steroid refractory acute gvhd

1. Steroid Refractory Acute GVHD Mark A. Schroeder, MD Hematology/Oncology Grand Rounds 2/16/2007

2. Outline and Objectives Case Presentation Epidemiology of GVHD Staging and grading GVHD Pathophysiology Primary treatment Secondary treatment Novel treatments and future directions

3. The Case of KH 64 yo WM MDS with nl cytogentics dx 4/04 progressing to AML status post MUD. Day 45 with 100% engraftment and acute abdominal pain, nausea, bilious emesis and voluminous watery diarrhea. No rash, no melana/BRBPR, +30 pound wt loss since initiating treatment. No fevers, sweats, chills. Recently completed course of Flagyl for C-diff colitis on October 25 and has had history of recurrent C.dif.

4. PMH MDS nl cytogenetics (IPSS 1) progressing to AML dx 4/04 with fatigue and shortness of breath and found to be anemic. BMBx showed 6% blasts and 85 to 90% cellularity c/w MDS, INT-1. Azacytidine x 18 months with CR until 3/06. BMBx with 16% blasts. SAHA (HDAC) study 6/06 but progression (circulating blasts = 87%). 6/06 standard induction with 7+3 c/b neutropenic fever and C-diff. Persistent disease on BMBx and 10% cellularity. Delayed count recovery and f/u BMBx on Day +48 showed persistent AML, 83% blasts. He was treated with five days of Decitabine at 20 mg/m2. He was readmitted 9/06 for MUD 10/10 HLA matched PBSC transplant. Conditioned with Busulfan + Cyclophosphamide transplanted on September 23 with MTX+Tacro + MMF GVHD prophylaxis. His hospital course at that time was complicated by acute renal failure and recurrent C-diff colitis. Post transplant BMBx at count recovery was normal cellular without AML and VNTR was 100% donor HTN

5. The Case of KH MEDS: 1. Tacrolimus 0.5 mg PO Q day. 2. Valtrex 500 mg PO Q day. 3. Voriconazole 200 mg PO Q day. 4. Recent course of Flagyl completed on October 25. 5. Prednisone 5 mg PO Q day for appetite. ALLERGIES: No known drug allergies. FAMILY HISTORY: sister with CML SOCIAL HISTORY: no bad habits PHYSICAL EXAMINATION: Afebrile, Normotensive mild distress from pain. anicteric sclera. Oropharynx was clear. NECK: No lymphadenopathy. Normal thyroid. LUNGS: CTA CARDIOVASCULAR: RRR no murmur ABDOMEN: soft, diffusely tender; no guarding or rebound; no HSM. Decreased bowel sounds EXTREMITIES: no C/C/E SKIN: no rash

6. The Case of KH CT Abd/Pelvis: moderate bowel wall thickening involving the entire small bowel with marked enhancement of the mucosa highly suspicious for graft versus host disease. Mild mucosal enhancement of the colon is also noted. NL liver, spleen, bilateral kidneys, pancreas and gallbladder. No LAD.

7. Epidemiology of GVHD Major cause of morbidity and mortality in the HSCT setting IBMTR retrospective review 2416 patients from 1995-2002 receiving CSA+MTX with (15%) or without (85%) other prophylactic agents 31% developed grade II-IV GVHD 50-75% of patients will have a clinical response to steroids (most are grade II) Steroid refractory aGVHD carries a high morbidity and mortality (>50%) GVHD occurs in 30 to 50% of HLA-matched sibling transplants and 60 to 90% of Mismatched or MUDs. Classically for ablative transplants acute GVHD is seen <100 days Non-myeloablative conditioning and DLI has resulted in delayed acute GVHD>100 days GVHD occurs in 30 to 50% of HLA-matched sibling transplants and 60 to 90% of Mismatched or MUDs. Classically for ablative transplants acute GVHD is seen <100 days Non-myeloablative conditioning and DLI has resulted in delayed acute GVHD>100 days

8. Predictors of acute GVHD HLA disparities Increasing age (>40) Gender mismatch / parity of donor Minor histocompatibility antigens CD34 dose Intensity of preparative regimen and XRT GVHD prophylaxis (dose and type) T-cell depletion in graft Advanced disease status SibAllo<<UCT<MUD Eosinophilia is protective cumulative incidence of grades II to IV acute GVHD was found to be significantly higher in patients without eosinophilia than in those with eosinophilia (68% vs. 43%; P < 0.001). cumulative incidence of grades II to IV acute GVHD was found to be significantly higher in patients without eosinophilia than in those with eosinophilia (68% vs. 43%; P < 0.001).

9. A balance of GVHand GVL 4174 HLA-identical sibling transplants for chronic myelogenous leukemia in first chronic phase TRM increased with increasing grades of aGVHD Increasing degrees of aGVHD reduced the risk of relapse 4174 HLA-identical sibling transplants for chronic myelogenous leukemia in first chronic phase, transplantation-related mortality (TRM) increased with increasing grades of acute GVHD: Grade 0 acute GVHD — hazard ratio (HR) for TRM: 1.0 Grade I — HR 1.5 (95% CI 1.2-2.0) Grade II — HR 2.5 (95% CI 2.0-3.1) Grade III — HR 5.8 (95% CI 4.4-7.5) Grade IV — HR 14.7 (95% CI 11-20) Conversely, increasing degrees of acute GVHD reduced the risk of relapse: Grade 0 acute GVHD — hazard ratio (HR) for relapse 1.0 Grade I — HR 0.94 (95% CI 0.8-1.2) Grade II — HR 0.60 (95% CI 0.5-0.8) Grade III — HR 0.48 (95% CI 0.3-0.8) Grade IV — HR 0.14 (95% CI 0.02-0.99) 4174 HLA-identical sibling transplants for chronic myelogenous leukemia in first chronic phase, transplantation-related mortality (TRM) increased with increasing grades of acute GVHD: Grade 0 acute GVHD — hazard ratio (HR) for TRM: 1.0 Grade I — HR 1.5 (95% CI 1.2-2.0) Grade II — HR 2.5 (95% CI 2.0-3.1) Grade III — HR 5.8 (95% CI 4.4-7.5) Grade IV — HR 14.7 (95% CI 11-20) Conversely, increasing degrees of acute GVHD reduced the risk of relapse: Grade 0 acute GVHD — hazard ratio (HR) for relapse 1.0 Grade I — HR 0.94 (95% CI 0.8-1.2) Grade II — HR 0.60 (95% CI 0.5-0.8) Grade III — HR 0.48 (95% CI 0.3-0.8) Grade IV — HR 0.14 (95% CI 0.02-0.99)

10. Pathophysiology Donor T-cells recognizing host major and minor histocompatability complexes are the major mediators of GVHD Triad of etiologic factors Inflammatory milieu (IL-1, TNFa, INFg) / Conditioning Activation phase (APCs and cytokines trigger expansion of donor T-cells to effector cells) Minor histocompatibility antigens IL-2, IFNg = Th1 phenotype potentiates acute GVHD Effector phase Fas-Fas ligand interactions, perforin-granzyme B, and cytokine production (TNFa) proliferation of activated T-cells leads to the production and secretion of a variety of cytokines which are responsible for the inflammatory effects and tissue damage associated with GVHD. Much of the damage is caused by inflammatory cytokines, such as interleukin (IL)-1, IL-2, tumor necrosis factor (TNF), and gamma-interferon TNFa is mainly produced by monocytes and macrophages and secondarily by T-lymphocytes and NK cells TNFa - induction of apoptosis in target tissues through TNFa receptor; activation of macrophages, neutrophils, eosinophils, B cells and T cells; stimulating production of additional inflammatory cytokines (IL-1, IL-6, IL-10, IL-12 and TNFa); increased expression of HLA; facilitates T-lymphocyte lysis. High levels of TNFa have been implicated in an increased incidence of GVHD in transplant recipients proliferation of activated T-cells leads to the production and secretion of a variety of cytokines which are responsible for the inflammatory effects and tissue damage associated with GVHD. Much of the damage is caused by inflammatory cytokines, such as interleukin (IL)-1, IL-2, tumor necrosis factor (TNF), and gamma-interferon TNFa is mainly produced by monocytes and macrophages and secondarily by T-lymphocytes and NK cells TNFa - induction of apoptosis in target tissues through TNFa receptor; activation of macrophages, neutrophils, eosinophils, B cells and T cells; stimulating production of additional inflammatory cytokines (IL-1, IL-6, IL-10, IL-12 and TNFa); increased expression of HLA; facilitates T-lymphocyte lysis. High levels of TNFa have been implicated in an increased incidence of GVHD in transplant recipients

11. Residual host APCs in murine models of acute GVHD were required for the induction phaseResidual host APCs in murine models of acute GVHD were required for the induction phase

12. Other T-cell subsets mediating GVHD CD4+ T cells are crucial for sustaining the secondary expansion of CD8+ T cells CD4+/CD25+/FoxP3+ regulatory T-cells suppress allo reactivity in murine and human allogeneic transplantation Contact-dependent IL-10, TGF-b In CD 4 knockout mice CD8 cells initially expand normally but are not sustained, no effector function Infusion of purified CD4+ t cells as DLI leads to the expansion of CD8+ t cells CD25 = the IL2 receptor alpha chain Murine models of aGVHD have shown that infusion of donor grafts enriched in Tregs suppress the incidence of lethal GVHD and facilitate allogeneic transplantation across HLA barriers In CD 4 knockout mice CD8 cells initially expand normally but are not sustained, no effector function Infusion of purified CD4+ t cells as DLI leads to the expansion of CD8+ t cells CD25 = the IL2 receptor alpha chain Murine models of aGVHD have shown that infusion of donor grafts enriched in Tregs suppress the incidence of lethal GVHD and facilitate allogeneic transplantation across HLA barriers

13. Clinical Manifestations Skin Most often involved Maculopapular rash Palms and soles initially Liver Hyperbili and increased alk phos GI Manifests as diarrhea Upper GI symptoms - nausea, anorexia Severe cases - ileus, cramping pain, bleeding Upper GI tract / oral mucosa Renal (rarely) Eye skin, liver, gastrointestinal tract, and the hematopoietic system are the principal target organs The rash seen in GVHD can be variable. A maculopapular rash affects the palms, soles, neck, or ears is commonly seen. The skin changes can be more severe including scleroderma-like changes, edema, bullous formation, or necrolysis. It can be described as a sunburn and may be pruritic or painful. From these initial areas of presentation, the rash may spread to involve the whole integument, eventually becoming confluent. The liver is the second most commonly involved organ in acute GVHD. Rarely, patients have moderate to severe hepatic GVHD without evidence of cutaneous disease The liver manifestations are primarily increases in the conjugated bilirubin and alk phos but can also involve transaminitis. This is a result of damage to biliary canaliculi causing stasis. The GI manifestations are diarrhea, nausea, and vomiting. DDx includes: VOD Infection Drug tox - conditioning or immunosuppression (MTX, CSA) GI involvement usually presents with volumanous diarrhea up to 10 liters/day diarrhea may initially be watery, but frequently becomes bloody, resulting in significant transfusion requirementsskin, liver, gastrointestinal tract, and the hematopoietic system are the principal target organs The rash seen in GVHD can be variable. A maculopapular rash affects the palms, soles, neck, or ears is commonly seen. The skin changes can be more severe including scleroderma-like changes, edema, bullous formation, or necrolysis. It can be described as a sunburn and may be pruritic or painful. From these initial areas of presentation, the rash may spread to involve the whole integument, eventually becoming confluent. The liver is the second most commonly involved organ in acute GVHD. Rarely, patients have moderate to severe hepatic GVHD without evidence of cutaneous disease The liver manifestations are primarily increases in the conjugated bilirubin and alk phos but can also involve transaminitis. This is a result of damage to biliary canaliculi causing stasis. The GI manifestations are diarrhea, nausea, and vomiting. DDx includes: VOD Infection Drug tox - conditioning or immunosuppression (MTX, CSA) GI involvement usually presents with volumanous diarrhea up to 10 liters/day diarrhea may initially be watery, but frequently becomes bloody, resulting in significant transfusion requirements

14. Histologic examination of acute GVHD of the skin reveals changes in the dermal and epidermal layers Characteristic findings include exocytosed lymphocytes, dyskeratotic epidermal keratinocytes, follicular involvement, satellite lymphocytes adjacent to or surrounding dyskeratotic epidermal keratinocytes, and dermal perivascular lymphocytic infiltrationHistologic examination of acute GVHD of the skin reveals changes in the dermal and epidermal layers Characteristic findings include exocytosed lymphocytes, dyskeratotic epidermal keratinocytes, follicular involvement, satellite lymphocytes adjacent to or surrounding dyskeratotic epidermal keratinocytes, and dermal perivascular lymphocytic infiltration

15. Rectal biopsy rectal biopsy is usually helpful in making the diagnosis of acute GVHD affecting the gastrointestinal tract. On histologic examination, crypt cell necrosis is observed with the accumulation of degenerative material in the dead crypts Must r/o CMV by stainingrectal biopsy is usually helpful in making the diagnosis of acute GVHD affecting the gastrointestinal tract. On histologic examination, crypt cell necrosis is observed with the accumulation of degenerative material in the dead crypts Must r/o CMV by staining

16. Stage and Grading of GVHD severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract Patients with moderate to severe GVHD have a significantly higher mortality rate compared to those with mild disease. a patient with grade IV GVHD of the skin alone would be expected to have a much more favorable outcome than a patient with grade IV gut GVHD alone, although both have overall grade IV GVHDseverity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract Patients with moderate to severe GVHD have a significantly higher mortality rate compared to those with mild disease. a patient with grade IV GVHD of the skin alone would be expected to have a much more favorable outcome than a patient with grade IV gut GVHD alone, although both have overall grade IV GVHD

17. Treatment Once established acute GVHD is difficult to treat The best primary treatments have a 50% response Once steroid refractory the chance of survival is slim and chronic GVHD is the rule

18. An Ounce of Prevention Most common regimen of MTX + CSA, reduced incidence of GVH from 55% to 30% A prospective RCT comparing the addition of steroids to the standard regimen of CSA and MTX did not demonstrate an improvement in the prevention of acute GVHD in patients with more advanced disease A large phase III study in patients with matched related allo, MTX+FK506 results in a lower incidence of acute GVHD compared to MTX+CSA (32% vs 44%) Current Phase III trial CTN 0402 at Wash U comparing Tacro/MTX vs Sirolimus/tacrolimus in matched related PBSC transplantation Incidence of high grade III-IV GVH is similar despite prophylactic regimens Advanced disease patients did worse with Tacro regimen than CSA at 2yrs with DFS and OS of 50 vs 40 and 57 vs 47% respectively Cumulative probability of acute grade II-IV graft-versus-host disease (GVHD) after bone marrow transplantation among 150 patients with leukemia or lymphoma. The patients were randomized to cyclosporine and prednisone without (two drug regimen) or with methotrexate (three drug regimen). The patients receiving the three drug regimen had a significantly lower incidence of acute GVHD than those receiving only cyclosporine and prednisone (9 versus 23 percent, p = 0.02). The lower incidence of acute GVHD did not result in a higher relapse rate of leukemia or lymphoma, as the disease-free survival at three years was the same in the two groups (64 versus 59 percent). Data from Chao, NJ, Schmidt, GM, Niland, JC, et al, N Engl J Med 1993; 329:1225. Incidence of high grade III-IV GVH is similar despite prophylactic regimens Advanced disease patients did worse with Tacro regimen than CSA at 2yrs with DFS and OS of 50 vs 40 and 57 vs 47% respectively Cumulative probability of acute grade II-IV graft-versus-host disease (GVHD) after bone marrow transplantation among 150 patients with leukemia or lymphoma. The patients were randomized to cyclosporine and prednisone without (two drug regimen) or with methotrexate (three drug regimen). The patients receiving the three drug regimen had a significantly lower incidence of acute GVHD than those receiving only cyclosporine and prednisone (9 versus 23 percent, p = 0.02). The lower incidence of acute GVHD did not result in a higher relapse rate of leukemia or lymphoma, as the disease-free survival at three years was the same in the two groups (64 versus 59 percent). Data from Chao, NJ, Schmidt, GM, Niland, JC, et al, N Engl J Med 1993; 329:1225.

19. Primary Treatment Disrupt the triad Non-specific Immunosuppressives methylpred 2mg/kg/day Steroid + calcineurin inhibitor (CSA, tacro) ~40% of sib transplants and 24% of MUDs will respond to steroids Response is worse with liver involvement and with higher grade Current phase II (CTN 0302) protocol underway at Wash U Etanercept vs MMF vs Pentostatin vs Denileukin diftitox in addition to steroids methylprednisolone is primarily bound to albumin Steroids may act to decrease pro-inflammatory cytokine release Complications of treating aGVHD are infection and recurrence of malignancy by affecting GVLmethylprednisolone is primarily bound to albumin Steroids may act to decrease pro-inflammatory cytokine release Complications of treating aGVHD are infection and recurrence of malignancy by affecting GVL

20. Secondary Therapies Defined as no response to steroid for 1 wk or progressive disease after 72hrs No consensus and uniformly poor outcomes (mostly phase I and II trials) ATG Variations in product and dosing 19-56% OR (59-79% in skin) without affect on OS and 90% 1 yr mortality Wash U experience Khoury et al. 58pts failing steroids treated with ATG (dif. dose schedules) 90% died at 40 days, mainly from infections Hopkins experience 4/69 patients survived Death mainly from infection ATG has wife range of dosing variations and antibody titre (horse or rabbit, 14 different kinds)Death mainly from infection ATG has wife range of dosing variations and antibody titre (horse or rabbit, 14 different kinds)

21. Target Therapy At Activation Phase 1, Cyclosporine; 2, Tacrolimus (FK506); 3, Rapamycin; 4, Corticosteroid.1, Cyclosporine; 2, Tacrolimus (FK506); 3, Rapamycin; 4, Corticosteroid.

22. Secondary Therapies: Targeting the IL2-receptor Denileukin Diftitox, Inolimomab, Basiliximab, Daclizumab Daclizumab humanized IgG1 anti-CD25, competative inhibition of IL-2R alpha 43 patients CR 47% (majority in GVH isolated to skin) OS 53% at 4 months (major cause of death GVH and infection) Daclizumab+steroid as primary treatment of GVH lead to decreased OS at day 100 (77% vs 94%) and 1yr OS 29% vs 60% Mortality related to GVH and recurrence Alpha subunit of IL2 is mainly expressed on activated T cells and has high affinity to IL2. Alpha subunit of IL2 is mainly expressed on activated T cells and has high affinity to IL2.

23. Secondary Therapy Denileukin Diftitox (Ontak) Recombinant fusion protein with diphteria toxin fusion selective for IL2-R N=24, OR 69% with 46% CR Response greatest in skin and GI 10 pts previously treated with Daclizumab and 8 patients had response Infection was leading cause of mortality If CR was obtained OS was 58% at 7.2 months, compared with <10% if PR

24. Secondary Therapies MMF Response rates of 29-67% Better results in skin GVH OS at 2 yrs 16% Pentostatin Neucleoside analog that inhibits adenosine deaminase, resulting in diminished T-cell fxn and lymphocyte apoptosis OR of 71% (64% CR) Median survival 91 days Highest response in skin and gut MMF: Basara trials used CSA/MTX/Pred GVH prophylaxisMMF: Basara trials used CSA/MTX/Pred GVH prophylaxis

25. Secondary Therapy Infliximab Humanized monoclonal Ab binding TNF?? (membrane bound and soluble) RR 65% and OS 31% reported by MDACC Substantial increased risk of infections (fungal) Visiluzumab Anti-CD3 humanized monoclonal antibody Induces apoptosis of activated T-cells Fred Hutch experience 6/17 patients achieved CR Median survival not met at 1yr

26. Summary

27. Secondary Therapy No secondary therapy to date provides an improved OS in steroid refractory aGVHD Focus remains on prevention and prediction

28. Novel Approaches Graft Engineering ECP Target multiple pathways MSCs

29. Residual host APCs in murine models of acute GVHD were required for the induction phaseResidual host APCs in murine models of acute GVHD were required for the induction phase

30. Graft engineering T-cells are required to develop GVH but without them engraftment fails, immune recovery is slow, and GVL is reduced T cell depleted grafts ex vivo depletion using mAbs (CD-2, CD-5/6/7, CD-4/8, CD25) Incidence of GVH ranged 5-28% Graft failure 3-60% Cell sort depletion of allo-reactive CD4 cells Ex vivo expansion of T regs (Rapamycin?) Deplete naïve T cells (murine model) Mesenchymal stromal cell therapy T-cell deplete graft followed by DLI after non-myeloablative conditioning T-cell Suicide gene therapy T-cell depleted grafts: increased graft failure and infections with delayed immune reconstitutionT-cell depleted grafts: increased graft failure and infections with delayed immune reconstitution

31. ECP Photoactivated 8-Methoxsalen damages cell membrane and DNA and is taken up by activated lymphocytes Expose PBMCs to 8-MOP ? expose to UVA and re-infuse More experience in cGVHD Single institution study of 21 pts 60% CR (100% CR in grade II GVH) OS 57% at 25 months for responders The number of CD4+CD25+Foxp3+ Treg in ECP-treated allo-BMT recipients was significantly increased The number of CD4+CD25+Foxp3+ Treg in ECP-treated allo-BMT recipients was significantly increased

32. Update from ASBMT/CIBMTR [34] Preserved Anti-Viral Responses and Improved Survival in Steroid Refractory GVHD Using a Combination of Daclizumab and Infliximab. Rao, K. et al. London, United Kingdom Daclizumab (1mg/kg, days 1,4,8,15,22) + Infliximab (10mg/kg, days 1,8,15,22), with rapid reduction of steroid dosage to = 1mg/kg N=15 children, grade 3 (n=5) or 4 (n=10) GVHD All had improvement median follow-up of 30 months and 10/15 (66%) children are alive

33. Update from ASBMT/CIBMTR EBMT MSC Expansion Consortium Used MSCs to treat grade III-IV second line refractory GVHD N=40, 1-5 doses given 19 CRs (48%), 7 PRs (18%) 21 pts alive at 6wks – 3.5 yrs MSCs are costly Timely to grow Unknown doseMSCs are costly Timely to grow Unknown dose

34. Update from ASBMT/CIBMTR [306] Successful Phase II Trial Using Mesenchymal Stem Cells (MSC) in Combination with Steroid Therapy for the Primary Treatment of Acute Graft-vs-Host Disease (aGVHD). Kebriaei, P.,et al. N=32, 66% had grade II GVHD 90% initially responded to aGVHD treatment 21 CRs with no evidence of GVHD 7 PRs with a reduction in 1 organ stage 100% with skin GVHD responded 83% with GI or single organ GVHD responded 9 pts (31%) eventually required a second line agent to control aGVHD

35. Update from ASBMT/CIBMTR [308] Treatment of Steroid Refractory, Severe Acute Graft Versus Host Disease with Expanded Mesenchymal Stem Cells in Children Having Undergone Allogeneic Stem Cell Transplantation: A Single Center Experience. Ball, L.M. et al. Netherlands N=8, 100% had grade 4 GVHD 5/8 (63%) had CR, 1 PR OS 4/8 (50%), deaths secondary to infection

36. Back to the Case of KH Started on methylpred 2mg/kg/day Did not enroll into CTN study Developed diffuse macular rash (Grade II) Persistent profuse diarrhea up to 5L/day (Grade IV) Persistent crampy abdominal pain with ileus (Grade IV) Started on Daclizumab (1mg/kg, days 1,4,8,15,22) Worsening liver failure and renal failure Mental status worsened Died 12/1/06, 25 days into hospitalization, multisystem organ failure

37. Conclusions GVHD is the major barrier to successful allogeneic stem cell transplantation Steroid refractory acute GVHD remains a major cause of early morbidity and mortality in the transplant setting and current approaches do little to affect OS Novel approaches to its prevention and treatment are needed Graft engineering remains a tantalizing option to prevent acute GVHD

38. Rapid and Wide Immunereconstitution Obtained with HSV-TK Engineered Donor Lymphocyte Add-Backs Permits Long-Term Survival after haplo-HSCTChiara Bonini et al., Milano, Italy, ASH 2006 Abstract #307 TK-DLI abolishes late mortality after CD34+ haplo-SCT in adults. A phase III multicentric study will start in 2007 to validate prospectively the advantage of TK-DLI in haplo-SCT TK-DLI abolishes late mortality after CD34+ haplo-SCT in adults. A phase III multicentric study will start in 2007 to validate prospectively the advantage of TK-DLI in haplo-SCT

39. Epidemiology in the era of umbilical cord transplantation and reduced intesity conditioning Reduced intensity conditioning regimens and matched UCT carry less risk for acute GVHD but aproximately equivalent risk for chronic GVHD UCT with greater HLA disparity carries higher rates of GVHD as mismatch increases Double UCTs have higher rates of aGVHD compared with single UCTs 6/6 UCT carries less risk of aGVHD compared to 6/6 MUD grades II-IV and III-IV acute GVHD were higher in recipients of double than single UCBT recipients (60% vs 33%, p.01) and (21% vs 11%, p=.01), respectively. grades II-IV and III-IV acute GVHD were higher in recipients of double than single UCBT recipients (60% vs 33%, p.01) and (21% vs 11%, p=.01), respectively.

40. Disclosures I have received nutritional support from Pharmion at the ASBMT meeting at the Ski Tip Lodge, including an appetizer of shrimp followed by roasted lamb with pulled bison, parmesan polenta with roasted vegetables and finished off with apple strudel and coffee I have received writing support from Amgen with continued donation of pens that run out of ink after 3-4 uses