An update on the pathogenesis and prevention of graft versus host disease

Transcription

1 An update on the pathogenesis and prevention of graft versus host disease Haematology Saturday March 3 rd Cockle Bay 2 Lecture 2 Haematology Saturday March 3 rd Cockle Bay 2 Lecture 2 Matthew Collin

2 Overview Bone marrow (hematopoietic stem cell) transplantation in the 21 st century Pathogenesis of graft versus host disease Current strategies for prevention and treatment Novel agents Diagnostic pitfalls

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4 D'Souza A, Fretham C. Current Uses and Outcomes of Hematopoietic Cell Transplantation (HCT): CIBMTR Summary Slides, Available at:

5 Graft vs Host LYMPHO-HAEMATOPIETIC SYSTEM GRAFT VERSUS LEUKAEMIA LYMPHOMA MYELOMA

6 SKIN GUT Graft vs Host LIVER LUNG LYMPHO-HAEMATOPIETIC SYSTEM GRAFT VERSUS LEUKAEMIA LYMPHOMA MYELOMA Therapeutic window

7 GVHD is driven by genomic diversity (minor antigens) Risk of GVHD related to genomic mismatching in siblings Martin, P.J., D.M. Levine, B.E. Storer, E.H. Warren, X. Zheng, S.C. Nelson, A.G. Smith, B.K. Mortensen, and J.A. Hansen Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood. 129:

8 Acute and chronic GVHD Skin (erythema) Gut Liver (Lung) Skin (poik, morphoea, sclerosis), nails, hair Eyes Mouth, upper GI, GU Liver Lung Fascia, Joints, Neuro-muscular Haematopoietic, immune

9 Acute and chronic GVHD Direct antigen presentation (recipient) Cellular immune response (mononuclear infiltration) Indirect antigen presentation (donor) Humoral immune response (fibrosis)

10 ACUTE: lichenoid inflammation skin gut liver Zeiser, R., and B.R. Blazar Acute Graft-versus-Host Disease - Biologic Process, Prevention, and Therapy. N Engl J Med. 377:

11 CHRONIC: inflammation, sclerosis, fibrosis Zeiser, R., and B.R. Blazar Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets. N Engl J Med. 377:

12 Grading Acute: Organ stage: 1-4 Clinical grade: I-IV (calculated from maximum organ stage) Grade I: skin stage 1-2 Grade II: skin stage 3 or gut/liver stage 1 Grade III-IV: skin stage 4 or gut/liver stage 2-4 topical steroids oral steroids iv steroids + experimental Chronic: Organ score: 1-3 Clinical severity: mild-moderate-severe (previously limited or extensive) mild: 1-2 organs score 1 moderate : lung score 1 or more than 2 organs score 1 or any organ score 2 severe: lung score 2 or any organ score 3 Clinical risk: low-moderate-high (accounts for rate of onset, thrombocytopenia, performance status etc)

13 ACUTE: Improved clinical risk scores Minnesota CIBMTR combined Grade I-II vs II-IV Grade A-B vs C-D Grade IA-IIIB (SR) Vs IIIC-IVD (HR) MacMillan ML, DeFor TE, Weisdorf DJ. What predicts high risk acute graftversus-host disease (GVHD) at onset?: identification of those at highest risk by a novel acute GVHD risk score. Br J Haematol. 2012;157 (6): MacMillan ML, Robin M, Harris AC et al. A refined risk score for acute graftversus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21 (4):

14 Ann Arbor biomarker score for risk of acute GVHD TNFR1, ST2, and REG3α; score

15 Risk OF chronic GVHD Arora M, Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis. Blood. 2011;117 (24):

16 Induction of acute GVHD 1) Conditioning therapy DAMPS PAMPS Acute inflammation 5) cell-mediated cytotoxic damage 2) Recipient DC activation and mobiliization Re-stimulation by long-lived recipient macrophages 3) Donor T cell priming and activation 4) Effector T cell trafficking to target organs

17 Not all about T cells....

18 CD8 Departments of Hematology and Pathology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan CD163 Many T Few Mac Many T Many Mac Few T Many Mac

19 CD8 Departments of Hematology and Pathology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan CD163 Many T Few Mac Inferior OS of MM (Many Mac) patients Many T Many Mac Few T Many Mac Corroborated by..... Terakura S, Martin PJ, Shulman HM, Storer BE. Cutaneous macrophage infiltration in acute GvHD. Bone Marrow Transplant. 2015;50 (8):

20 Myeloid and T cell infiltrates Myeloid cells Myeloid cells T cells Resident macs Control GVHD GVHD biopsies Dermal sheets

21 GVHD Control FXIIIA CD11c CD3 100mm Xiao-Nong Wang

22 T cell infiltrates in cutaneous GVHD phenotype collagenase Sort-analyse

23 T cell infiltrates in cutaneous GVHD phenotype collagenase Sort-analyse Total T cells intracellular cytokine staining

24 CD14+ CD11c+ myeloid cells dominate the GVHD lesion collagenase Sort-analyse phenotype

25 CD14+ CD11c+ myeloid cells dominate the GVHD lesion collagenase Sort-analyse phenotype

26 CD14+ CD11c+ myeloid cells dominate the GVHD lesion

27 CD14+ CD11c+ myeloid cells dominate the GVHD lesion 84% sensitive and 81% specific for the diagnosis of GVHD at a ratio of >0.55

28 MLR Macrophages cause skin explant GVHD MLR 5 days + skin 3 days Histopath Grade 1 Grade 2 Grade Grade 3 Grade 4 sib MUD MM HLA match

29 MLR Macrophages cause skin explant GVHD MLR 5 days sort Medium or T cells or Macrophages + skin 3 days Histopath

30 MLR Macrophages cause skin explant GVHD MLR 5 days sort Medium or T cells or Macrophages + skin 3 days Histopath

31 1) Conditioning therapy 2) Recipient DC activation and mobiliization Donor myeloid cells potentiate afferent immunity 3) Donor T cell priming and activation 4) Effector T cell trafficking to target organs 5) Recruitment of donor macrophages

32 1) Conditioning therapy Donor myeloid cells potentiate afferent immunity 2) Recipient DC activation and mobiliization 3) Donor T cell priming and activation 4) Effector T cell trafficking to target organs IFNg TAP MHC CD80 CCL5 CXCL10 TNFb TRAIL Perforin Granzyme 5) Recruitment of donor macrophages

33 Tissue damage chronic Immune activation

34 Thymic dysfunction

35 Humoral responses in cgvhd Fluorescence immunoassay FLISA or human serum on a keratinocyte cell line Wang, K.S., H.T. Kim, S. Nikiforow, A.T. Heubeck, V.T. Ho, J. Koreth, E.P. Alyea, P. Armand, B.R. Blazar, R.J. Soiffer, J.H. Antin, C.S. Cutler, and J. Ritz Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease. Blood. 130:

36 Prevention of GVHD stem cells + mononuclear cells CD34+ selection T depletion In vivo T cell depletion Alemtuzumab ATG cyclophosphamide methotrexate ciclosporin, tacrolimus sirolimus, everolimus mycophenolate

37 Prevention of GVHD stem cells + mononuclear cells CD34+ selection T depletion In vivo T cell depletion Alemtuzumab ATG cyclophosphamide methotrexate ciclosporin, tacrolimus sirolimus, everolimus mycophenolate

38 Prevention of GVHD stem cells + mononuclear cells CD34+ selection T depletion In vivo T cell depletion Alemtuzumab ATG cyclophosphamide methotrexate ciclosporin, tacrolimus sirolimus, everolimus mycophenolate

39 Prevention of GVHD stem cells + mononuclear cells CD34+ selection T depletion In vivo T cell depletion Alemtuzumab ATG cyclophosphamide methotrexate ciclosporin, tacrolimus sirolimus, everolimus mycophenolate

40 Prevention of GVHD stem cells + mononuclear cells CD34+ selection T depletion In vivo T cell depletion Alemtuzumab ATG cyclophosphamide methotrexate ciclosporin, tacrolimus sirolimus, everolimus mycophenolate

41 Treatment of acute GVHD CORTICOSTEROIDS PLUS... refractory ECP Experimental Poor outcome DAMPS cytokines trafficking signalling Novel antiinflammatory drugs PX7 NLRP3 ST2 Wnt agonist IL-22 MABs and Chimerics TNF etanercept infliximab IL-1 canakinumab anakinra IL-6 tocilizumab IL-12/23 ustekinumab IL-23 guselkumab Biologics INTEGRINS vedolizumab natalizumab etrolizumab Small molecules FTY720 JAK inhibitors ruxolotinib 1/2 tofacitinib 3 Kinase inhibitors ROCK 1 Aurora A MEK CDK2

42 Lancet Oncology 2014 II-IV II-IV cgvhd TRM Relapse Comparison with matched control data DFS

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45 Anti-integrins Ley, K., J. Rivera-Nieves, W.J. Sandborn, and S. Shattil Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov. 15:

46 JAK inhibitors TPO G-CSF EPO cytopenia O Shea, J.J., and R. Plenge JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 36:

47 Ruxolitinib trials

48 Treatment of chronic GVHD CORTICOSTEROIDS RESTART calcineurin inhibitor PLUS... refractory ECP Experimental Poor outcome cytokines B cell T cells fibrosis Pentostatin Treg infusion Low dose IL-2 RORgT (TH 17 ) Tocilizumab IL-6 Anti-B cell Rituximab (CD20) Thalidomide Bortezomib TLR responsiveness chloroquine Kinase inhibitors Ruxolotinib JAK1/2 Ibrutinib BTK SYK ROCK 2 Signalling Pirfenidone TGFb Imatinib PDGFR

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51 Back to pathology When is a biopsy still useful?

52 Case 1 56 year old female Normocytic anaemia and IgA K paraprotein (2015) 1q- Intolerant of thalidomaide (CTD) Velcade (VCD) Auto and planned tandem allo from matched sibling Seattle conditioning (Flu + 2Gy TBI T replete) Discharged after uneventful transplant day +16

53 Post-transplant recovery BMT

54 Then what happened? BMT 6/12 IS stopped

55 BMT

56 Case 1 Discharged after uneventful transplant day +16 Myeloma in CR at 3/12 Immunosuppression tapered at 6/12 Fulminant hepatic failure All viral serology and autoimmune screens negative Collapsed liver on MRI Offered urgent listing for liver transplant but declined Died 2 weeks later

57 Seronegative hepatitis

58 Case 2 62 year old female Type II DM, osteoarthritis, high cholesterol Fatigue and high WCC B-ALL t(1;19) Ph-negative Commenced UKALL 60+ (intensive) Remission after first induction Fludarabine Melphalan Alemtuzumab RIC Discharged after uneventful transplant day +22 Developed diarrhoea at 10 weeks Low grade CMV reactivation No rash

59 Post-transplant recovery BMT

60 Post-transplant recovery BMT

61 Then what happened? Given budesonide and ciprofloxacin Plain rice diet for 7-10 days All symptoms resolved Alive and well now off immunosuppression

62 Neutrophilic colitis

63 Dedication One of the good guys Derek Hart

64 Thank you Bev Rowbotham Eve Propper

65 Human DC lab Paul Milne Laura Jardine Clare Lendrem Amy Publicover Venetia Bigley Urszula Cytlak Ana Resteu Kile Green