Bone Marrow Transplantation

OVERVIEW

• used in a wide range of malignant and non-malignant disorders
• can be autologous or allogeneic

• autologous = donor and recipient are the same person (avoids GVHD)
• allogeneic = genetically different but from the same species (GVHD and doesn’t need to be stored, but a limited amount of GVHD may have an anti-tumour effect)

• don’t take an entirely nihilistic approach to these patients if marrow recovery is imminent.
• however, prolonged ventilation and/or dialysis in these patients results in a poor prognosis.
• hematopoietic stem cells are obtained from either marrow aspiration or from peripheral blood by apheresis using a blood cell separator following stimulation of the marrow with hematopoietic growth factors +/- chemotherapy.

PRINCIPLES

• tumour must be responsive to chemotherapy +/- radiotherapy
• the limitation of chemotherapeutic agents used must related to bone marrow toxicity and not other organs
• must have a source of un- or minimally contaminated hematopoietic stem cells (autologous or allogeneic)
• appropriate hematopoietic supportive therapy must be available during the marrow aplastic period
• high quality clinical and laboratory must be available for the collection and preservation of hematopoietic stem cells.
• strong MDT commitment
• well-documented clinical protocols and effective implementation

GENERAL OVERVIEW OF COMPLICATIONS

NEUROLOGICAL COMPLICATIONS

• > with allogeneic transplantation
• risk factors: high dose chemotherapy, immunosuppression, GVHD, thrombocytopaenia

CVA

• median day of presentation = 28
• usually haemorrhage (intracerebral, SAH) from thrombocytopaenia
• other causes: infarction from infection or thrombosis, non-bacterial endocarditis and embolism
• high mortality (70%)
• standard management

CNS Infections

• aspergillosis (main cause), CMV, HSV, toxoplasma, Candida, Cryptococcus, bacterial meningitis
• prognosis is extremely poor

Metabolic Encephalopathy

• > in allogeneic transplantation
• altered mental status, seizures, Wernicke encephalopathy (altered mental status, ataxia, ophthalmoplegia)
• causes: hypoxaemia, electrolyte abnormalities, metabolic acidosis, sepsis, hepatic failure, medications (sedatives and analgesics), thiamine deficiency
• supportive care

Treatment related neurological complications

• OKT3: aseptic meningitis (can decrease risk with corticosteroids)
• cranial radiation
• imipenem: seizures
• corticosteroids: myopathy, psychosis
• cyclosporine A: encephalopathy, leukoencephalopathy, generalised cerebellar dysfunction, hemiparesis, quadriplegia, seizures.

Graft vs Host Disease

• acute GVHD: encephalopathy associated with other organ dysfunction
• chronic GVHD: polyneuropathy, polymyositis, MG
• treatment: intensification of immunosuppressive therapy

CARDIAC COMPLICATIONS

Pulmonary oedema

• commonest cardiac indication for ICU admission
• risk factors: low EF, fluid overload, ARF, veno-occlusive disease, severe sepsis, anaemia and high dose chemotherapy

Pericardial tamponade

• rare
• usually related to: cyclophosphamide toxicity, viral syndrome, chronic GVHD, renal failure, bacterial infection (rarely)

Endocarditis

• rare (1.3%)
• clinical features are subtle: left sided murmurs, indwelling CVC’s, disruption of skin and mucosal barriers by high dose chemotherapy and GVHD
• organisms: Staph aureus, Strep viridans, fungal, aseptic

Arrhythmia

• electrolyte abnormalities
• hypoxaemia
• sepsis
• MOF

PULMONARY COMPLICATIONS

• many reasons
• bilateral pulmonary infiltrate differential =

(1) Pneumonia

• Viral – CMV, HSV, VSV
• Bacterial – see Pneumonia in the immunocompromised Document
• Fungal – Pneumocystis, Aspergillus, Candida
• Protozoa – Toxoplasma

(2) Engraftment syndrome

(3) Bronchiolitis obliterans +/- organizing pneumonia (BOOP)

(4) Diffuse alveolar haemorrhage

(5) Idiopathic pneumonia syndrome

• organisms causing infection are temporally distributed:
  -> early (< 30 days): bacteria, candida, aspergillus, HSV, RSV
  -> mid (30-100 days): CMV, PCP, adenovirus, HZV, aspergillus
  -> late (> 100 days): CMV

GASTROINTESTINAL COMPLICATIONS

GVHD of Intestine

• clinical features: abdominal pain, N+V, diarrhoea, bleeding, may have peritonism, often associated with hepatitis and a skin rash (acute GVHD)
• CT: bowel wall oedema
• treatment: intensification of immunosuppressive therapy

Intestinal Pseudo-obstruction

• supportive and minimizing aggravating factors

Veno-occlusive Disease of Liver

• common
• may be mild -> rapidly fatal (in 40%)
• pathogenesis: thrombosis of the small central hepatic venules due to endothelial cell damage by high dose chemotherapy
• clinical features: during first 21 days following transplant, weight gain, tender liver, jaundice
• investigations: transaminitis, hyperbilirubinaemia, Doppler U/S showing reversal or diminished portal flow.
• management: supportive, fluid restriction, diuresis, paracentesis, avoid infections and hepatotoxic medications, oral ursodeoxycholic acid (lowers bilirubin) possibly thrombolytics

GI Bleeding

• diffuse mucosal bleeding of the small intestine, mucosal ulcers and necrosis
• causes: chemotherapy induced, GVHD, adenovirus, CMV
• management: supportive, endoscopy (rarely required), surgery

Enteritis

• mild to self limiting -> severe dehydration, hypotension and ARF
• causes: GVHD, bacterial infection (clostridia), viral infections (rotavirus, adenovirus, CMV, HSV, HZV)
• treatment: supportive, octreotide (decrease secretory hormones), rotavirus (oral immunoglobulins)

Intestinal Perforation

• causes: CMV ulcers, corticosteroids, GVHD
• treatment: standard care

Pancreatitis

• rare
• causes: medications (cotrimoxazole, corticosteroids, cyclosporine A), infections (CMV and adenovirus), GVHD, biliary sludge
• treatment: standard

Other Liver Disease

• viral hepatitis: adenovirus, HSV, HZV, CMV, Hep B and C
• acute GVHD: rarely producers fulminant liver failure
• fungal infection: liver involvement of Candida and Aspergillus

RENAL COMPLICATIONS

• if develops the need for dialysis -> mortality 90%

Tumour Lysis Syndrome

• rare as tumour burden is reduced prior to transplantation
• clinical features: hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia, renal failure
• treatment: IVF, allopurinol, rasburicase, phosphate binders, dialysis

Infusion of Stem Cells

• haemolysis -> haemoglobinuria -> proximal ATN -> ARF
• treatment: hydration, alkalinsation

Haemorrhagic Cystitis

• risk factors: cyclophosphamide, busulfan, irradiation, viral infections
• prevention: IVF, diuresis, irrigation of the bladder, mesna

Veno-occlusive Renal Disease

• clinical features: day 10-21 post transplant, hepatorenal syndrome
• risk factors: mismatched graft, age > 25 years, pre-existing renal failure, sepsis, amphotericin B

Drug Nephrotoxicity

• cyclosporine A: intensive renal arteriolar vasoconstriction
• nitrourea
• methotrexate
• cyclophosphamide
• amphotericin B
• acyclovir
• foscanet
• aminoglycosides
• tacrolimus

INFECTIOUS COMPLICATIONS

Viral

• CMV: pneumonitis is the most lethal -> ganciclovir/foscarnet, Ig’s
• RSV: URTI -> LRTI -> nasal wash/BAL, aerosolized ribavirin, Ig’s
• HSV-6: pneumonitis, marrow suppression, encephalitis -> ganciclovir/foscarnet
• HZV: pneumonia, hepatitis, skin rash, encephalitis, DIC -> high dose acyclovir

Bacterial

• risk factors: neutropenia, mucositis, skin breakdown, GI problems, IV catheters
• organisms: gram negatives (Pseudomonas, Klebsiella), gram positives (MRSA, Strep viridans, enterococci)

Fungal

• invasive pulmonary aspergillus: lungs to haematogenous dissemination -> CXR: halo sign and air crescent sign, sputum, BAL, voriconazole/caspofungin
• candida: fluconazole or caspofungin (evidence of endophthalmitis or resistant organisms)
• PCP: rare now c/o co-trimoxazole prophylaxis -> requires a BAL

SUMMARY

Acute (< 30 days)

• neutropenia
• acute tumour lysis
• infection: bacterial, fungal and viral
• respiratory: engraftment, haemorrhage
• cardiovascular: CHF, arrhythmias, tamponade
• gastrointestinal: GIH, enteritis, veno-occlusive disease of liver
• nervous: CVA, encephalopathy
• other: haemorrhagic cystitis

Early (30-100 days)

• acute GVHD
• graft failure
• pneumonitis
• BOOP
• infection: bacterial, viral, fungi

Late (>100 days)

• chronic GVHD
• myopathy
• neuropathy
• HUS
• infection: CMV
• infertility
• second malignancy
• cataracts

PROGNOSIS

• critical illness during engraftment period (< 30 days post BMT) -> mortality 33%
• acute GVHD (moderate to severe) -> mortality 90%
• more than two organ systems and need for mechanical ventilation/RRT are associated with very poor outcome

References and Links

LITFL

• Paul Young’s ICU Mind Maps — Bone Marrow Transplant – Cardiac
• Paul Young’s ICU Mind Maps — Bone Marrow Transplant – Complications
• Paul Young’s ICU Mind Maps — Bone Marrow Transplant – Gastrointestinal
• Paul Young’s ICU Mind Maps — Bone Marrow Transplant – Infections
• Paul Young’s ICU Mind Maps — Bone Marrow Transplant – Neurological
• Paul Young’s ICU Mind Maps — Bone Marrow Transplant – Renal