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. veno-occlusive disease capillary leak syndrome engraftment syndrome conditioningCsAGvHDengraftment diffuse alveolar haemorrhage day 0day 60 BMT associated thrombotic microangiopathy Overlapping clinical manifestations idiopathic pneumonia syndrome MODSMODS MODSMODS

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

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

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

7. VOD/SOS – diagnosis - clinical criteria Before day 21 after HSCT Jaundice  Weigh gain  Hepatomegaly  Ascites  Clinical criteria 22233334 SEATTLE BALTIMORE No other explanation for these signs and symptoms could be present

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

9. P-450 enzymatic system CY toxic metabolites (acrolein ) hepatocyte endothelial cell sinusoid CY space of Disse extracellular matrix  glutathione enzymatic system Endothelial damage glutathione enzymatic system 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 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

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 AuthorPts (n)CR Rate D+100 Survival Richardson et al, Blood 1998 1942%30% Chopra et al, BJH 2000 2836% Richardson, et al Blood 2002 8836%35% Corbacioglu, et al BMT 2004 2250%36% Carreras et al. ASH 2007 33252%46% recommended dose: 6.25 mg/kg in 2 h infusion q6h 14 days

14. Diffuse alveolar haemorrhage

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

16. Diffuse alveolar haemorrhage 60% overall mortality rate) Evolution 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 Unknown: difficult differential diagnosis with VOD, engraftment syndrome, or idiopathic pneumonia syndrome Incidence (absence of well-established criteria!!) - Use of G-CSF/GM-CSF/K-CSF - Unrelated / mismatch donor HSCT - High cumulative doses of chemotherapy prior to HSCT Risk factors

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

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 Isolation + GVN without measures Febrile episodes40%80%* Clinically doc. Infect.25%55%* Bacteriol. doc. Infect.21%53%* Related deaths8%26%* Ribas-Mundó et al. Cancer 1981 * p<0.01 Hospital Clínic Barcelona     Gentamicin Vancomicin Nistatin (Aerobic + anaerobic flora) HPA rooms Sterile diets

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

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 infections Pathogeny and epidemiology

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

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

34. 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) Preventing exposure / reactivation - CMV - Patient sero (-) If possible CMV (+) donor (BI) Pharmacological prophylaxis (AI) Patient sero (+)

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

41. aGVHD: a 3-step process phasecellscytokines 1conditioning Host APC Epith cell TNFα, IL1 2 T-cell activation Donor T- cells IL2, IFNγ 3 Effector phase CTLs, NK TNFα, IL1 Cytokine storm Cytokine storm

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

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

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

50. Staging of aGVHD stageskin Liver (bil:µmol/l) Gut diarrhoea 1<25%34-50 >500 ml 225-50%51-102>1000 3>50%103-255>1500 4Lyell>255 pain++ pain++

51. Prevention and treatment of acute GVHD

52. Prophylaxis of GVHD with CsA + MTX « Gold standard » protocol since 1986 « Gold standard » protocol since 1986 Cyclosporine 3 mg/kg/d d-1 to d+30 then orally untill d+180 Methotrexate 15 mg/m² D+1, 10 mg/m² d+3, 6, + 11 (Storb et al. N Engl J Med 1986) Both agents inhibit activated donor T cell proliferation

53. Phase III trial CsA + MTX / Tacro + MTX Ratanatharathorn et al Blood 1998 CsA +MTX Tacro + MTX

54. tacrolimus+sirolimus

55. 1st line treatment  « High dose » steroids 2 mg/kg: primary Tt for more than 25y  Questions: Higher dose? Lower dose? 1st line combination of steroid + other IS treatment?

56. 2nd line treatment Treatmentresponsesurvival ATG51%35% AntiRIL240-70% <30% AntiTNF67%38% CsA to tacro 10% Tacro + ATG 35% MMF40% 16% - 37% pentostatin50%26% OKT350%45%

57. Supportive Care +++  Intensified infection prophylaxis ++++ (viral, bacterial and mycotic infections are the most common causes of death in patients with severe aGVHD)  Nutritional support, replacement therapy of enteral losses of fluids...  Bone mineral retention and repair  Pain control

58. Conclusion  Poor prognosis of steroid- refractory AGVHD  Many IS agents are active…but predispose to infections+++  Lack of uniform criteria of response to various therapies  None of these Tt has been consistently successful in salvaging patients  Initial control of AGVHD is critical