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  • 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
  • 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).
  • 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)
  • 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
  • Residual host APCs in murine models of acute GVHD were required for the induction phase
  • 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
  • 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:
    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
  • 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 infiltration
  • 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 staining
  • 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 GVHD
  • 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.
  • 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 GVL
  • Death mainly from infection
    ATG has wife range of dosing variations and antibody titre (horse or rabbit, 14 different kinds)
  • 1, Cyclosporine; 2, Tacrolimus (FK506); 3, Rapamycin; 4, Corticosteroid.
  • Alpha subunit of IL2 is mainly expressed on activated T cells and has high affinity to IL2.
  • MMF:
    Basara trials used CSA/MTX/Pred GVH prophylaxis
  • Residual host APCs in murine models of acute GVHD were required for the induction phase
  • T-cell depleted grafts: increased graft failure and infections with delayed immune reconstitution
  • The number of CD4+CD25+Foxp3+ Treg in ECP-treated allo-BMT recipients was significantly increased
  • MSCs are costly
    Timely to grow
    Unknown dose
  • 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
  • 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.
  • Transcript

    • 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. 129 58 1.519 Gap 18 236 WBC 6.7 H/H 15/45 Plts 230 LDH 136 alkaline phos 136 AST 17 ALT 24, bilirubin 1.3 albumin 2.7 total protein 6.2 Surgical Pathology: LARGE INTESTINE: ACUTE GRAFT-VERSUS-HOST DISEASE, GRADE 3 SMALL INTESTINE: ACUTE GRAFT-VERSUS-HOST DISEASE, GRADE 4. Negative staining for CMV
    • 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%) Couriel, D, Caldera, H, Champlin, R, Komanduri, K. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer 2004; 101:1936.
    • 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 Couriel et al. Cancer. 2004. 101(9):1936-1946 ASBMT 2007 Abstract #25 Blood Eosinophilia as a Marker of Favorable Outcome after Allogeneic Stem Cell Transplantation Aisa, Y., Mori, T., Nakazato, T., Shimizu, T., Yamazaki, R., Ikeda, Y., Okamoto, S.. Keio University Hospital, Tokyo, Japan
    • 9. A balance of GVH and GVL Gratwohl, A. et al. Blood 2002;100:3877-3886 • 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 OS TRM Relapse Incidence
    • 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, TNFα, INFγ) / Conditioning – Activation phase (APCs and cytokines trigger expansion of donor T-cells to effector cells) • Minor histocompatibility antigens • IL-2, IFNγ = Th1 phenotype potentiates acute GVHD – Effector phase • Fas-Fas ligand interactions, perforin-granzyme B, and cytokine production (TNFα) Couriel et al. Cancer. 2004. 101(9):1936-1946 Antin, JH, Ferrara, JL. Cytokine dysregulation and acute graft-versus-host disease. Blood 1992; 80:2964. Ferrara, JL, Deeg, HJ. Graft-versus-host disease. N Engl J Med 1991; 324:667.
    • 11. Phase I (Initiation) Phase II (Activation) Phase III (Effector) Conditioning Tissue Damage GI Skin Endotoxin (LPS) and cytokine release (TNFa, IL-1, IL-6) M0 and Monocytes Donor Tcell Host APC IL-2 IFNg CTL NK Treg Cell Death IL-12 Donor APC MLR MiHC
    • 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-β
    • 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
    • 14. Skin Biopsy in Acute GVHD Cancer. 2004;101:1936
    • 15. Rectal biopsy
    • 16. Stage and Grading of GVHD Przepiorka, D, Weisdorf, D, Martin, P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15:825.
    • 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 Chao, N et al. BBMT 2000;6:28 Ratanatharathom V. et al. Blood. 1998;92:2303 Storb R et al. NEJM. 1986;314:729
    • 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 Antin J et al. BBMT. 2004;10:655 Weisdorf D et al. Blood. 1990;75:1024 Roy J et al. BMT. 1992;10:77 Martin PJ et al. Blood. 1991;77:1821
    • 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 BMT. 2001;27:1059-1064 Antin J et al. BBMT. 2004;10:655
    • 21. Target Therapy At Activation Phase C S A Tacro Rapamycin 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 Przepiorka et al. Blood. 2000;95:83 Lee SJ et al. Blood. 2004;104:1559
    • 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 Ho V et al. Blood. 2004;104:1224
    • 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 Antin J et al. BBMT.2004;10:655 BMT. 2001;27:1059-1064
    • 25. Secondary Therapy • Infliximab – Humanized monoclonal Ab binding TNFα (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 Antin J et al. BBMT.2004;10:655 Couriel et al. Blood. 2004;104:649 Ho et al. Blood. 2004;104:1224
    • 26. Antin J et al. Blood. 2004.BBMT;10:665 Summary •Higher grade GVHD does worse •Nearly all survivors of acute GVHD go on to develop cGVHD
    • 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. Phase I (Initiation) Phase II (Activation) Phase III (Effector) Conditioning Tissue Damage GI Skin Endotoxin (LPS) and cytokine release (TNFa, IL-1, IL-6) M0 and Monocytes Donor Tcell Host APC IL-2 IFNg CTL NK Treg Cell Death IL-12 Donor APC MLR MiHC
    • 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
    • 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 Extracorporeal Photopheresis for Acute and Chronic Graft-versus-Host Disease: Does It Work?. Blood. 2006;12(1)Sup2:37
    • 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
    • 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