The Impact of Endothelial Injury in Hematopoietic Stem Cell - PowerPoint PPT Presentation

The Impact of Endothelial Injury in Hematopoietic Stem Cell Transplant (HSCT) April 2020

Terms • • HSCT-TMA, hematopoietic stem cell transplant – associated ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 thrombotic microangiopathy • • aGVHD, acute graft-vs-host disease ICU, intensive care unit • • IL-1 β, interleukin 1 β CKD, chronic kidney disease • • CLS, capillary leak syndrome IPS, idiopathic pneumonia syndrome • • CMV, cytomegalovirus LDH, lactate dehydrogenase • • CNI, calcineurin inhibitor MAC, membrane attack complex • • CNS, central nervous system MASP, mannose-binding lectin-associated serine protease • • DAH, diffuse alveolar hemorrhage MBL, mannose-binding lectin • • DAMP, damage-associated molecular pattern mTOR, mammalian target of rapamycin • • EIS, endothelial injury syndromes PT/PTT, prothrombin time/partial thromboplastin time • • ES, engraftment syndrome RBC, red blood cell • • ESRD, end-stage renal disease SCr, serum creatinine • • FO, fluid overload SOS, sinusoidal obstruction syndrome • • GI, gastrointestinal TMA, thrombotic microangiopathy • • GVHD, graft-vs-host disease TNF, tumor necrosis factor • • HLA, human leukocyte antigen TTP, thrombotic thrombocytopenic purpura • • HSCT, hematopoietic stem cell transplant VOD, veno-occlusive disease

The Impact of Endothelial Injury Syndromes in HSCT 1 2 3 EIS and the threat Endothelial injury Conclusion of HSCT-TMA syndromes (EIS) HSCT-TMA causes high mortality After HSCT, EIS may put The unmet need in HSCT-TMA and significant morbidity successful transplant is significant. in those who survive. outcomes at risk. • Need for more robust vigilance • Pathophysiology and differentiating • Clear identification of high-risk TMA • HSCT process contributes to EIS HSCT-TMA from other post-HSCT • Need for consensus diagnostic criteria • Types of EIS complications • Role of the lectin pathway of • Differential diagnoses and complement diagnostic challenges • Risk factors and negative clinical outcomes • Economic burden of disease • Warning signs for HSCT-TMA • Patient case study

1 Endothelial Injury Syndromes (EIS)

Endothelial Injury Damage to endothelial cells can occur in many ways — physically, chemically and immunologically 1-3 Endothelial injury plays a role Stroke Viral infections Chronic kidney in the pathogenesis of 4 : disease Peripheral Insulin resistance Venous thrombosis vascular disease Cancer Heart disease Diabetes The HSCT process and adoptive cell therapy involve multiple factors that can affect endothelial cells, and endothelial damage is a common result. 5-7 References: 1. Carreras E et al. Bone Marrow Transplant. 2011;46(12):1495-1502. doi:10.1038/bmt.2011.65 2. Gust J et al. Cancer Discov. 2017;7(12):1404-1419. doi:10.1158/2159-8290.CD-17-0698 3. Hay KA et al. Blood. 2017;130(21):2295-2306. doi:10.1182/blood-2017-06-793141 4. Rajendran P et al. Int J Biol Sci. 2013;9(10):1057-1069. doi:10.7150/ijbs.7502 5. Gavriilaki E et al. Bone Marrow Transplant. 2017;52(10):1355-1360. doi:10.1038/bmt.2017.39 6. Jodele S et al. Biol Blood Marrow Transplant . Published online April 2014. 2014;20(4):518-525. doi:10.1016/j.bbmt.2013.12.565 7. Laskin BL et al. Blood. 2011;118(6):1452-1462. doi:10.1182 /blood-2011-02-321315

Multiple Factors Can Lead to EIS in HSCT 1-3 Before, during, and after transplant, multiple factors can lead to EIS Chemoradiotherapy Cytokines released Immunosuppressive Bacterial endotoxins Engraftment Allogeneic reactions included in by injured tissues therapies translocated through process with donor-derived conditioning regimens GI damage immune cells HSCT and adoptive cell therapy require careful monitoring to manage the risk of EIS. References: 1. Carreras E et al. Bone Marrow Transplant. 2011;46(12):1495-1502. doi:10.1038/bmt.2011.65 2. Gust J et al. Cancer Discov. 2017;7(12):1404-1419. doi:10.1158/2159-8290.CD-17-0698 3. Hay KA et al. Blood. 2017;130(21):2295-2306. doi:10.1182/blood-2017-06-793141

Various Endothelial Injury Syndromes May Result From HSCT 1,2 Several syndromes result Types from transplant-related TMA DAH of EIS endothelial damage and can overlap in presentation and classification. 1-4 Thrombotic microangiopathies aGVHD IPS Acute graft-vs-host disease Veno-occlusive disease/sinusoidal obstruction syndrome VOD FO Engraftment syndrome SOS Capillary leak syndrome Fluid overload ES CLS Idiopathic pneumonia syndrome Diffuse alveolar hemorrhage Evidence shows that the complement system becomes activated in the large majority of these syndromes. 1,2,5-13 References: 1. Carreras E et al. Bone Marrow Transplant. 2011;46(12):1495-1502. doi:10.1038/bmt.2011.65 2. Rondόn G et al. Biol Blood Marrow Transplant. 2017;23(12):2166-2171. doi:10.1016/j.bbmt.2017.08.021 3. Gust J et al. Cancer Discov . 2017;7(12):1404-1419. doi:10.1158/2159-8290.CD-17-069 4. Hay KA et al. Blood . 2017;130(21):2295-2306. doi:10.1182/blood-2017-06-793141 5. Khosla J et al. Bone Marrow Transplant. 2018;53(2):129-137. doi:10.1038/bmt.2017.207 6. Collard CD et al. Am J Pathol. 2000;156(5):1549-1556. doi:10.1016/S0002-9440(10)65026-2 7. Jodele S et al. Transfus Apher Sci. Published April 2016. 2016;54(2):181-190. doi:10.1016/j.transci .2016.04.007 8. Heying R et al. Bone Marrow Transplant. 1998;21(9):947-949. doi:10.1038/sj.bmt.1701211 9. Rubio MT et al. Blood. 2009:114(22):1166. doi:10.1182/blood.V114.22.1166.1166 10. Bucalossi A et al. Biol Blood Marrow Transplant. 2010;16(12):1749-1750. doi:10.1016/j.bbmt.2010.09.002 11. Bhargava M et al. Biol Blood Marrow Transplant. 2016;22(8):1383-1390. doi:10.1016/j.bbmt.2016.04.021 12. Spitzer TR. Bone Marrow Transplant. 2001;27(9):893-898. doi:10.1038/sj.bmt.1703015 13. Spitzer TR. Bone Marrow Transplant. 2015;50(4):469-475. doi:10.1038/bmt.2014.296

EIS Can Critically Harm a Number of End Organs Damage can occur through several mechanisms, including capillary flow obstruction, fibrin-related aggregates, platelet and leukocyte adhesion, and endothelial apoptosis 1,2 Kidneys Gastrointestinal tract Lungs Brain Liver While EIS may manifest differently based on the end organ affected, across syndromes, EIS contributes to significant rates of transplant-related mortality . 3-8 References: 1. Carreras E et al. Bone Marrow Transplant. 2011;46(12):1495-1502. doi:10.1038/bmt.2011.65 2. Jodele S et al. Blood Rev. Published online May 1, 2016. 2015;29(3):191-204. doi:10.1016/j.blre.2014.11.001 3. Rondόn G et al. Biol Blood Marrow Transplant. 2017;23(12):2166-2171. doi:10.1016/j.bbmt.2017.08.021 4. Senzolo M et al. World J Gastroenterol. 2007;13(29):3918-3924. doi:10.3748/wjg.v13.i29.3918 5. Lucchini G et al. Biol Blood Marrow Transplant. 2014;20(2)(suppl):S175. doi:10.1016/j.bbmt.2013.12.284 6. Afessa B et al. Am J Respir Crit Care Med. 2002;166(5):641-650. doi:10.1164/rccm.200112-141cc 7. Afessa B et al. Bone Marrow Transplant. 2001;28(5):425-434. doi:10.1038/sj.bmt.1703142 8. Spitzer TR. Bone Marrow Transplant. 2001;27(9):893-898. doi:10.1038/sj.bmt.1703015

Understanding the Complement System CLASSICAL PATHWAY LECTIN PATHWAY Immune complex Tissue injury MBL, ficolins, C1q collectins The complement system is + C4 C2 C1r/C1s MASP-2 Prothrombin an important part of the C4 bypass Thrombin C3 convertase innate immune system that protects against C3 C3a foreign cells and helps Coagulation Factor B Factor D pro-Factor D remove damaged Inflammation, C3b host cells . 1 platelet activation, MASP-3 leukocyte recruitment, endothelial cell activation C5 convertases ALTERNATIVE Three distinct pathways PATHWAY C5a C5 (classical, lectin, and alternative) can activate the Terminal Pathway C5b complement system — all C6-9 (C5b-9) converging on a common, MAC terminal pathway. 1 Cell lysis References: 1. Merle NS et al. Front Immunol. 2015;6:262. doi:10.3389/fimmu.2015.00262 2. Khosla J et al. Bone Marrow Transplant. 2018;53(2):129-137. doi:10.1038/bmt.2017.207 3. Collard CD et al. Am J Pathol. 2000;156(5): 1549-1556. doi:10.1016/S0002-9440(10)65026-2 4. Jodele S et al. Transfus Apher Sci. Published April 2016. 2016;54(2):181-190. doi:10.1016/j.transci.2016.04.007 5. Farrar CA et al. Immunobiology. 2016;221(10):1068-1072. doi:10.1016/j.imbio.2016.05.004 6. Joseph K et al. J Biol Chem. 2013;288(18):12753-12765. doi:10.1074/jbc.M112.421891 7. Bohlson SS et al. Front Immunol. 2014;5:402. doi:10.3389/fimmu.2014.00402 8. Gulla KC et al. Immunology. 2010;129(4):482-495. doi:10.1111/j.1365-2567.2009.03200.x 9. Anders HJ et al. J Am Soc Nephrol. 2014;25(7):1387-1400. doi:10.1681/ASN.2014010117 10. Stover C et al. Genes Immun. 2001;2(3):119-127. doi:10.1038/sj.gene.6363745 11. Kozarcanin H et al. J Thromb Haemost. 2016;14(3):531-545. doi:10.1111/jth.13208 12. Klos A et al. Pharmacol Rev. 2013;65(1):500-543. doi:10.1124/pr.111.005223 13. Asgari E et al. FASEB J . 2014;28(9):3996-4003. doi:10.1096/fj.13-246306 14. Banda NK et al. J Immunol . 2017;199(5):1835-1845. doi:10.4049/jimmunol.1700119 15. Schwaeble WJ et al. Proc Natl Acad Sci U S A . 2011;108(18):7523-7528. doi:10.1073/pnas.1101748108 16. Dobό J et al. Front Immunol. 2018;9:1851. doi:10.3389/fimmu.2018.01851 17. Ma YJ et al. Exp Mol Med. Published online April 21, 2017. 2017;49(4):e320. doi:10.1038/emm.2017.51