Slides-Reports, last accessed 03 August 2023.
Strategies after HSCT to prevent infections
- HSCT: haematopoietic stem cell transplantation.
- 1. Mikulska, M. et al., J Infect. 2018; 76:20-37, 2. Maertens, JA. et al., J Antimicrob Chemother. 2018; 73:3221-30, 3. Ljungman, P. et al., Lancet Infect Dis. 2019; 19:e260-72, 4. Cordonnier, C. et al., Lancet Infect Dis. 2019; 19:e200-12, 5. Foster, JH. et al., Pediatr Blood Cancer. 2018; 65:e27348.
Guidelines for infection prophylaxis after HSCT*
European Conference on Infections in Leukaemia (ECIL) Guidelines
| Prophylaxis | Population | Recommendations |
|---|---|---|
|
Bacterial infections |
Adult1 |
Antibacterial prophylaxis with fluoroquinolones for neutropenic patients with an expected length of neutropenia >7 days |
|
Paediatric2 |
No routine antibacterial prophylaxis |
|
|
Fungal infections |
Adult3 |
Fungal prophylaxis recommended and differs depending on treatment centre’s incidence of mould infection |
|
Paediatric4 |
Strongly recommended in patients who are at high risk of developing invasive fungal diseases |
|
|
Cytomegalovirus |
Adult and paediatric5 |
Pre-emptive antiviral therapy based on detection of cytomegalovirus DNA (or antigen) in whole blood or plasma is effective for the prevention of cytomegalovirus disease |
|
Pneumocystis jiroveci |
Adult and paediatric6 |
Trimethoprim/sulfamethoxazole given up to 3 times a week, depending on the dose, is the drug of choice for primary prophylaxis |
|
Vaccinations |
Adult and paediatric7 |
Vaccination with inactivated vaccines from 3 months after transplant |
- * Table updated September 2023.
- DNA: deoxyribonucleic acid; ECIL: European Conference on Infections in Leukaemia; HSCT: haematopoietic stem cell transplantation
- 1. Bucaneve, G. et al., Eur J Cancer Suppl. 2007; Suppl 5:5-12, 2. Lehrnbecher, T. et al., Lancet Oncol. 2021; 22:e270-80, 3. Maertens, JA. et al., J Antimicrob Chemother. 2018; 73:3221-30, 4. Groll, AH. et al., Lancet Oncol. 2021; 22:e254-69, 5. Ljungman, P. et al., Lancet Infect Dis. 2019; 19:e260-72, 6. Maertens, JA. et al., J Antimicrob Chemother. 2016; 71:2397-404, 7. Cordonnier, C. et al., Lancet Infect Dis. 2019; 19:e200-12.
Despite use of antibiotic prophylaxis, the incidence of infection remains high
Cumulative incidence of bacteraemia1
- HSCT: haematopoietic stem cell transplantation; IgRT: immunoglobulin replacement therapy.
- 1. Junghanss, C. et al., Biol Blood Marrow Transplant. 2002; 8:512-20, 2. Foster, J. et al., Pediatr Blood Cancer. 2018; 65:e27348.
Scientific evidence for the use of IgRT after HSCT
Studies have shown that prophylactic IgRT can reduce the incidence and severity of infections after HSCT.1-3
In 16 studies with 4462 patients, IgRT:4
- Reduced incidence of serious and moderate infection.
- Provided longer infection-free periods.
- Reduced morbidity compared with control groups.
- Reduced infection-related hospitalisations.*
- Showed a tolerable safety profile.
Cumulative incidence of mortality without relapse in patients ≥20 years old who received HLA-identical transplants.1
As HSCT and treatments for HSCT-related complications have evolved substantially over the past 30 years,5 more robust and newer clinical data on the use of IgRT in patients after HSCT are urgently required.2,6
- * In one study.
- GvHD: graft-versus-host disease; HLA: human leukocyte antigen; HSCT: haematopoietic stem cell transplantation; IgRT: Immunoglobulin replacement therapy.
- 1. Sullivan, KM. et al., N Engl J Med. 1990; 323:705–12, 2. Ahn, H. et al., Transfusion. 2018; 58:2437–52, 3. Foster, J. et al., Pediatr Blood Cancer. 2018; 65:e27348; 4. Shah, N. et al., Crit Rev Oncol Hematol. 2023; 181:103896, 5. Granot, N. and Storb, R., Haematologica 2020; 105:2716-2729; 6. Ohmoto, A. et al., Bone Marrow Transplant 2022; 57:874-880.
Recommendations for IgRT in HSCT recipients
|
Publication year: Society/Group |
Patients who should receive IgRT |
|
|---|---|---|
|
2009: |
American Society for Blood and Marrow Transplantation (ASBMT)1 |
High-risk recipients who undergo unrelated HSCT with IgG <400 mg/dL |
|
2017: |
Japan Society for Hematopoietic Cell Transplantation (JSHCT)2 |
Allogenic-HSCT recipients with pre-transplant IgG <400 mg/dL or with delayed immunoglobulin recovery |
|
2018: |
American Society for Blood and Marrow Transplantation (ASMBT) and Canadian Blood and Marrow Transplant (CBMT)3 |
CBT recipients, children who undergo transplantation for inherited or acquired disorders associated with B cell deficiency, and chronic GvHD patients with recurrent sinopulmonary infections |
|
2019: |
European Society for Blood and Marrow Transplantation (EBMT)4 |
Patients who underwent HSCT with IgG <400 mg/dL |
|
2021: |
European expert consensus5 |
All allogenic-HSCT recipients (particularly patients with low IgG level (<400 mg/dL) or with GvHD on immunosuppressive treatment) |
|
2021: |
U.S. National Comprehensive Cancer Network (NCCN)6 |
Allogenic-recipients who had recurrent infection with a serum IgG <400 mg/dL |
|
2022: |
American Academy of Allergy Asthma & Immunology (AAAAI)7 |
Recipients with IgG <400 mg/dL who had bacteraemia or recurrent sinopulmonary infection |
- CBT: cord blood transplantation; GvHD: graft-versus-host disease; HSCT: haematopoietic stem cell transplantation; IgG: immunoglobulin G; IgRT: immunoglobulin replacement therapy.
- 1. Tomblyn, M., et al. Biol Blood Marrow Transplant. 2009; 15:1143–238; 2. The Japan Society for Hematopoietic Cell Transplantation. Post-transplant infectious control guidelines (version 4.2017). https://www.jstct.or.jp/uploads/files/guideline/01_01_kansenkanri_ver04.pdf, last accessed 03 August 2023, 3. Bhella, S. et al., Biol Blood Marrow Transplant. 2018; 24:909–13, 4. Carreras, E. et al., The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. 7th ed. Cham: Springer; 2019. PMID:32091673, 5. Jolles, S. et al., Eur J Haematol. 2021; 106:439–49, 6. U.S. National Comprehensive Cancer Network, Guidelines for management of immunotherapy-related-toxicities - Version 2.2021, Guidelines Detail (nccn.org), last accessed 03 August 2023, 7. Otani, IM. et al., J Allergy Clin Immunol. 2022; 149:1525-60.
Harmonisation of clinical practice across Europe: European consensus statements on IgRT prophylaxis
"All patients undergoing allogeneic HSCT should be considered as candidates for IgRT."
"Particularly in patients with low IgG levels (<400 mg/L) or with GvHD on immunosuppressive treatment."
When initiating IgRT, "the dose should be weight-based."
In patients who are about to start IgRT, "both SCIg and IVIg should be discussed."
"Patients should be involved in the decision on the best route of administration."
In patients who require IgRT, "discontinuation should be considered after a clinically significant period without infections or if there is evidence of immunological recovery."
- GvHD: graft-versus-host disease; HSCT: haematopoietic stem cell transplantation; IgG: immunoglobulin G; IgRT: immunoglobulin replacement therapy; IVIg: intravenous immunoglobulin; SCIg: subcutaneous immunoglobulin.
- Jolles, S. et al., Eur J Haematol. 2021; 106:439–49
European Medicines Agency: Recommendations for IgRT notably in SID
Therapeutic indications for IVIg1
- Replacement therapy in adults, children, and adolescents (0–18 years) in:
- PID with impaired antibody production.
- SID in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure* or serum IgG level of <4 g/L.
- Measles pre-/post-exposure prophylaxis for susceptible adults, children and adolescents (0–18 years) in whom active immunisation is contraindicated or not advised.
- Immunomodulation in adults, children and adolescents (0–18 years) in:
- Primary immune thrombocytopenia, in patients at high risk of bleeding or prior to surgery to correct the platelet count.
- Guillain Barré syndrome.
- Kawasaki disease (in conjunction with acetylsalicylic acid).
- Chronic inflammatory demyelinating polyradiculoneuropathy.
- Multifocal motor neuropathy.
Therapeutic indications for SCIg2
Replacement therapy in adults, children, and adolescents (0–18 years) in:
- PID with impaired antibody production.
- Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed or are contraindicated.
- Hypogammaglobulinaemia and recurrent bacterial infections in multiple myeloma patients.
- Hypogammaglobulinaemia in patients pre- and post- allogeneic HSCT.
- * Failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines.
- HSCT: haematopoietic stem cell transplantation; IgG: immunoglobulin G; IgRT: Immunoglobulin replacement therapy; IVIg: intravenous immunoglobulin; PID: primary immunodeficiency syndromes; SCIg: subcutaneous immunoglobulin; SID: secondary immune deficiency.
- 1. Guideline on core SmPC for normal immunoglobulin for IVIg. Dec 2021, 2. Guideline on core SmPC for normal immunoglobulin for SCIg. Feb 2015.
Summary
- HSCT is used to re-establish haematopoietic function in patients with a damaged or defective haematopoietic system.1
- HSCT may result in prolonged secondary immunodeficiency.2
- Immune reconstitution occurs faster after autologous HSCT compared to allogeneic HSCT.3,4
- Immune reconstitution after allogeneic HSCT depends on a myriad of factors, e.g. donor source, age.5,6
- Immune reconstitution is a critical process for preventing infections and disease relapse.7,8
- Prophylactic IgRT can reduce the incidence and severity of infections after HSCT.9-12
- HSCT patients with hypogammaglobulinaemia are candidates for IgRT.13
- The use of IgRT is generally considered beneficial, in patients with low IgG levels (<400 mg/L) or with GvHD on immunosuppressive treatment.12
- GvHD: graft-versus-host disease; HSCT: haematopoietic stem cell transplantation; IgG: immunoglobulin G; IgRT: Immunoglobulin replacement therapy.
- 1. Saria, MG. and Gosselin-Acomb, T., Clin J Oncol Nurs. 2007; 11:53–63, 2. Barrow, M. et al., Front Immunol. 2022; 13:928062, 3. Wiegering, V. et al. J Pediatr Hematol Oncol. 2019 Jul;41(5):e302-e307, 4. Olkinuora, H. et al. Bone Marrow Transplantation. 2007;39(3):149-156, 5. Stern, L. et al., Front Immunol. 2018; 9:1672, 6. Gaytán-Morales, JF. et al., Bol Med Hosp Infant Mex. 2021; 78:191-9, 7. Mehta, RS. and Rezvani, K., Virulence. 2016; 7:901-16, 8. Elfeky, R. et al., Exp Rev Clin Immunol. 2019; 15:735-51, 9. Sullivan, KM. et al., N Engl J Med. 1990; 323:705–12, 10. Ahn, H. et al., Transfusion. 2018; 58:2437–52, 11. Foster, J. et al., Pediatr Blood Cancer. 2018; 65:e27348, 12. Shah, N. et al., Crit Rev Oncol Hematol. 2023; 181:103896, 13. Ohmoto A et al. Bone Marrow Transplant 2022; 57:874-880.