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

• 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)

veno-occlusive disease

capillary leak syndrome

engraftment syndrome

conditioning CsA GvHDengraftment

diffuse alveolar haemorrhage

day 0 day 60

BMT associated thrombotic microangiopathy

Overlapping clinical manifestations

idiopathic pneumonia syndrome

MODS

MODS

VOD/SOS - diagnosis

• clinical

• haemodynamic studies

• ultrasound studies

• biological markers

Clinical syndrome of:

• Hepatomegaly

• Fluid retention

• Jaundice

Veno-occlusive disease of the liver after SCT

VOD/SOS h aemodynamicdiagnosis

VODspecificity >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

VOD/SOS – diagnosis - clinical criteria• Before day 21 after HSCT

Jaundice Weigh gain Hepatomegaly Ascites Clinical criteria 2 2 2 3 3 3 3 4

SEATTLE BALTIMORE

No other explanation for these signs and symptoms could be present

• 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 cytokinescyclosporine / 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

P-450 enzymatic system

CY toxic metabolites (acrolein )

hepatocyte

endothelial cellsinusoid

CY

space of Disse

extracellular matrix

glutathione enzymatic system

Endothelial damage

glutathione enzymatic system

Less toxicity if:

CyBu than BuCyMeresse, et al. BMT 1992; 10: 135

IV Bu (less GSH)Lee, et al, Ann Hematol 2005 (Epub)

Adjusted dose of Cy or TBIMcDonald, et al. Blood 2003; 101: 2043

McDonald Hematology (ASH Educ Program). 2004; 380

Less toxicity if:

CyBu than BuCyMeresse, et al. BMT 1992; 10: 135

IV Bu (less GSH)Lee, et al, Ann Hematol 2005 (Epub)

Adjusted dose of Cy or TBIMcDonald, et al. Blood 2003; 101: 2043

McDonald Hematology (ASH Educ Program). 2004; 380

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

VOD/SOS – first line therapySymptomatic

– 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

VOD/SOS – other therapeutic measures

Symptomatic- analgesia- paracentesis, thoracocentesis- haemodialysis / haemofiltration- mechanical ventilation

Specific- peritoneovenous shunt- transjugular intrahepatic porto-systemic shunt (TIPS)- liver transplantation

Clinical experience with defibrotide in severe VOD/MOF

Author Pts (n) CR RateD+100

SurvivalRichardson et al,

Blood 1998 19 42% 30%Chopra et al,

BJH 2000 28 36% 36%Richardson, et al

Blood 2002 88 36% 35%Corbacioglu, et al

BMT 2004 22 50% 36%Carreras et al.

ASH 2007 332 52% 46%

recommended dose: 6.25 mg/kg in 2 h infusion q6h 14 days

Diffusealveolar

haemorrhage

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%

Diffuse alveolar haemorrhage

• <15% die as direct consequence of DAH, but frequent evolution to MODS (>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)

Capillaryleak

syndrome

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

Infections in HSCT

Montserrat Rovira, Enric Carreraswith the collaboration of Josep MensaHospital Clinic, Barcelona, Spain

Targu Mures, Romania 24 - 26 May, 2010

Tomblyn et al. BB&MT 2009

Immune reconstitution after HSCT

Tomblyn et al. BB&MT 2009

Bacterial infectionsProphylaxis

Gastro-intestinal decontamination (GID) + low bacterial diets

Profilaxis with non-absorbable antibiotics (GVN) + isolation measures in 95 consecutive severe

neutropenic patients

Isolation +

GVNwithout

measures

Febrile episodes 40% 80%*

Clinically doc. Infect. 25% 55%*

Bacteriol. doc. Infect. 21% 53%*

Related deaths 8% 26%*

Ribas-Mundó et al. Cancer 1981

* p<0.01

Hospital Clínic Barcelona

GentamicinVancomicin

Nistatin(Aerobic + anaerobic

flora)HPA roomsSterile diets

HEAPA and LAF isolation and survival after HSCT

Passweg, et al. BMT 1998

bacteria fungi

TRM SRV

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

Fungal infections

Pathogeny and epidemiology

Prophylaxis with fluconazole in HSCT recipients

Marr et al. Blood 2000

Survival

Allogeneic

Fluco

Placebo

Autologous

Survival

Fluco

Placebo

Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease

Ullmann et al. NEJM 2007

Voriconazole vs itraconazole for Prophylaxis (IMPROVIT)

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

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

Viral infections

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

HH = see handouts

• 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 (+)

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?

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?

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

Acute GVHDAcute GVHDESH-EBMT 2009ESH-EBMT 2009

LatimerLatimer

A. DevergieA. Devergie

Acute GVHDAcute GVHD

Activated Donor T cells damage Activated Donor T cells damage host epithelial cells after an host epithelial cells after an inflammatory cascade that inflammatory cascade that begins after the preparative begins after the preparative regimenregimen

GVHD is the major barrier to GVHD is the major barrier to successful HSCTsuccessful HSCT

Risk factorsRisk factors

DonorDonor Related/unrelatedRelated/unrelated HLA mismatchedHLA mismatched Sex mismatchedSex mismatched AlloimmunisationAlloimmunisation Source of stem Source of stem

cellscells

RecipientRecipient AgeAge Conditioning Conditioning

regimenregimen Prevention of Prevention of

GVHDGVHD

Incidence 10 to 80% (median ~ 40%)

aGVHD: a 3-step processaGVHD: a 3-step process

phasephase cellscells cytokinescytokines

11 conditioningconditioning Host APCHost APC

Epith cellEpith cellTNFTNFαα, IL1, IL1

22 T-cell activationT-cell activation Donor T-Donor T-cellscells

IL2, IFNIL2, IFNγγ

33 Effector phaseEffector phase CTLs, NKCTLs, NK TNFTNFαα, IL1 , IL1 Cytokine storm Cytokine storm

Classical targets of aGVHDClassical targets of aGVHD

Epithelial cells ofEpithelial cells of

SKIN: keratinocytesSKIN: keratinocytes LIVER: biliary ductsLIVER: biliary ducts DIGESTIVE TRACT: enterocytesDIGESTIVE TRACT: enterocytes

« satellite cell necrosis »« satellite cell necrosis »(infiltrating immune cell + apoptotic cell)(infiltrating immune cell + apoptotic cell)

HistopathologyHistopathology

Clinical manifestations Clinical manifestations and gradingand grading

Maculo-papular rashMaculo-papular rash

Gastro-intestinal involvementGastro-intestinal involvement

Anorexia, nauseaAnorexia, nausea Green watery diarrhoeaGreen watery diarrhoea Abdominal pain, bloody Abdominal pain, bloody

diarrhoeadiarrhoea

Gastro-duodenal biopsiesGastro-duodenal biopsies

Liver involvementLiver involvement

Cholestatic hepatopathy…Cholestatic hepatopathy…

(other causes of hepatopathy: (other causes of hepatopathy: toxicity, infection, VOD…)toxicity, infection, VOD…)

Other symptomsOther symptoms

Fever, eosinophilia …..Fever, eosinophilia …..

Staging of aGVHDStaging of aGVHD

stagestage skinskin Liver Liver (bil:(bil:µmol/l)µmol/l)

Gut Gut diarrhoeadiarrhoea

11 <25%<25% 34-5034-50 >500 ml>500 ml

22 25-50%25-50% 51-10251-102 >1000>1000

33 >50%>50% 103-255103-255 >1500>1500

44 LyellLyell >255>255 pain++pain++

Prevention and treatment of Prevention and treatment of acute GVHDacute GVHD

Prevention Primary Tt Secondary Tt CsA + MTX MethylPDN

2 mg/kg High dose

methyl PDN TCD ATG/MoAb

Tacrolimus Tacrolimus MMF MMF

MethylPDN Pentostatin Sirolimus

Prophylaxis of GVHD Prophylaxis of GVHD with CsA + MTXwith CsA + MTX

« Gold standard » protocol « Gold standard » protocol since 1986 since 1986

Cyclosporine 3 mg/kg/d d-1 to d+30 Cyclosporine 3 mg/kg/d d-1 to d+30 then orally untill d+180then orally untill d+180

Methotrexate 15 mg/m² D+1, 10 Methotrexate 15 mg/m² D+1, 10 mg/m² d+3, 6, mg/m² d+3, 6, ++ 11 11

(Storb et al. N Engl J Med 1986)(Storb et al. N Engl J Med 1986)

Both agents inhibit activated donor T cell Both agents inhibit activated donor T cell proliferationproliferation

Phase III trial CsA + MTX / Tacro + MTXPhase III trial CsA + MTX / Tacro + MTXRatanatharathorn et al Blood 1998Ratanatharathorn et al Blood 1998

CsA +MTX

Tacro + MTX

tacrolimus+sirolimus

1st line treatment1st line treatment

« High dose » steroids 2 mg/kg: « High dose » steroids 2 mg/kg: primary Tt for more than 25yprimary Tt for more than 25y

Questions:Questions:

Higher dose?Higher dose?

Lower dose?Lower dose?

1st line combination of 1st line combination of steroid steroid + other IS treatment?+ other IS treatment?

2nd line treatment2nd line treatment

TreatmentTreatment responseresponse survivalsurvival

ATGATG 51%51% 35%35%

AntiRIL2AntiRIL2 40-70%40-70% <<30%30%

AntiTNFAntiTNF 67%67% 38%38%

CsA to tacroCsA to tacro 10%10%

Tacro + ATGTacro + ATG 35%35%

MMFMMF 40%40% 16% - 37%16% - 37%

pentostatinpentostatin 50%50% 26%26%

OKT3OKT3 50%50% 45%45%

Supportive Care +++Supportive Care +++

Intensified infection prophylaxis Intensified infection prophylaxis ++++ (viral, bacterial and ++++ (viral, bacterial and mycotic infections are the most mycotic infections are the most common causes of death in common causes of death in patients with severe aGVHD)patients with severe aGVHD)

Nutritional support, replacement Nutritional support, replacement therapy of enteral losses of therapy of enteral losses of fluids...fluids...

Bone mineral retention and repairBone mineral retention and repair Pain controlPain control

ConclusionConclusion Poor prognosis of steroid-refractory Poor prognosis of steroid-refractory

AGVHDAGVHD Many IS agents are active…but Many IS agents are active…but

predispose to infections+++predispose to infections+++ Lack of uniform criteria of response Lack of uniform criteria of response

to various therapiesto various therapies None of these Tt has been None of these Tt has been

consistently successful in salvaging consistently successful in salvaging patientspatients

Initial control of AGVHD is criticalInitial control of AGVHD is critical