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

• ADAMTS-13, a disintegrin and metalloproteinase with

• aGVHD, acute graft-vs-host disease
• CKD, chronic kidney disease
• CLS, capillary leak syndrome
• CMV, cytomegalovirus
• CNI, calcineurin inhibitor
• CNS, central nervous system
• DAH, diffuse alveolar hemorrhage
• DAMP, damage-associated molecular pattern
• EIS, endothelial injury syndromes
• ES, engraftment syndrome
• ESRD, end-stage renal disease
• FO, fluid overload
• GI, gastrointestinal
• GVHD, graft-vs-host disease
• HLA, human leukocyte antigen
• HSCT, hematopoietic stem cell transplant
• HSCT-TMA, hematopoietic stem cell transplant–associated

• ICU, intensive care unit
• IL-1β, interleukin 1β
• IPS, idiopathic pneumonia syndrome
• LDH, lactate dehydrogenase
• MAC, membrane attack complex
• MASP, mannose-binding lectin-associated serine protease
• MBL, mannose-binding lectin
• mTOR, mammalian target of rapamycin
• PT/PTT, prothrombin time/partial thromboplastin time
• RBC, red blood cell
• SCr, serum creatinine
• SOS, sinusoidal obstruction syndrome
• TMA, thrombotic microangiopathy
• TNF, tumor necrosis factor
• TTP, thrombotic thrombocytopenic purpura
• VOD, veno-occlusive disease

The Impact of Endothelial Injury Syndromes in HSCT

1

After HSCT, EIS may put successful transplant

• utcomes at risk.
• HSCT process contributes to EIS
• Types of EIS
• Role of the lectin pathway of

Endothelial injury syndromes (EIS)

2

EIS and the threat

• f HSCT-TMA

HSCT-TMA causes high mortality and significant morbidity in those who survive.

• Pathophysiology and differentiating

• Differential diagnoses and

• Risk factors and negative

• Economic burden of disease
• Warning signs for HSCT-TMA
• Patient case study

3

Conclusion

The unmet need in HSCT-TMA is significant.

• Need for more robust vigilance
• Clear identification of high-risk TMA
• Need for consensus diagnostic criteria

1 Endothelial Injury Syndromes (EIS)

Endothelial Injury

Damage to endothelial cells can occur in many ways— physically, chemically and immunologically1-3

Endothelial injury plays a role in the pathogenesis of4:

• 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.

Multiple Factors Can Lead to EIS in HSCT1-3

Before, during, and after transplant, multiple factors can lead to EIS

Various Endothelial Injury Syndromes May Result From HSCT1,2

• bstruction syndrome

Types

• f EIS

Several syndromes result from transplant-related endothelial damage and can overlap in presentation and classification.1-4

TMA VOD SOS ES CLS FO IPS DAH aGVHD

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 apoptosis1,2

• 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.

• 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

The complement system is an important part of the innate immune system that protects against foreign cells and helps remove damaged host cells.1 Three distinct pathways (classical, lectin, and alternative) can activate the complement system—all converging on a common, terminal pathway.1

+

• 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.

Injured endothelial cells can activate the lectin pathway of complement— a key factor contributing to post-transplant complications.2-4

The Role of the Lectin Pathway of Complement

+

• 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.

The Role of the Lectin Pathway of Complement

Lectin pathway activation is initiated via binding of pattern recognition molecules called lectins (mannose-binding lectin, ficolins, collectins). Lectins recognize damage- associated molecular patterns (DAMPs) on the surface of injured cells.5-9

+

• 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.

Lectin complexes containing mannose- binding lectin-associated serine protease-2 (MASP-2) bind to DAMPs.5,8 MASP-2 is the effector enzyme of the lectin pathway.10

The Role of the Lectin Pathway of Complement

+

• 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.

MASP-2 can activate the coagulation cascade through cleavage of prothrombin to generate thrombin. Activated thrombin is a key driver of fibrin deposition and clot formation, which may contribute to the progression

• f HSCT-associated

thrombotic microangiopathy (HSCT-TMA).8,11

The Role of the Lectin Pathway of Complement

+

• 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.

Complement proteins located early in the lectin pathway are cleaved by MASP-2, triggering a cascade of protein cleavage and complex formation.5

The Role of the Lectin Pathway of Complement

+

• 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.

Two important cleavage products—C3a and C5a— are both proinflammatory, prothrombotic, chemotactic anaphylatoxins.7,8,12 C3a and C5a trigger monocyte and macrophage activation through various signaling mechanisms and have been shown to stimulate production

• f TNF-α and IL-1β.7

The Role of the Lectin Pathway of Complement

+

• 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.

MASP-2 can directly cleave C3 independently of C4/C2 through the “C4 bypass” mechanism, similarly activating the downstream complement cascade.5,13-15

The Role of the Lectin Pathway of Complement

+

• 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.

Lectin pathway cleavage of C3 generates C3b, which results in an amplification loop with the alternative pathway, increasing terminal pathway activity and formation of the membrane attack complex (MAC).1,16

The Role of the Lectin Pathway of Complement

+

• 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.

MACs are formed from C5b-9 protein complexes, leading to cell lysis and further damage to the endothelium.17

The Role of the Lectin Pathway of Complement

+

• 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.

2

HSCT-TMA is a significant, often lethal complication—particularly in allogeneic transplants1-3

The Threat of HSCT-TMA

• 3. 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

1

• Transplant. 2018;53(2):129-137. doi:10.1038/bmt.2017.207 4. Postalcioglu M et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353. doi:10.1016/j.bbmt.2018.05.010

Potential Risk Factors for Development of HSCT-TMA1-4

2

3

Inherent/nonmodifiable risk factors Transplant-associated risk factors Post-transplant event risk factors

• Transplant conditioning
• Total-body irradiation
• Unrelated donor transplants
• HLA mismatch
• Administration of growth factor
• Prolonged immobilization
• Venous thromboembolism
• Other factors
• Female sex
• African American race
• Severe aplastic anemia
• CMV seropositive recipient
• Prior stem cell transplant
• Genetic variants, including

• High baseline LDH levels
• High/very high disease risk index
• Calcineurin inhibitors
• mTOR inhibitors
• aGVHD
• Infection

Pathophysiology: 3-Phase Model of HSCT-TMA

Phase 1: Initiation1

• Calcineurin and mTOR inhibitors
• aGVHD
• Infection
• Total-body irradiation

• 3. Ricklin D et al. Nat Rev Nephrol. Published online July 1, 2017. 2016;12(7):383-401. doi:10.1038/nrneph.2016.70

Phase 1: Initiation1

• Calcineurin and mTOR inhibitors
• aGVHD
• Infection
• Total-body irradiation

Pathophysiology: 3-Phase Model of HSCT-TMA

• 3. Ricklin D et al. Nat Rev Nephrol. Published online July 1, 2017. 2016;12(7):383-401. doi:10.1038/nrneph.2016.70

Phase 2: Progression1-3

• Injured endothelial cells present

• Injured endothelium releases procoagulant

Phase 1: Initiation1

• Calcineurin and mTOR inhibitors
• aGVHD
• Infection
• Total-body irradiation

Phase 3: Outcome1

• rgan damage, and organ failure

Pathophysiology: 3-Phase Model of HSCT-TMA

• 3. Ricklin D et al. Nat Rev Nephrol. Published online July 1, 2017. 2016;12(7):383-401. doi:10.1038/nrneph.2016.70

Phase 2: Progression1-3

• Injured endothelial cells present

• Injured endothelium releases procoagulant

Time To Presentation: HSCT-TMA Cases Typically Present Within the First 100 Days After Transplantation1-13

• 2014-0018 6. Mohty M et al. Bone Marrow Transplant. 2016;51(7):906-912. doi:10.1038/bmt.2016.130 7. Lee JL et al. Biol Blood Marrow Transplant.1999;5(5):306-315. doi:10.1016/s1083-8791(99)70006-6 8. Ueda N et al. Biol

• Med. 2002;166(5):641-650. doi:10.1164/rccm.200112-141cc 11. Peña E et al. Radiographics. 2014;34(3):663-683. doi:10.1148/rg.343135080 12. Panoskaltsis-Mortari A et al; American Thoracic Society Committee on Idiopathic

• grading-of-acute-graft-versus-host-disease

TMA

Time To Presentation: HSCT-TMA Cases Typically Present Within the First 100 Days After Transplantation1-13

• 2014-0018 6. Mohty M et al. Bone Marrow Transplant. 2016;51(7):906-912. doi:10.1038/bmt.2016.130 7. Lee JL et al. Biol Blood Marrow Transplant.1999;5(5):306-315. doi:10.1016/s1083-8791(99)70006-6 8. Ueda N et al. Biol

• Med. 2002;166(5):641-650. doi:10.1164/rccm.200112-141cc 11. Peña E et al. Radiographics. 2014;34(3):663-683. doi:10.1148/rg.343135080 12. Panoskaltsis-Mortari A et al; American Thoracic Society Committee on Idiopathic

• grading-of-acute-graft-versus-host-disease

32

Median time to presentation was reported as 32 days in one prospective study.

721

However, diagnosis has reportedly occurred as late as 721 days after HSCT.

Diagnostic Challenges: Shared Elements of GVHD and HSCT-TMA

• verall survival and longer hospital

Diagnostic Challenges: Nonspecific Criteria

• 3. Masias C et al. Blood. 2017;129(21):2857-2863. doi:10.1182/blood-2016-11-743104 4. Khosla J et al. Bone Marrow Transplant. 2018;53(2):129-137. doi:10.1038/bmt.2017.207 5. Gavriilaki E et al. Bone Marrow Transplant.

Identification of HSCT-TMA remains challenging due to the variability within guidelines1

• Accurate diagnostic testing • Reliable prognostic markers • Uniform diagnostic criteria

HSCT-TMA is largely a diagnosis of exclusion1-3

• Calls for a high index of suspicion
• Requires routine prospective monitoring
• Lack of consensus on diagnostic or prognostic markers

Diagnostic Challenges: Summary

• 3. Elsallabi O et al. Clin Appl Thromb Hemost. 2016;22(1):12-20. doi:10.1177/1076029615598221

Need for earlier recognition

Greater consensus around comprehensive diagnostic criteria may allow for earlier disease recognition and intervention for patients who are at high risk of developing HSCT-TMA

No single defining standard3

• Multiple and differing guidelines for diagnostic criteria
• Varying categories for positive identification of HSCT-TMA

Incidence: Substantial in Allo-HSCT

39

%

Up to

HSCT-TMA occurs in

up to 39%

(12%-39%) of patients who

undergo allogeneic HSCT1-5

• 3. Nakamae H et al. Am J Hematol. 2006;81(7):525-531. doi:10.1002/ajh.20648 4. Arai Y et al. Biol Blood Marrow Transplant. 2013;19(12):1683-1689. doi:10.1016/j.bbmt.2013.09.005 5. Willems E et al.

• f HSCT-TMA

cases may be

severe

50

%

Defining severe cases

Patients with severe disease may be defined by multiorgan impairment, uncontrolled hypertension, worsening renal function, and a lack of response to therapeutic plasma exchange; predicting severity at initial diagnosis can be difficult2,3

Incidence: Severe HSCT-TMA

• 3. 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
• f patients with

HSCT-TMA display at least one

high-risk

feature1

80

%

Up to

~90

%

• r more
• f severe cases of

HSCT-TMA can be

fatal

Incidence: Severe HSCT-TMA

• f HSCT-TMA

cases may be

severe

50

%

• f patients with

HSCT-TMA display at least one

high-risk

feature1

80

%

Up to

• 3. 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

4×

In a retrospective analysis, the risk of transplant-related mortality was ~4 times higher in patients with confirmed HSCT-TMA than in patients without HSCT-TMA.1

(P < 0.001)a

mortality risk

Mortality: 4 Greater Risk With HSCT-TMA ×

Mortality: Fatalities Due to HSCT-TMA

In another retrospective analysis, patients with HSCT-TMA demonstrated significantly higher non-relapse mortality and lower overall survival than those without HSCT-TMA1

• 2. Postalcioglu M et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353. doi:10.1016/j.bbmt.2018.05.010 3. Bonardi M

Morbidity: Long-Term Challenges for Patients With HSCT-TMA

Patients with nonlethal cases of HSCT-TMA have an increased risk of chronic organ injury and other conditions, including1-3:

• CNS complications

• Hypertension
• Pulmonary hypertension
• CKD
• GI disease

Morbidity: Long-Term Challenges for Patients With HSCT-TMA

Poor outcomes, as measured by 2 major types of kidney complications1

City of Hope diagnostic criteria for TMA1:

• 1. Presence of schistocytes
• r nucleated RBCs
• 2. Thrombocytopenia
• 3. LDH >2 × ULN
• 4. SCr >1.5 × baseline

“Probable” TMA

• 3 criteria

“Definite” TMA

• 4 criteria

Poor outcomes, as measured by 2 major types of kidney complications1

• Measured 6 months post-HSCT
• Significant difference maintained

2 years post-HSCT

• rgan injury invariably leads to long-term morbidity, which may require ongoing hospital visits and continued patient care.1,2

Morbidity: Long-Term Challenges for Patients With HSCT-TMA

Economic Burden: Cost of HSCT-TMA

Costs associated with treatment for patients with HSCT-TMA may be affected by:

• ICU length of stay (LOS)
• Non-ICU hospital LOS
• Dialysis sessions
• RBC transfusions
• Platelet transfusions
• Pulmonary disease
• Cardiovascular complications
• GI complications
• CKD
• ESRD
• Acute GVHD

• 3. Rai V et al. Expert Rev Clin Immunol. Published online May 1, 2017. 2016;12(5):583-593. doi:10.1586/1744666X.2016.1145056 4. Cooke KR et al. Biol Blood Marrow Transplant. 2008;14(1)

Efficacy and safety of current interventions, including off-label options, have not been established1-4:

• Reducing or discontinuing CNI and mTOR inhibitor (anti-GVHD) therapies

– Reducing or discontinuing these therapies may elevate the risk of GVHD

• Therapeutic plasma exchange
• Anti-CD20 antibody therapies
• Terminal complement inhibitors
• Oligonucleotide therapies

Current Treatment Options: No Approved Therapies

• 3. Rai V et al. Expert Rev Clin Immunol. Published online May 1, 2017. 2016;12(5):583-593. doi:10.1586/1744666X.2016.1145056 4. Cooke KR et al. Biol Blood Marrow Transplant. 2008;14(1)

Efficacy and safety of current interventions, including off-label options, have not been established1-4:

• Reducing or discontinuing CNI and mTOR inhibitor (anti-GVHD) therapies

– Reducing or discontinuing these therapies may elevate the risk of GVHD

• Therapeutic plasma exchange
• Anti-CD20 antibody therapies
• Terminal complement inhibitors
• Oligonucleotide therapies

Current Treatment Options: No Approved Therapies

WARNING SIGNS FOR HSCT-TMA

Elevated levels of LDH, proteinuria, and hypertension

persisting beyond what is typically observed with steroid or CNI use may suggest that a more in-depth evaluation of HSCT-TMA is warranted. Other diagnostic criteria include presence of schistocytes, decreased hemoglobin, negative Coombs test, thrombocytopenia, decreased haptoglobin, and terminal complement activation (elevated plasma concentration of C5b-9).1

!

HSCT-TMA Patient Case Study1

Presentation

• 54-year-old male with multiple myeloma
• Allogeneic HSCT from human leukocytic antigen–matched, unrelated

donor after conditioning with reduced-intensity chemotherapy

HSCT-TMA Patient Case Study1

Interventions

• GVHD prophylaxis consisted of sirolimus, tacrolimus, and methotrexate
• On day +27 post-treatment, the patient developed acute kidney injury (creatinine of

2.6 mg/dL)

• Patient was switched to mycophenolate mofetil and corticosteroids for GVHD prophylaxis
• On day +132, patient returned to hospital with diarrhea, GI bleeding, and thrombocytopenia

(93,000/μL); colonic biopsies revealed CMV infection and GVHD

• Patient was started on ganciclovir, and prednisone dose was increased

27

132

HSCT-TMA Patient Case Study1

27

132

146

Interventions (continued)

• Patient remained hospitalized for 2 weeks
• Patient was readmitted on day +146 with profuse bloody diarrhea and was restarted
• n tacrolimus
• Patient continued to have maroon-colored stool output, persisting thrombocytopenia

(30,000-50,000/μL range), elevated LDH levels (731 U/L), and low haptoglobin (22 mg/dL); colonic biopsy again suggested CMV infection and GVHD

• Tacrolimus was discontinued, sirolimus was reintroduced, and patient was maintained on

a combination of sirolimus, mycophenolate mofetil, and steroids for GVHD treatment

HSCT-TMA Patient Case Study1

27

132

146

211

217

Interventions (continued)

• Patient was readmitted on day +211 with melenic stool, low platelet count (37,000/μL),

and elevated LDH (1,254 U/L)

• Sirolimus was again discontinued
• The patient remained anemic and intermittently refractory to red blood cell transfusions.

On day +217, patient was transferred to ICU for high-volume, bloody stool as well as low hemoglobin (6.3 g/dL) and light-headedness

HSCT-TMA Patient Case Study1

Outcome

• The patient expired on day +217 secondary to uncontrolled GI bleeding
• A postmortem analysis revealed extensive TMA involving numerous arteries and

arterioles in the GI submucosa as well as in the muscularis propria and deep lamina propria of the mucosa

• A retrospective review of the patient’s previous colonic biopsies was performed

and additional subtle features of TMA were found

27

132

146

211

217

3 Conclusion

• 10. Jodele S et al. Transfus Apher Sci. Published April 2016. 2016;54(2):181-190. doi:10.1016/j.transci.2016.04.007 11. Gavriilaki E et al. Bone Marrow Transplant. 2017;52(10):1355-1360. doi:10.1038/bmt.2017.39
• 12. Postalcioglu M et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353. doi:10.1038/bmt.2017.39 13. Jodele S et al. Blood Rev. Published online May 1, 2016. 2015;29(3):191-204. doi:10.1016/j.blre.2014.11.001
• 14. Rosenthal J. J Blood Med. 2016;7:181-186. doi:10.2147/JBM.S102235 15. Ho VT et al. Biol Blood Marrow Transplant. 2005;11(8):571-575. doi:10.1016/j.bbmt.2005.06.001 16. Elsallabi O et al. Clin Appl Thromb Hemost.

• Multiple factors involved in the HSCT process can damage endothelial cells1-3
• This damage can lead to a host of endothelial injury syndromes, including

DAH, IPS, FO, CLS, ES, VOD/SOS, aGVHD, and HSCT-TMA1,4-7

• HSCT-TMA8-16:

– Is an endothelial injury syndrome mediated by activation of the lectin pathway of complement – Has a significant mortality rate and long-term morbidity – Is difficult to diagnose and treat – Has no FDA-approved or EMA-licensed therapies

Summary

In post-transplant patients, be aware of early signs— beyond what is typically observed with steroid or CNI use— that may indicate the presence of HSCT-TMA.1

Proteinuria Acute elevation in LDH Hypertension Thrombocytopenia Terminal complement activation

Presence of schistocytes Negative Coombs test Decreased hemoglobin Decreased haptoglobin