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Complications de l’allogreffe de moelle osseuse

Complications de l’allogreffe de moelle osseuse. An update on the management of haematological malignancies Tunis, octobre 2010. Early complications of SCT. Direct action of chemo-radiotherapy Nausea, vomiting, diarrhoea, alopecia, pain Mucositis Haemorrhagic cystitis

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Complications de l’allogreffe de moelle osseuse

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  1. Complications de l’allogreffe de moelle osseuse An update on the management of haematological malignancies Tunis, octobre 2010

  2. Early complications of SCT • Direct action of chemo-radiotherapy • Nausea, vomiting, diarrhoea, alopecia, pain • Mucositis • Haemorrhagic cystitis • Endothelial dysfunction by conditioning • Veno-occlusive disease / Capillary leak synd. / Thrombotic microangiopathy / Idiopathic pneumonia syndrome / Engraftment syndrome • Drug toxicity (CsA/FK, G-CSF, Antibiotics,) • Infections • Immune complications (GvHD, graft failure)

  3. day 0 day 60 conditioning CsA engraftment GvHD M O D S veno-occlusive disease capillary leak syndrome BMT associated thrombotic microangiopathy diffuse alveolar haemorrhage idiopathic pneumonia syndrome engraftment syndrome Overlapping clinical manifestations

  4. VOD/SOS - diagnosis • clinical • haemodynamic studies • ultrasound studies • biological markers

  5. Veno-occlusive disease of the liver after SCT Clinical syndrome of: • Hepatomegaly • Fluid retention • Jaundice

  6. HVPG > 10 mmHg specificity >90% sensitivity 60% VOD VOD/SOS haemodynamic diagnosis Only indicated to confirm VOD before adopting a therapeutic approach that may be potentially hazardous to the patient Carreras, et al. Ann Hematol 1993

  7. VOD/SOS – diagnosis - clinical criteria • Before day 21 after HSCT SEATTLE BALTIMORE No other explanation for these signs and symptoms could be present

  8. What are the biochemical mediators of sinusoidal damage? Higher incidenceof VOD/OS in: - allo-HSCT > auto-HSCT - unrelated HSCT > related HSCT - non-TCD HSCT >TCD HSCT - patients w hepatitis or cirrhoses • Generation of metabolites toxic to endothelial cell • Nitric oxide & metalloproteinases • Procoagulant status (epiphenomenon?) • Other contributing factors allo-reactivity / pro-inflammatory cytokines cyclosporine / endothelin-1 vascular endothelial growth factor  GSH due to previous liver disease

  9. glutathione enzymatic system CY toxic metabolites (acrolein ) glutathione enzymatic system P-450 enzymatic system CY Endothelial damage Less toxicity if: CyBu than BuCy Meresse, et al. BMT 1992; 10: 135 IV Bu (less  GSH) Lee, et al, Ann Hematol 2005 (Epub) Adjusted dose of Cy or TBI McDonald, et al. Blood 2003; 101: 2043 McDonald Hematology (ASH Educ Program). 2004; 380  hepatocyte extracellular matrix space of Disse endothelial cell sinusoid

  10. VOD/SOS - prophylaxis General measures • delay transplantation if hepatitis • TBI:  dose,  dose-rate, fractionated • avoid Cy and/or Bu • Cy-Bu: adjust doses of Bu or IV Bu • avoid hepatotoxic drugs • consider RIC-HSCT

  11. VOD/SOS – first line therapy Symptomatic • Restriction salt and water • Maintain intravascular volume and renal perfusion(albumin, plasma expanders, transfusions –Hct >30%-) Specific (pharmacological) • diuretics • PGE-1 (occasionally effective) • rt-PA (effective < 30% cases) • activated PC or ATIII (probably not eff.) • defibrotide

  12. VOD/SOS – other therapeutic measures • Symptomatic • - analgesia • - paracentesis, thoracocentesis • - haemodialysis / haemofiltration • - mechanical ventilation • Specific • - peritoneovenous shunt • - transjugular intrahepatic porto-systemic shunt (TIPS) • - liver transplantation

  13. Clinical experience with defibrotide in severe VOD/MOF recommended dose: 6.25 mg/kg in 2 h infusion q6h 14 days

  14. Diffuse alveolar haemorrhage

  15. Risk factors • Not related to low platelet counts • Older age • Previous thoracic radiation • Allogeneic, myeloablative and 2nd HSCT Diffuse alveolar haemorrhage Incidence auto-SCT = 1 - 5% allo-SCT = 3 - 7%

  16. Evolution • <15% die as direct consequence of DAH, but frequent evolution to MODS (>60% overall mortality rate) Diffuse alveolar haemorrhage Treatment • Methylprednisolone 250-500 mg every 6 h (5 days); tapering off over 2-4 weeks (in discussion) • Recombinant FVIIa (some success)

  17. Capillary leak syndrome

  18. Capillary leak syndrome Incidence (absence of well-established criteria!!) Unknown: difficult differential diagnosis with VOD, engraftment syndrome, or idiopathic pneumonia syndrome Risk factors - Use of G-CSF/GM-CSF/K-CSF - Unrelated / mismatch donor HSCT - High cumulative doses of chemotherapy prior to HSCT

  19. Infections in HSCT Montserrat Rovira, Enric Carreras with the collaboration of Josep Mensa Hospital Clinic, Barcelona, Spain Targu Mures, Romania 24 - 26 May, 2010

  20. Immune reconstitution after HSCT Tomblyn et al. BB&MT 2009

  21. Tomblyn et al. BB&MT 2009

  22. Bacterial infections Prophylaxis Gastro-intestinal decontamination (GID) + low bacterial diets

  23.    Profilaxis with non-absorbable antibiotics (GVN) + isolation measures in 95 consecutive severe neutropenic patients Hospital Clínic Barcelona Gentamicin Vancomicin Nistatin (Aerobic + anaerobic flora) HPA rooms Sterile diets * p<0.01 Ribas-Mundó et al. Cancer 1981

  24. HEAPA and LAF isolation and survival after HSCT  bacteria  fungi  TRM  SRV Passweg, et al. BMT 1998

  25. A, B, C of treatment of febrile neutropenia It must be: • Started immediately after onset of fever • Based in an empirical approach • Adapted to the flora usually observed in each centre • Adapted to the type of patient • Adapted to the clinical situation

  26. Fungal infectionsPathogeny and epidemiology

  27. Autologous Allogeneic Survival Survival Fluco Fluco Placebo Placebo Prophylaxis with fluconazole in HSCT recipients Marr et al. Blood 2000

  28. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease Ullmann et al. NEJM 2007

  29. Voriconazole vs itraconazole for Prophylaxis (IMPROVIT)

  30. Primary antifungal prophylaxis in SCT Allo-SCT: neutropenic phase Fluconazole 400 mg qd iv/oral: AI Itraconazole 200 mg IV followed by oral 200 mg bid: BI Posaconazole 200 mg tid oral: no data Micafungin 50 mg qd iv: CI Polyene iv: CI Voriconazole 200 mg bid oral: provisional AI Aerosolized liposomal AMB plus fluconazole: BII UPDATE ECIL-3 2009: Summary slide

  31. Primary antifungal prophylaxis in SCT Allo-SCT : GvHD phase Fluconazole 400 mg qd iv/oral: CI Itraconazole 200 mg IV followed by oral 200 mg bid: BI Posaconazole 200 mg tid oral: AI Candins iv: insufficient data Polyene iv: CI Voriconazole 200 mg bid oral: provisional AI Aerosolized lipo-AmB + fluconazole: insufficient data UPDATE ECIL-3 2009: Summary slide

  32. Viral infections

  33. Viral infections after HSCT reactivation (intracellular) exogenous (inhalation) HSV CMV VZV HHV6 EBV Respiratory viruses Adenovirus BK/JK HBV/HCV 0 1 2 3 4 5 6 months after HSCT H = see handouts

  34. Patient sero (+) • If possible CMV (+) donor (BI) • Pharmacological prophylaxis (AI) Preventing exposure / reactivation- CMV - Patient sero (-) • Avoid sharing cups, glasses, eating tools (BIII) • Non long term monogamous  condoms (AII) • After handling or changing diapers or secretions and saliva  regular hand washing (AII) • Transfusions CMV(-) o filtered (AI) • If possible CMV (-) donor (BI)

  35. CMV: management strategies Primary prophylaxis(before infection or reactivation) - high dose acyclovir / ganciclovir (BI) - universally administered to all patients - effective but toxic and no cost-effective - how long? day 100?

  36. CMV: management strategies Pre-emptive approach (before CMV disease) - monitoring until at least day +100 - administered only when Ag or PCR (+) - preferred for most teams (high risk patients?) - ganciclovir / foscarnet (AI) - valganciclovir in low risk patients (CII)(concern about renal function and low body weight) - until Ag becomes negative? 14 days?

  37. CMV disease treatment • CMV pneumonia • ganciclovir (or foscarnet) + • high-dose IgIV (500 mg/kg/48 h) (BII) • treatment 21-28 days + maintenance 14 d. • mortality 50-70% • Other forms of CMV disease • ganciclovir or foscarnet w/o IgIV (BII) • 2nd line therapy • cidofovir (BII) • ganciclovir + foscarnet (BII) • Other therapeutic agents • valganciclovir / marivabir

  38. Acute GVHD ESH-EBMT 2009 Latimer A. Devergie

  39. Acute GVHD • Activated Donor T cells damage host epithelial cells after an inflammatory cascade that begins after the preparative regimen • GVHD is the major barrier to successful HSCT

  40. Donor Related/unrelated HLA mismatched Sex mismatched Alloimmunisation Source of stem cells Recipient Age Conditioning regimen Prevention of GVHD Risk factors Incidence 10 to 80% (median ~ 40%)

  41. aGVHD: a 3-step process

  42. Classical targets of aGVHD Epithelial cells of • SKIN: keratinocytes • LIVER: biliary ducts • DIGESTIVE TRACT: enterocytes « satellite cell necrosis » (infiltrating immune cell + apoptotic cell)

  43. Histopathology

  44. Clinical manifestations and grading

  45. Maculo-papular rash

  46. Gastro-intestinal involvement • Anorexia, nausea • Green watery diarrhoea • Abdominal pain, bloody diarrhoea Gastro-duodenal biopsies

  47. Liver involvement Cholestatic hepatopathy… (other causes of hepatopathy: toxicity, infection, VOD…) Other symptoms Fever, eosinophilia …..

  48. Staging of aGVHD

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