Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Endothelial damage syndromes Tapani Ruutu Helsinki University Central Hospital
E Carreras, EBMT Handbook 2008
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Early endothelial damage syndromes in HSCT • Veno-occlusive disease of the liver (VOD, SOS) • Transplant-associated microangiopathy (TAM) • Diffuse alveolar haemorrhage • Engraftment syndrome • Capillary leak syndrome
Diagnostic criteria for VOD • • • • •
Enlarged liver (hepatomegaly) Right upper quadrant pain Ascites Weight gain Increased bilirubin levels
• Within 20-30 days from the transplantation
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
JA Coppel et al, BBMT 2010
Diagnostics of VOD • Specific finding: liver biopsy - Usually not feasible, may be dangerous • Studying blood flow in big veins? - Not essential • Clinically a combination of findings (set of criteria) - No specific clinical findings
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
VOD • Up to 30 per cent may develop VOD with no (Seattle criteria) or too late hyperbilirubinaemia • Close to 30 per cent of the cases occur after day +21 and about 10 per cent after day +30
Incidence of VOD • Wide range in reported incidences, especially in earlier years: allogeneic 0-62 % autologous 1-44 % • Recent data indicate that the incidence is at present approximately 8% in allogeneic and 1-2 % in autologous HSCT.
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Severity of VOD Retrospective classification
•
Mild (8-23 %) – Self-limiting – No treatment required
•
Moderate (48-64 %) – Requires treatment (pain medication, diuretics) – Complete resolution of symptoms and signs before day +100
•
Severe (23-28 %) – Unresolved symptoms/ signs before death or day +100 – ± multiorgan failure (MOF) Seattle group -
Model for predicting fatal outcome of VOD after marrow transplantation S Bearman et al, JCO 1993 Based on the rate of – increase in bilirubin level – weight gain during days -7 to +16 Specificity good, sensitivity modest, generalizability?
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Risk factors for VOD • • • • • • • • • • •
Advanced disease (burden of preceding treatment) Prior stem cell transplantation Hepatic disease (severe hemosiderosis, viral hepatitis, fibrosis, ‘transaminitis’) Gemtuzumab ozogamicin (Mylotarg®) Intensity of conditioning Busulfan, especially when combined with melphalan/ and or cyclophosphamide; busulfan administration (p.o., non-adjusted) Unrelated or mismatched donor Sirolimus (in combination with tacrolimus) Hepatotoxic drugs (progestogens, ketoconazole etc) Genetic predisposition etc
Outcome of VOD • Depends largely on the severity grade (which again is defined by the outcome…..) • Severe VOD is a serious disorder, with high mortality • Patients often have other concomitant complications • Mortality attributable to VOD by day +100: – All VOD 10-15 (-28) % – Severe VOD 25-50 (-95) %
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Prophylaxis of VOD • Avoiding risk factors and tailoring the treatment accordingly • Pharmacological – Ursodeoxycholic acid: evidence for efficacy – Sodium heparin: efficacy uncertain, may be dangerous – LMWH: efficacy unclear, relatively safe – Prostaglandin E1: no clear benefit – Defibrotide
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EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Conclusions Corbacioglu et al
• Prophylactic defibrotide significantly reduced: – Incidence of VOD (by 40%) – VOD related morbidity and mortality – Acute GvHD, both in incidence and severity • No indication of increased relapse rate • No drug-related adverse effects
Treatment of VOD Table 3.- VOD treatment Symptomatic (a)
Specific
Symptomatic (a)
Specific
First line therapy restriction of salt and water intake ± diuretics maintain intravascular volume and renal perfusion by means of albumin, plasma expanders and transfusions (haematocrit >30%) Defibrotide: 6.25 mg/kg IV in 2 h infusion q 6 h x 14 d → 50 - 55% CR in severe VOD with MOF and 47-60% of survival at day +100 with no secondary effects (15). — Other agents b, c Other measures - Analgesia - Paracentesis / thoracocentesis - Haemodialysis / Haemofiltration - Mechanical ventilation - TIPS (transvenous intrahepatic portosystemic shunt) (d) - Surgical shunt - Liver transplantation Carreras E. EBMT Handbook 2012
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Defibrotide
• Sodium salt of a mixture of single-stranded polydeoxyribonucleotides • Prepared by controlled depolymerisation of DNA obtained from porcine intestinal mucosa • Available for i.v. administration
Biological properties of defibrotide • A great variety of biological effects have been documented in preclinical and clinical studies • The main mechanisms in the clinical therapeutic effect have not been completely clarified • Defibrotide can be regarded as an agent that stabilizes endothelium without enhancing systemic bleeding
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Defibrotide for the treatment of VOD • Efficacy convincingly shown • Early start of treatment essential • Optimal dose 25 mg/kg/day i.v. • Practically no adverse effects
Transplantation-associated microangiopathy, TAM Differences from idiopathic acquired TTP
• absence of severe ADAMTS-13 deficiency • little evidence for systemic microthrombus formation • different spectrum of clinical symptoms • poor response to plasma exchange
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Incidence of TAM following HSCT(%) Range Allogeneic
0.5 – 76
Commonly 5-10%
Autologous
0 – 27
Lower than allo
Holler & al 1989
Morphological and biochemical changes indicating generalized endothelial damage in 49 of 66 allogeneic transplant patients
= 74 %
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Onset of TAM • Usually within 100 days • George et al, review of 35 reports (Transfusion 2004) : Median time of onset 19-210 days Range 3-890 days
Risk factors for TAM, identified in different studies • • •
Unrelated donor Female sex Acute GVHD
• • • • • • • • • •
Older age Advanced primary disease Mismatched donor Non-myeloablative (fludarabine-based) conditioning High-dose busulfan Total body irradiation CsA or tacrolimus Sirolimus or everolimus in addition to CNI Infection ABO incompatibility
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Incidence of TAM Myeloablative vs. reduced intensity conditioning
Myeloablative
Reduced intensity
Shimoni et al 2004
16 %
23 %
Nakamae et al 2006
13,2 %
25,5 %
Willems et al 2010
15 %
13 %
Pathogenesis of TAM • Not well understood • Probably multifactorial • Endothelial toxicity a central factor
chemo-radiotherapy
infections
immunosuppressive drugs cyclosporine A, tacrolimus, sirolimus
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
graft-versus-host disease
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Histopathological evidence for thrombotic microangiopathy in clinical TAM • Histopathological findings indicating microangiopathy are usually limited to the kidneys and not always found • Microangiopathic findings in other organs are rare
Criteria for TAM • Highly variable • 35 articles - 28 sets of criteria • 19 different parameters used as criteria, many of them same factors phrased differently George et al Transfusion 2004
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Definition of Transplant-Associated Microangiopathy (TAM) by the International Working Group
Ruutu et al, Haematologica 2007
BMT CTN Toxicity Committee Consensus Definition for TMA
1. RBC fragmentation and ≥2 schistocytes per highpower field on peripheral smear 2. Concurrent increased serum LDH above institutional baseline 3. Concurrent renal and/or neurologic dysfunction without other explanations 4. Negative direct and indirect Coombs test results Ho et al, BBMT 2005
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
TAM definition: specific problems • Red blood cell fragmentation how
standardized ?
• Platelet and red blood cell consumption / decrease how how
to define ? severe ?
• Renal and neurological complications role
in the criteria ?
• Role of infections
Outcome of TAM • The outcome has varied greatly in published reports, largely due to different definitions • Mortality usually > 50 % (0-100 % in different reports) • Patients have usually multiple problems • TAM the sole or main cause of death in only a minority
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Treatment of TAM •
No established treatment
•
Plasma exchange or infusions: generally not effective and may be risky
•
Discontinuation of CsA or tacrolimus?
•
Generally no effect: corticosteroids antiplatelet agents antifibrinolytics prostacyclin infusions vincristine heparin thrombolytic therapy i.v. immunoglobulins splenectomy
Treatment of TAM cont.
• Some positive reports: Defibrotide Daclizumab Rituximab Mesenchymal stem cells
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Capillary leak syndrome •
Injury to capillary endothelium which leads to leakage of intravascular fluids into the interstitial space
•
Probably caused by cytokines and VEGF
•
No well-established clinical criteria; incidence unclear
•
Rapid weight gain and generalised oedema within the first 15 days post-HSCT, poor response to furosemide; sometimes hypotension, renal insufficiency of pre-renal origin, hypoalbuminaemia
•
Risk factors: use of G-CSF, GM-CSF or K-CSF, high cumulative doses of chemotherapy pre-HSCT, unrelated of mismatched donor
•
Treatment: withdrawal of growth factors. Some reports of successful use of i.v. Ig and bevacizumab. Response to corticosteroids usually poor.
•
High mortality, especially when multi-organ failure develops
Engraftment syndrome • Pathogenesis: massive release of proinflammatory cytokines (e.g. IL-2, TNF-alpha, IFN-gamma, IL-6), M-CSF, EPO, products of degranulation and oxidative metabolism of neutrophils and systemic endothelial damage • Mostly in autologous but also in allogeneic HSCT, incidence 5-25 %
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Engraftment syndrome: clinical features and criteria for diagnosis •
Major criteria: – Non-infectious fever – Skin rash – Pulmonary oedema, hypoxaemia
•
Minor criteria: – Weight gain – Hepatic or renal dysfunction – Transient encephalopathy
•
Two sets of criteria with some differences (Spitzer, Maiolino); ”within 96 h of engraftment” or ”from 24 h before or at any time after the first appearance of neutrophils”
Engraftment syndrome • Risk factors: mainly observed in patients who have not received intensive chemotherapy before undergoing autologous HSCT or those receiving less intensive conditioning • Treatment: corticosteroids, excellent response in most cases with complete resolution of symptoms and signs in a few days
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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Tapani Ruutu | Endothelial damage syndromes (VOD, TAM…)
Diffuse alveolar haemorrhage (DAH) • Disruption of alveolar-capillary basement membrane by conditioning, immune-mediated events and the return of neutrophils with marrow recovery • Pathological observations on small arteries resemble those observed in veins affected by VOD • Incidence 1-21% in autologous and 2-17% in allogeneic SCT • Median time of onset 12-19 days, but episodes after the first month are not uncommon
DAH •
Clinical features: – shortness of breath, nonproductive coughing; haemoptysis rare – hypoxaemia – local or diffuse interstitial or alveolar infiltrates located in the middle and inferior lung fields
•
Diagnosis: bloody BAL fluid
•
Risk factors: older age, previous thoracic radiotherapy, TBI and myeloablative conditioning
•
Treatment: corticosteroids may be tried but the effect is uncertain
•
Outcome: the mortality is approximately 50 % at present. The prognosis is better in autologous HSCT and early-onset DAH compared with allogenic transplantation and late onset.
EBMT Severe Aplastic Anaemia and Complications QoL WP | Budapest,Hungary | 1-3 Nov 2012
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