Haematopoietic Stem Cell Transplant

Historically referred to as bone marrow transplant.

Haematopoietic stem cell transplant is a potentially curative treatment for haematological malignancies, and classified by the source of replacement stem cells:

Indications

Include:

  • Haematological malignancy
    • Leukaemias
    • Lymphomas
    • Myelofibrosis
    • Myelodysplastic syndrome
  • Bone marrow failure syndromes
  • Certain other malignancies
    • Breast cancers
    • Ovarian cancer
    • Germ cell tumours
    • Small cell lung cancer
    • Renal cell cancer
  • Autoimmune diseases
    • MS
    • Systemic sclerosis
    • Crohn’s disease
    • SLE
    • MG
    • Various systemic vasculitides
  • Inborn Errors of Immunity
    • Severe Combined Immunodeficiencies
    • Primary HLH

Contraindications

Principles

Transplantation can be divided into four phases:

  1. Myeloablation
    Destruction of all haematopoietic cells, aimed to kill all tumour cells.
    • Usually consists of both:
      • Chemotherapy
      • Total body irradiation
    • Reduced intensity options exist for older or frailer patients
      Provide enough immunosuppression to permit engraftment.
    • Impaired cellular and humoral immunity
      Degree depends on the intensity of myeloablation and the primary pathology.
    • Common infections include:
      • Gram negative
      • Pneumonia
      • Systemic sepsis

Infusion of new cells (autologous or allogeneic) occurs after myeloablation, and signals the start of the pre-engraftment period.

  1. Pre-engraftment
    Time between infusion and when stem cells begin haematopoiesis.
    • Usually lasts <30 days
    • Profound neutropenia and susceptibility to bacterial infections
      • Gram positive infections predominate
        Due to the wide variety of Gram negative-covering antibiotics available.
      • Fungal infections
        • Candida
      • Neutropenic enterocolitis
      • HSV
    • Most ICU admissions occur during this phase

  2. Early post-engraftment
    Time from recovery of cell counts.
    • Classically day 30-100
    • Cell mediate immunity partially recovers, humoral immunity remains impaired
    • Vulnerability persists to:
      • Viral infections
        • CMV
          Prophylactic ganciclovir used for CMV positive recipients, or with positive donors.
        • HSV
        • Viral pneumonias
      • Fungal infections
        • Candida spp.
        • PJP
        • Aspergillus spp.

  3. Late post-engraftment
    Indefinite period that consists of some degree of impaired cell mediated and humoral immunity.
    • Viral infections
    • Encapsulated organism infections
      Meningococcal and streptococcal vaccination required.

Bacterial capsules are a polysaccharide envelope that inhibits binding of complement. Encapsulated organisms include:

  • S. pneumoniae
  • H. influenzae
  • N. meningitidis

  • Enterococcus spp.
  • Bacteroides spp.
  • Salmonella
  • Bartonella
  • Pseudomonas pseudomallei

Practice

Management depends on the stage of therapy:

  1. Myeloablation
  2. Pre-engraftment
    • Acyclovir
      Continue until resolution of mucositis.
    • Prophylactic trimethoprim
  3. Early post-engraftment
  4. Late post-engraftment

Complications

  • B
    • Diffuse alveolar haemorrhage
      Pulmonary endothelial injury secondary to chemotherapy. Risks include:
      • Age
      • Intensity of myeloablation
      • GvHD
      • Total body irradiation
      • Allogeneic transplant
    • Idiopathic pneumonia
  • D
    • PRES
  • H
    • Graft failure
      Failure to establish new population of bone marrow cells.
      • <5% after allogeneic infusion
      • Causes include:
        • Inadequate dose
        • Infection
        • GvHD
      • Management:
        • G-CSF
        • Stem cell re-infusion
        • Repeat transplant
    • Veno-occlusive disease
      Thrombotic occlusion of small hepatic veins.
      • Occurs early in post-transplantation period
      • Presents as:
        • Painful hepatomegaly
        • Jaundice
        • Ascites/oedema
        • Hyponatraemia
      • Risk factors:
        • Certain myeloablative regimens
        • Pre-existing abnormal LFTs
      • Complications:
        • AKI
        • CKD
          25% will require haemodialysis.
      • Management consists of:
        • Cease hepatotoxins
        • Immunosuppression:
          • Corticosteroids
          • Tacrolimus
          • Methotrexate
        • Defibrotide
          Inhibits platelet activation, aggregation, restores endothelial function, and improves microvascular thrombosis.
    • Post-transplant lymphoproliferative disorder
      Uncontrolled proliferation of EBV-infected B cells, causing impaired T-cell immunity.
    • TTP
  • I
    • Engraftment syndrome
      Transient inflammatory state occurring due to release of cytokines by engraftment of donor cells.
      • Features include:
        • Fever
        • Rash
        • Non-cardiogenic pulmonary oedema
        • Abnormal LFTs
        • Encephalopathy
      • ↑ Risk with G-CSF
      • Management with steroids and supportive care
    • Infection
      Highest risk in the pre-engraftment, followed by early post-engraftment phase.
      • Almost any pathogen can cause significant disease in the immunocompromised host
    • GvHD

Diffuse alveolar haemorrhage is covered under Diffuse Alveolar Haemorrhage.

TTP (and other microangiopathies) is covered under Thrombotic Microangiopathies.

GvHD is covered in detail under Graft versus Host Disease.

Baltimore criteria for veno-occlusive disease requires:

  • Bilirubin >34mmol/L
  • Two or more of:
    • Hepatomegaly
    • Ascites
    • Weight gain >5%
  • Within 21 days of BMT

Febrile neutropaenia is the combination of both:

  • Fever
    • Single temperature ⩾38.5°C
    • Sustained temperature ⩾38.0°C for >1 hour
  • Neutropaenia
    • Current count <0.5×109/L
    • Current count <1×109/L, with predicted nadir <0.5×109/L over next 48 hours

References

  1. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
  2. Snowden JA, Sánchez-Ortega I, Corbacioglu S, et al. Indications for haematopoietic cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2022. Bone Marrow Transplant. 2022;57(8):1217-1239.