Advances in the Management of Veno Occlusive Disease in the Adult Transplant Patient

Transcription

1 Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the current evidence related to risk factors for developing VOD/SOS Assess the optimal monitoring strategies for early diagnosis of VOD/SOS Evaluate recent efficacy and safety data regarding management of VOD/SOS Discuss the mechanisms of action of novel agents for VOD/SOS Introduction Veno-occlusive disease (VOD) is a potentially life-threatening complication after hematopoietic cell transplantation (HCT) Arises from endothelial cell damage and hepatocellular injury due to the conditioning regimen Severe VOD is characterized by multi-organ failure (MOF) and high mortality rate Case 1: Presentation A 27-year-old female with AML and complex cytogenetics with an extensive treatment history presents for consultation: Achieved 1 st complete remission (CR) with idarubicin and cytarabine induction 2 cycles of consolidation with high-dose cytarabine + allogeneic HCT from a matched unrelated donor conditioned with cyclophosphamide and total body irradiation After 3 years: relapsed with leukemic infiltration in the right eye Received re-induction with high-dose cytarabine and achieved CR2 Course complicated by persistent fevers, renal failure requiring dialysis, mental status changes requiring prolonged intubation and medical intensive care unit (MICU) stay, and deep vein thrombosis requiring anticoagulation Case 1: Treatment after Relapse Following relapse: One year later had morphologic relapse Received re-induction with idarubicin and cytarabine and achieved CR3 Course complicated by sepsis, renal failure, prolonged cytopenias, extensive MICU stay, fungal pneumonia treated with voriconazole Decision is made to proceed to a second allogeneic HCT from a matched unrelated donor with a reduced-intensity conditioning regimen (FluBu2) with tacrolimus and methotrexate for graft-versushost disease (GVHD) prophylaxis Case 1: Discussion Points What risk factors does the patient have for developing VOD? What strategies can be used to reduce the risk of VOD in this patient? 1

2 Typical Chronology of HSCT Complications Incidence of VOD Infectious causes Neutropenic phase (<30 days post HCT) Bacterial Early phase ( days post HCT) Late phase (>100 days post HCT) Review of 135 studies consisting of 24,920 HCT recipients Fungal Cytomegalovirus Herpes simplex virus Pneumocystis jiroveci pneumonia Non-infectious causes Engraftment syndrome Pulmonary edema Diffuse alveolar hemorrhage VOD Bronchiolitis obliterans Bronchiolitis obliterans organizing pneumonia Acute GVHD Chronic GVHD Idiopathic pneumonia syndrome Hemorrhagic cystitis Coppell JA et al. Biol Blood Marrow Transplant. 2010;16: Clinical Implications of VOD Pathophysiology of VOD Endothelial cell and hepatocyte damage Triggering of multiple pathways Inflammation Cytoskeletal structure Sinusoidal narrowing Severity of VOD VOD Richardson PG et al. Expert Opin Drug Saf. 2013;12: Clinical Presentation of VOD/SOS Diagnostic Tools: Baltimore and Seattle Criteria Fluid retention Ascites Weight gain Seattle Criteria 1 At least 2 of the 3 following criteria within the first month after transplant: Modified Seattle Criteria 2 Two of the following criteria must be present within 20 d of transplant: Baltimore Criteria 3 Bilirubin must be >342 µmol/l (2 mg/ dl) within 21 d of transplant and 2 of the following criteria must be present: Painful hepatomegaly Jaundice New onset of transfusion-refractory thrombocytopenia Jaundice Hepatomegaly and right upper quadrant pain Ascites and/or unexplained weight gain Bilirubin >342 µmol/l (2 mg/dl) Hepatomegaly or right upper quadrant pain Weight gain (>2% from pretransplant weight) Painful Hepatomegaly Ascites Weight gain (>5% from pre-transplant/basal weight) Multi-organ failure Carreras E. Br J Haematol. 2015;168: Bearman SI. Blood. 1995;85: McDonald GB et al. Hepatology. 1984;4: Coy DL et al. Radiographics. 2005;25: McDonald GB et al. Hepatology. 1984;4: Shulman HM, Hinterberger W. Bone Marrow Transplant. 1992;10: Jones RJ et al. Transplantation. 1987;44:

3 Considerations for Diagnostic Tools Baltimore and Seattle Criteria Both tools have high specificity of 91%-92%, but low sensitivity Most experts agree that the time limit is not appropriate and that presentation in children and recipients of IV busulfan may be different Reversal of portal vein flow on liver ultrasound is suggestive of VOD Pathologic confirmation with liver biopsy is the most accurate diagnostic tool Not always feasible due to risks of invasive procedure New EBMT Diagnostic and Severity Criteria Classical SOS/VOD ( 21 days after HCT) Bilirubin must be 2 mg/dl within 21 d of transplant and 2 of the following criteria must be present: Painful Hepatomegaly Ascites Weight gain (>5% from pre transplant/basal weight) Late onset SOS/VOD (>21 days after HCT) Classical VOD/SOS beyond day 21 OR Histologically proven SOS/VOD OR 2 of the following criteria must be present: Bilirubin 2 mg/dl Painful Hepatomegaly Ascites Weight gain (>5% from pre transplant/basal weight) AND hemodynamic or/and ultrasound evidence of SOS/VOD Carreras E et al. Ann Hematol. 1993;66: Carreras E. Br J Haematol. 2015;168: Mohty M et al. Bone Marrow Transplant. 2016;51: Risk Factors Patient and disease-related factors Transplant-related factors Patient and Disease-related Factors Risk factor Patient population Odds ratio Age Ped, adults Increased transaminase levels Ped, adults Pre-existing liver disease Viral hepatitis Cytomegalovirus positivity Ped, adults Prior HCT 1.9 Active disease at time of HCT Prior abdominal radiation Adults 2.9 Prior gemtuzumab ozogamicin Ped, adults 19.8 Prior treatment with norethisterone Adults 10.1 Poor performance status Ped, adults 2.7 (Karnofsky score <90%) Ferritin levels >1,000 ng/ml Ped 3.1 Biliburin >1.5 mg/dl Ped, adults 23.5 Myelofibrosis Adults Metabolic syndrome Adults Genetic factors (GSTM1) Ped, adults 4.1 Carreras E. Br J Haematol. 2015;168: Wong KM et al. Biol Blood Marrow Transplant. 2012;18: Mohty M et al. Bone Marrow Transplant. [Epub ahead of print]. 16 May Transplant-related Factors Risk factor Patient population Odds ratio Allogeneic vs autologous HCT Pediatrics, adults 2.8 Unrelated donor/hla mismatch Pediatrics, adults 1.4 Haploidentical Pediatrics, adults 1.9 Myeloablative conditioning Pediatrics, adults Busulfan-based conditioning vs. others Pediatrics, adults Busulfan + cyclophosphamide Pediatrics, adults Order of busulfan + cyclophosphamide Adults administration High-dose TBI ( 12 Gray) Pediatrics, adults 2.8 Role for Biomarkers in Diagnosis and Prognosis of VOD ST2, ANG2, L-Ficolin, HA, and VCAM1 may help confirm diagnosis of VOD L-Ficolin, HA, and VCAM1 levels on day of HCT may help predict risk of developing VOD These data are still experimental and need to be confirmed in large, prospective, multicenter trials GVHD prophylaxis CNI + sirolimus High-dose melphalan Adults Adults CNI = calcineurin inhbitor; HLA = human leukocyte antigen; TBI = total body irradiation. Carreras E. Br J Haematol. 2015;168: Mohty M et al. Bone Marrow Transplant. [Epub ahead of print]. 16 May Akil A et al. Biol Blood Marrow Transplant. 2015;21:

4 Reducing the Risk of VOD Correct Modifiable Risk Factors Correct modifiable risk factors Modifying intensity of the conditioning regimen Pharmacologic prophylaxis Avoid concurrent administration of hepatotoxic medications Iron overload (chelation if possible) Antiviral therapy for viral hepatitis Consider avoiding calcineurin inhibitor + sirolimus combination for GVHD prophylaxis Delay HCT (if possible) VOD Incidence According to Conditioning Intensity Retrospective analysis of 763 allogeneic HCT recipients Median age 36 years Karnofsky score 90: 71% Underlying diseases: AML/MDS (32%), CML (28%), ALL (18%) GVHD prophylaxis: CSA/MTX (54%), CSA/prednisone (32%), CSA/MMF (12%) MAC RIC P-value Total cohort 26/310 (8%) 3/142 (2%) Sibling donors 15/204 (7%) 0/103 (0) Pharmacologic Prophylaxis Against VOD Robust evidence supporting effective pharmacologic options is limited Most relevant agents that have demonstrated promise for VOD prophylaxis: Ursodiol Heparin Defibrotide Unrelated donors 11/106 (11%) 3/39 (8%) 0.56 MAC = myeloablative conditioning; RIC = reduced-intensity conditioning Carreras E et al. Biol Blood Marrow Transplant. 2011;17: Meta-analysis: Ursodiol for the Prevention of VOD in HSCT Recipients Meta-analysis: Heparin for the Prevention of VOD in HSCT Recipients Compared with no treatment, ursodiol reduced the incidence of VOD (RR, 0.34; 95% CI, ) No benefit with heparin prophylaxis (RR, 0.90; 95% CI, ) Tay J et al. Biol Blood Marrow Transplant. 2007;13: Imran H et al. Bone Marrow Transplant. 2006;37:

5 Defibrotide Defibrotide for Prophylaxis of VOD in Pediatric HSCT Sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA with anti-thrombic, anti-inflammatory, and anti-ischemic properties Phase 3 (N=356) Age < 18 years Myeloablative conditioning At least 1 risk factor for VOD Primary endpoint Incidence of VOD by day +30 R A N D O M I Z E Defibrotide 25 mg/kg IV daily starting on day of conditioning regimen and continued until day +30 (n=180) Placebo (n=176) Pescador R et al. Vascul Pharmacol. 2013;59:1-10. Corbacioglu S, et al. Lancet 2012;379: Defibrotide for Prophylaxis of VOD in Pediatric HCT VOD diagnosed by day+30 (ITT) Competingrisk analysis* Kaplan-Meier analysis VOD diagnosed by day+30 (PPA) Competingrisk analysis* Kaplan-Meier analysis Defibrotide Control P- value 22/180 (12%) 13% (8-19) 13% (9-19) 18/159 (11%) 11% (7-17) 11% (7-18) 35/176 (20%) 20% (15-27) 20% (15-27) 34/166 (20%) 20% (15-28) 21% (15-28) Day +100 mortality: 2% vs. 6%; P=.1 Summary Prevention of VOD Correct any reversible risk factors Consider a reduced-intensity conditioning regimen Consider using ursodiol prophylactically The use of defibrotide for VOD prophylaxis is supported by the BCBS/ESBMT guidelines There is insufficient evidence to support the use of heparin, glutamine, antithrombin III, pentoxifylline, or prostaglandin E1 for the prevention of VOD ITT, intention-to-treat; PPA, per-protocol analysis. No difference in adverse events between the two arms *CIs were calculated by log transformation. Three patients in defibrotide group and two patients in the control group were competing risks (non-vod death before 30 days). Corbacioglu S, et al. Lancet 2012;379: Case 1 (cont) Our patient proceeds to a second allogeneic HCT from a matched unrelated donor with a reduced-intensity conditioning regimen (FluBu2) with tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. Case 1 (cont): Our Patient after Assessment for HSCT Baseline Features Karnofsky Performance Score (KPS): 80% Vital signs: normal AST/ALT: 2.6 x ULN Ferritin: 2000 Creatinine (Cr): 1.4 Echocardiogram: 55% Hepatitis B and C: neg PFT: DLCO and FEV 1 >85% predicted Spleen: 18 cm 5

6 Case 1 (cont): Troubling Post-SCT Complications Timeline Day of SCT: Receives peripheral blood stem cells from an HLA-identical male donor procured through the National Marrow Donor Program Day 8 Post-SCT: Weight gain, 10 kg (baseline kg); bilirubin: 2.8 History Fludarabine/busulfan Busulfan dose adjusted to AUC of 5000 and ursodiol given 2 times/d for prophylaxis Tacrolimus and methotrexate for GVHD prophylaxis Receiving micafungin 3 times/wk for fungal prophylaxis Patient is now experiencing complications that may point to the emergence of VOD: but what is the next step? A Transplant Timeline: When Does VOD Typically Occur? 1,2 Central catheter placed, conditioning administered Symptoms of VOD/SOS usually occur within 30 days after Patient admitted HSCT but can also occur later -1 week Follow-up after patient discharge -4 to 6 days Day Day +30 Day Stem cells infused day 0 Count recovery PB analyzed Biopsy 1. Bearman SI. Blood. 1995;85: Carreras E. Early complications after HSCT. In: Apperley J, Carreras E, Gluckman E Masszi T, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. Genova: Forum Service Editore; 2012: Monitoring for VOD in the Transplant Recipient 1 Pts undergoing allohsct Suggested monitoring strategies Weekly or more frequent measurement of LFTs Alkaline phosphatase Alanine aminotransferase Bilirubin Gamma glutamyl transpeptidase Daily monitoring for Weight gain Fluid overload, Ascites Hepatomegaly Patients undergoing auto HSCT should also have daily assessment of fluid balance, with LFTs checked several times per week Differential Diagnosis of VOD Syndromes to Consider Hyperacute GVHD Cholestasis of sepsis Medication side effect Biliary obstruction Fungal abscess 1. Dignan FL et al. Br J Haematol. 2013;163: Diagnostic Imaging: Ultrasound VOD/SOS: Ultrasound Scan Showing Reversal of Flow in Two Points Ultrasound Imaging May be helpful in the exclusion of other disorders in patients with suspected VOD Findings that may suggest VOD Ascites, reversal of flow in the portal veins Hepatic artery resistance index: 0.75 Abnormal portal vein waveform 6

7 The Role of Liver Biopsy Prognosis of VOD Severity Transjugular approach preferred Hepatic wedge pressure >10 mmhg Perforation of liver capsule potential risk Adequacy of specimen (portal areas) Most useful Severe VOD (svod) Rate of rise of bilirubin 1 Rate of weight gain 1 MOF 2-8 Oxygen requirement Renal dysfunction Encephalopathy MOF has emerged as the best parameter (to date) for predicting bad outcomes 3 All-cause mortality >80% 3,4,6,7,9 Previous standard: best supportive care 2,7,9 Only approved treatment: defibrotide 1. Bearman SI et al. J Clin Oncol. 1993;11: Cesaro S et al. Haematologica. 2005;90: Coppell JA et al. Biol Blood Marrow Transplant. 2010;16: McDonald GB et al. Ann Intern Med. 1993;118: Bulley SR et al. Pediatr Blood Cancer. 2007;48: Lee SH et al. Bone Marrow Transplant. 2010;45: Wadleigh M et al. Curr Opin Hematol. 2003;10: Pihusch M et al. Transplantation. 2005;80: Cheuk DK et al. Bone Marrow Transplant. 2007;40: Prognosis of VOD Severity (cont) 1 Grading of VOD Parameter Mild Moderate Severe Bilirubin, mg/dl < >8 Liver function <3 X normal 3 8 X normal >8 X normal Weight above baseline <2% 2% 5% >5% Renal function Normal <2 X normal >2 X normal Rate of change Slow Moderate Rapid Case 1 (cont): Troubling Post-SCT Complications Timeline Day 0 of SCT: Receives peripheral blood stem cells from an HLA identical male donor procured through the National Marrow Donor Program Day 8 Post SCT: Weight gain, 10 kg (baseline kg); bilirubin: 2.8 History Fludarabine/busulfan Busulfan dose adjusted to AUC of 5000 and ursodiol given 2 times/d for prophylaxis Tacrolimus and methotrexate for GVHD prophylaxis Receiving micafungin 3 times/wk for fungal prophylaxis Patient is now experiencing complications that may point to the emergence of VOD: but what is the next step 1. Chao N. Blood. 2014;123: Case 1 (cont): Confirmation of svod in a Patient with Post-PV after SCT Timeline Day 8 post SCT Day 9 post SCT History Ultrasound rules out other syndromes, shows reversal of portal venous flow Bilirubin continues to rise (5.8), weight >5% of baseline weight Evidence of renal dysfunction noted (creatinine >2X normal) Based on these events, svod diagnosed The Impact of svod on Survival Correlation between severe VOD with MOF and high mortality (comparison with defibrotide study group data) 1,2 Day +100 mortality of 79%, with 8 of 38 patients alive at this time point Strong statistical association between CR and day +100 survival; P< % day +100 mortality in non-responders (right) 1. Richardson P et al. Blood. 2007;110: Richardson P et al. Blood. 2006;108:43. 7

8 Potential Points for Intervention in VOD/SOS 1,2 Epidemiologic stratification Conditioning regimen Identification of genetic predisposition Cell injury Ursodiol Drug levels (Bu/Cy) GSH N acetylcysteine Risk PGE Heparin AT III APC LMWH Inflammation Microthrombosis Pentoxifylline TNF antibodies Steroids Fibrosis tpa Defibrotide Necrosis TIPS Liver transplant Charcoal hemofiltration CVVHD APC = activated protein C; AT III = antithrombin III; Bu/Cy = busulfan/cyclophosphamide; CVVHD = continuous veno venous hemodialysis; GSH = glutathione; LMWH = low molecular weight heparin; TIPS = transjugular intrahepatic portosystemic shunt; TNF = tumor necrosis factor; PGE = prostaglandin E. 1. Richardson P, Guinan E. Acta Haematol. 2001;106: McDonald GB. ASH Educational Book Current Management of VOD Current management strategies: primarily supportive measures + defibrotide 1,2 Heparin plus tpa 1. DeLeve LD et al. Hepatology. 2009;49: Helmy A. Aliment Pharmacol Ther. 2006;23: Bearman SI et al. Blood. 1997;89: Diuresis, paracentesis, hemofiltration, mechanical ventilation, and hemodialysis Defibrotide Response in up to 30% of patients, but survival is poor 2,3 Associated with increased risk of life threatening bleeding 2,3 Not recommended in pts with svod who have already developed MOF 3 Avoid in patients with pulmonary/renal failure 2 No large prospective trials Current Management of VOD (cont) Defibrotide for the Treatment of Severe VOD: Phase II Dose-finding Study (Adults and Pediatrics) Liver transplant TIPS Only case reports showing potential benefit Only considered in patients with severe liver failure; feasibility a challenge 1,2 Generally contraindicated in cases of malignancy because of high recurrence rates 1,3 Shown to relieve ascites in some patients (but in others it worsened the process) 1,3,4 Patients treated for at least 14 days or until CR achieved Median duration of treatment was 19 days (2-82) in Arm A and 20 days (2-65) in Arm B Primary endpoint: CR rate 49% in Arm A vs 43% in Arm B (P=0.6) Day +100 survival: 44% in Arm A vs 39% in Arm B (P=0.6) Arm A - Defibrotide 25 mg/kg/day Arm B - Defibrotide 40 mg/kg/day Less bleeding events (68% vs 52%) and hypotension (52% vs 26%) with 25 mg/kg/day dose in pediatric patients 1. Helmy A. Aliment Pharmacol Ther. 2006;23: Richardson P, Guinan E. Acta Haematol. 2001;106: DeLeve LD et al. Hepatology. 2009;49: Azoulay D et al. Bone Marrow Transplant. 2000;25: Richardson PG et al. Biol Blood Marrow Transplant. 2010;16: Pivotal Treatment Trial: Historically Controlled, Multicenter, Open-Label, Phase III Study: Baseline Characteristics Eligible patients (n = 134) based on Baltimore criteria by day +21 and either renal and/or pulmonary failure by day +28 DF a arm: median treatment duration: 22 d (range 1-60 d) HC arm: subjects selected by an independent Medical Review Committee, blinded to outcome Evaluable patients (n = 102) Evaluable patients (n = 32) a DF 25 mg/kg/d IV in four divided doses approximately every 6 h. Primary endpoint: day +100 overall survival (propensity score adjusted estimators used) Patients treated for a minimum of 21 d Contemporaneous and validated HC Patient Characteristics Defibrotide (N=102) Historical control (N=32) Due to the life threatening nature of VOD/MOF, a trial randomizing patients to placebo or best supportive care was considered and rejected on the basis of ethical concerns Richardson PG et al. Blood. 2016;127: Richardson PG et al. ASH Abstract 654; Richardson PG et al. Blood. 2016;127: P value Mean age Gender 62.7% male 56.3% male.511 Allo HCT 88.2% 84.4%.567 Prior HCT 12.7% 9.4%.608 Ventilator or dialysisdependent 33.3% 21.9%.220 8

9 Results: Survival Benefit at Day +100 in Patients with svod Historical control Day +100 OS: 38.2% vs. 25% (P=.01) CR rate higher with defibrotide 25.5% vs 12.5% (P=0.016) Defibrotide Results: Safety Grade 3-5 AEs Defibrotide Historical control Hypotension 25.5% - Pulmonary alveolar 6.9% 4.9% hemorrhage GI hemorrhage 4.9% - Sepsis 3.9% 4.9% Catheter site hemorrhage 2.9% - Intracranial hemorrhage 2.9% 1% Cerebral hemorrhage 2% 1% Median time to CR with defibrotide 34.5 days Richardson PG et al. Blood. 2016;127: Richardson PG et al. Blood. 2016;127: Results: Comparison with Previous Trials Outcomes in Pediatric and Adult Patients Children ( 16 years of age) had higher survival and CR rates compared with adults Outcome Pediatric Patients (n = 232) Adult Patients (n = 192) P CR (Day +100) 41% (94/232) 27% (52/192) Survival (Day +100) 60% 49% Day +100 mortality rate in phase 3 pivotal trial HC arm 1 was comparable to that observed in previous trials 2 1. Defitelio (defibrotide) Summary of Product Characteristics. Package%20Insert%20Information%20Defitelio.pdf. Accessed January 11, Coppell JA et al. Biol Blood Marrow Transplant. 2010;16: Richardson PG et al. Presented at: ASH Abstract 700. Delaying Defibrotide Treatment Negatively Impacts Results 1 Delay in the initiation of defibrotide >1 day from VOD/sVOD diagnosis results in significantly lower survival rate, higher mortality at Day +100 post-sct Statistically significance was observed for initiation on days 1, 2, 3, 4, 7, except for day 14 initiation. Initiation Period HSCT VOD/SOS (n = 573) Alive; Dead HSCT VOD/SOS with MOD (n = 351) Alive; Dead 1 Day 53.5%; 41.5% 50.2%; 45.4% >1 Day 45.5%; 50.2% 38.4%; 58.2% 2 Day 55.7%; 39.3% 52.2%; 43.9% >2 Day 35.1%; 60.9% 27.6%; 68.4% 1. Richardson PG et al. Presented at: ASH Abstract Initiation Period HSCT VOD/SOS (n = 573) Alive; Dead HSCT VOD/SOS with MOD (n = 351) Alive; Dead 3 Day 53.5%; 41.2% 49.5%; 46.2% >3 Day 35.6%; 62.5% 29.2%; 68.1% 4 Day 52.6%; 42.4% 48.7%; 47.3% >4 Day 34.2%; 63.0% 25.5%; 70.6% 7 Day 51.6%; 43.5% 47.4%; 48.6% >7 Day 32.5%; 65.0% 23.3%; 73.3% Defibrotide Practical Considerations Pharmacokinetics Short half-life (0.71 hours) 98% of drug is cleared within 4 hours of infusion Not removed by dialysis Contraindicated with systemic anticoagulant or fibrinolytic therapy Treatment modifications Severe hypersensitivity: permanently discontinue Bleeding 1 st episode: hold defibrotide, treat bleed, and consider resuming at the same dose once bleeding has stopped and patient is hemodynamically stable Recurrent episode: discontinue permanently Invasive procedure: discontinue defibrotide 2 hours prior and resume after procedure if no bleeding 9

10 Summary Current management of VOD/SOS primarily involves pharmacologic management and supportive care There is an urgent unmet need for better treatment strategies for the treatment and prevention of VOD/SOS Defibrotide FDA approved for treatment of severe VOD in patients with pulmonary or renal dysfunction 6.25 mg/kg every 6 hours for at least 21 days and up to a maximum of 60 days (until SOS resolution or hospital discharge) Conclusions VOD/SOS is a potentially life-threatening complication of HSCT Mortality rate can be up to 80% or greater in cases of svod/mof Diagnosis of VOD/SOS relies on clinical criteria Be vigilant: use ALL the tools at our disposal to recognize, diagnose, and assess VOD severity (imaging, laboratory testing, biopsy) Patient Resources Patient Brochure: A copy has been provided with your syllabus Excellent resource for patients and families discussing expectations, side effects, and management options Can be shipped to your office (no charge for S&H) Available online with additional resources at: Be the Match: Professional Resources Education on VOD for healthcare professionals: Center for International Blood & Marrow Transplant Research (CIBMTR): American Society for Blood and Marrow Transplantation (ASBMT): CME/CE Credit CME/CE Evaluation If you re seeking credit, ensure you ve filled in your name and demographic information on page 1 and complete the CME/CE Evaluation on your form (after the Activity Survey) Return all forms to on-site staff Thank you for joining us today! 10