New Thinking on GVHD Management in HSCT Recipients: Focus on Underlying Immunology and Innovative Therapeutics

This CME activity is jointly provided by The Medical College of Wisconsin and PVI, PeerView Institute for Medical Education. This activity is supported by educational grants from Incyte Corporation and Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. Welcome and Introduction

David Miklos, MD, PhD Associate Professor of Medicine Clinical Director, Cancer Cell Therapy Program Photo Pending Stanford University, Division of Blood and Marrow Transplantation Stanford, California Disclosures

David Miklos, MD, PhD, has a financial John F. DiPersio, MD, PhD, has a financial interest/relationship or affiliation in the form of: interest/relationship or affiliation in the form of:

Grant/research support from: Consultant for: Amphivena Therapeutics, Inc.; Adaptive Biotechnologies; Kite Pharma; and Asterias Biotherapeutics; BioLineRx; Bristol-Myers Pharmacyclics LLC. Squibb Company; Cellworks Group Inc.; Rivervest; and Vasculox, Inc. Other financial or material support from: Scientific Advisory Board for Adaptive Biotechnologies; Speakers bureau participant with: Dava Oncology. Kite Pharma; Novartis Pharmaceuticals Corporation; Pharmacyclics LLC; and Pfizer Inc. Stock shareholder in: Magenta Therapeutics (founder).

Advisory board for: Amphivena Therapeutics, Inc.; Asterias Biotherapeutics; BioLineRx; Bristol-Myers Squibb Company; Cellworks Group Inc.; Rivervest; and Vasculox, Inc.

Other financial or material support from: Grant review for Hemedicus.

Visit us at www.peerview.com/GVHD18

• Watch for the onDemand version in the coming weeks • Download the slides and Practice Aids • Apply for CME credit • Join the conversation on Twitter @PeerView • Need more information? Send an email to [email protected] This Afternoon’s Agenda: Two Modules on GVHD Management

1. Acute GVHD: Current paradigms and insights on emerging strategies

2. Chronic GVHD: The changing management landscape—what novel options mean for patient care

Both modules will include an overview of the biology and mechanistic rationale for ongoing clinical research

Be prepared to vote again: Follow-up polling questions will be presented after the scientific sessions Management of Acute GVHD: Biologic Basis and Novel Strategies

John F. DiPersio, MD, PhD Virginia E. and Samuel J. Golman Professor in Medicine Chief, Division of Oncology Photo Deputy Director, Alvin J. Siteman Cancer Center Pending Professor of Medicine, Pathology & Immunology Washington University School of Medicine St. Louis, Missouri GVHD

Caused by the interaction between the transplanted immune system (graft) and recipient tissues (host)

Rejection

Transplanted organ Host immune system

GVHD

Transplanted graft Host target tissues Acute and Chronic GVHD1,2

CLASSIC LATE ACUTE ACUTE CHRONIC OVERLAP

CLASSIC

Day 0 Day 100

 Skin (erythema)  Skin (lichenoid, sclerotic...)  Musculoskeletal  Gastrointestinal (secretory)  Mouth  Hematopoietic  Liver  Nails and hair  Gastrointestinal (esophageal)  Eyes  Liver  Lung  Other

Subsequent episode 1st episode: Any sign of acute GVHD? • Recurrent Classical • Persistent No = Yes = • New onset or late acute Classic chronic Overlap syndrome

1. Lee SJ. Blood. 2017;129:30-37. 2. Socié G, Ritz J. Blood. 2014;124:374-384. aGVHD1,2

• Clinicopathologic syndrome occurring in 35% (matched/related donor) and 50% (unrelated donor) of BMT patients – Skin: 75% of all GVHD; 45% isolated cutaneous disease

 Erythematous rash  bullae  desquamation – Gut: Up to 50% of all GVHD patients  secretory diarrhea  ileus – Liver: 20% of GVHD patients

 Hyperbilirubinemia  hepatic failure

1. Jacobsohn D. Orphanet J Rare Dis. 2007;2:35. 2. Sung AD et al. Stem Cells Transl Med. 2013;2(1):25-32. aGVHD Risk Factors

Factor Condition That Increase Risk of aGVHD Donor-Recipient Factors HLA mismatched related donor > matched related Major HLA disparity (HLA class I, II) donor Minor HLA disparity (mHA) Unrelated donor > related donor Sex matching Mismatch > match Donor parity Multiparity > nulliparity Donor age Older donor > younger donor ABO type ABO mismatch > ABO match Donor CMV serostatus CMV positive > CMV negative Cytokine gene polymorphisms Numerous associated with aGVHD Stem Cell Graft Factors Stem cell source PBSC > BM > UCB Graft composition Higher CD34+ count > lower CD34+ cell count Higher T cell dose > lower T cell dose Transplantation Factors Conditioning intensity Myeloablative > reduced-intensity regimens Defining Risk in aGVHD: Clinical (Minnesota Scoring)1

GVHD Risk Score One Organ (n)a Two Organs (n) Three Organs (n) Stages I-III skin plus Stages I-III skin (901) f Standard risk stage I GI (223) (N = 1454, 84%) c Stages I-III skin plus Stages I-II GI (279) stages I-IV liver (51) Stages I-III skin plus Stages I-III skin plus stages I-II Stage IV skin (13) stage II GI (54) GI plus stages I-III liver (23)

d Stages I-II lower GI plus b Stages III-IV GI (74) High risk stages I-III liver (12) (N = 269, 16%) e Stages III-IV GI plus Stages I-III skin plus stages III-IV Stages I-IV liver (25) stages I-III skin (45) GI plus stages I-IV liver (13) Stages III-IV GI plus stages I-IV liver (10)

a UGI plus lower GI considered as single organ disease. c Stages I-II GI includes: e Stages I-IV liver includes:

• UGI alone (n = 115) • Stage I liver alone (7) b For high-risk disease, the degree of organ involvement is the • Stages I-II lower GI alone (100) • Stage II liver alone (10) minimum necessary to be deemed high risk. Patients with • UGI and stage I lower GI (64) • Stage III liver alone (5)

higher stage of GVHD than observed in the high-risk group • Stage IV liver alone (3) should also be considered high risk. d Stages III-IV GI includes: f • Stage III lower GI alone (65) Stages I-III skin plus stage I GI includes: • Stage IV lower GI alone (9) • Stages I-III skin plus UGI (90)

• Stages I-III skin plus stage I lower GI (71) • Stages I-III skin plus UGI and stage I lower GI (62)

1. MacMillan ML et al. Biol Blood Marrow Transplant. 2015;21:761-767. Defining Risk in aGVHD: Biological1

High panel, n = 41 Low panel result, n = 63 Elafin (P = .01) IL2Rα (P = .08) TNFR1 (P = .001)

100 10

90 9

80 8

7 70

HGF (P = .37) IL8 (P = .02) REG3α (P = .01) 50

0 4

Day 0Biomarker Day

0 3

Overall Survival, % Survival, Overall 20

P < .0001 at day 180 4

10 2

0 0 30 60 90 120 150 180 210 240 270 Alive Dead Alive Dead Alive Dead Day 180 Survival Status Post-Randomization, d (Alive, n = 77; Dead, n = 35)

1. Levine JE et al. Blood. 2012;119:3854-3860. Biomarkers in aGVHD1

1. Vander Lugt MT et al. N Engl J Med. 2013;369:529-539. Biomarkers in aGVHD1

• Suppression of tumorigenicity 2 (ST2) • High levels at day +14 and initiation of aGVHD treatment ─ 2.3 x as likely to be treatment resistant ─ 3.7 x as likely to die at 6 months

1. Vander Lugt MT et al. N Engl J Med. 2013;369:529-539. Individual Biomarkers in aGVHD1 Role in Diagnosis, Risk Stratification, and Response to Therapy

Systemic Organ-specific • MiR-155 • REG3α • MiR-586 • S100A8/A9 (stool) • ST2 (lower GI) • TIM-3/Galectin-9 • Ceruloplasmin • CK-18 • TNFR1 • HGF (liver) • IL7 • Elafin (skin) • sBAFF • TIRC7

1. Ali AM et al. Biol Blood Marrow Transplant. 2016;22:1552-1564. Biomarker Panels in aGVHD

• TIM3, IL6, sTNFR1, and ST2 (single institution)1

• IL2Ra, TNFR1, HGF, IL8, elafin, and REG3α (multicenter)2

• TNFR1, ST2, and REG3α (multicenter)3

• Multiple markers (single institution)4

1. McDonald GB et al. Blood. 2015;126:113-120. 2. Levine JE et al. Blood. 2012;119:3854-3860. 3. Levine JE et al. Lancet Haematology. 2015;2:e21-29. 4. Te Boome LC et al. Leukemia. 2015;29:1839-1846. Graft-Versus-Leukemia1

1.0

0.8 Twins (N = 70) 0.6 T Depletion (N = 401)

0.4 No GVHD (N = 433) aGVHD only (N = 738) 0.2 cGVHD only (N = 127)

Probability Probability Relapse of CML aGVHD + cGVHD (N = 485) 0.0 0 12 24 36 48 60 72 Months

1. Horowitz MM et al. Blood. 1990;75(3):555-562. Prevention of aGVHD: Agents and Mechanisms1

1. Choi SW, Reddy P. Nat Rev Clin Oncol. 2014;11:536-547. GVHD Prophylaxis: Standard of Care

• Immune suppression with calcineurin inhibitor (tacrolimus or cyclosporine) PLUS methotrexate • Standard since mid 1980s • Associated with aGVHD rates of:1 – 35% MRD – >50% URD/Mismatch

1. Al-Kadhimi Z et al. Biol Blood Marrow Transplant. 2012;18:1734-1744. PTCy as GVHD Prophylaxis1-8

• Limits both acute and chronic GVHD

• Effective across donor types: MSD, MUD, haplo, and mMUD (degree of match, if >50%, irrelevant)

• Consider MMF plus CNI/sirolimus (60-90 d) for all donor types

• Caution extrapolating PB data to haplos/mMUD ─ Most haplo/mMUD data are with BM

• Addition of pre-BMT ATG essentially eliminates GVHD and NRM in nonmalignant indications

1. Slide courtesy of Leo Luznik. 2. Luznik L et al. Blood. 2010;115:3224-3230. 3. Kanakry CG et al. J Clin Oncol. 2014;32:3497-3505. 4. Kanakry CG et al. Blood. 2014;124:3817-3827. 5. Kasamon YL et al. Biol Blood Marrow Transplant. 2010;16:482-489. 6. McCurdy SR et al. Haematologica. 2017;102:391-400. 7. Peccatori J et al. Leukemia. 2015;29:396-405. 8. Cieri N et al. Biol Blood Marrow Transplant. 2015;21:1506-1514. Initial Therapy for aGVHD: Steroids +/- Mycophenolate Mofetil1

1.0 Placebo at day 360: 64.7% (95% CI: 55.2%, 72.6%)

0.8

0.6

MMF at day 360: 57.8% (95% CI: 48.2%, 66.3%)

0.4 Survival Probability Survival

0.2

MMF, N = 116 Placebo, N = 119 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 Post-Randomization, mo

1. Bolaños-Meade J et al. Blood. 2014;124:3221-3227. Management of Steroid-Refractory aGVHD

• After failure of corticosteroids, there is no current consensus on an optimal second-line treatment choice • Many retrospective and prospective studies suggest high response rates with second-line treatment options ─ Results are hard to interpret because of suboptimal study designs • Treatment choices are based on: ─ Physician experience ─ Ease of use ─ Need for monitoring ─ Risk of toxicity Novel Therapies in Development for aGvHD

• Currently accepted prophylaxis agents: methotrexate, steroids, CNI, CY, MMF, sirolimus, T cell antibody (ATG, alemtuzumab), phototherapy, topical therapies (eg, clobetasol, beclomethasone) • Newer therapies: – T cell trafficking modulators: CCR5 inhibitors, α4 Integrin inhibitors, JAK1/2 inhibitors – Proteasome inhibitors: bortezomib, ixazomib; deplete alloreactive T cells and attenuate APC activation and antigen presentation – Epigenetic modulators: DNA hypomethylating drugs, histone deacetylase inhibitors (vorinostat and suberoylanilide hydroxamic acid), histone methyltransferase/EZH2 inhibitors – Costimulatory antagonists: Anti-CD137L, CTLA-4Ig, CD28 shRNA, anti-IOS, TNF family inhibitors (infliximab, etanercept, antibodies to OX40/OX40L, CD30/CD30L) – MoAB and ADC to T cell activation antigens: CD7, CD2, CD3, AB to DLL4 – Treg expansion or TNFRII agonists – Deletion of naïve T cells – Inhibitors of a-1 antitrypsin

Effect of IFNγ and IFNγR on GVHD and Overall Survival1

100

XRT 50 BM WT ] P < .0001 Survival, Survival, % 25 IFNγR-/- γIFN-/- 0 0 25 50 75 100 After HSCT, d

1. Choi J et al. Blood. 2012;120:4093-4103. IFNγR Signaling in GVHD1

WT T cells IFNγR-/- T cells 10 25 WT IFNγR-/- 10 10 25 104 104 spleen 16.6 16.2 2.29 1.18 8 8 spleen 20 103 103

6 x10 x10 6 x10

LN LN 15

6 15

4 2 2 LN4 10 10 10 Pre- GI tract

2 2 5 LN LN GI tract 1 1

10 10 activation FL5-H: IFNgR bio_SAAPCCY7 IFNgR FL5-H: 5 bio_SAAPCCY7 IFNgR FL5-H: Color2 Bar Color Bar Color Bar Min = 7.6309e+05Min = 7.6309e+05 Min = 2.182e+06 Max = 1.0273e+07Max = 1.0273e+07 Max = 2.6348e+07 R

100 58.9 8.31 100 77 19.6 γ

0.25 0 1 2 3 4 0 1 2 3 4 bkg sub bkg sub bkg sub 10 10 10 10 10 10 10 10 10 10 ) flat-fieldedPflat-fielded = .0054 flat-fielded 4 FL4-H: CXCR3 APC 4 FL4-H: CXCR3 APC cosmic 10 10

cosmic (x 10 cosmic Click # JLP20100823142949Click # JLP20100823142949 User: JLPUser: JLP Click # JLP20100823144424 User: JLP pan T cells_WT pan T cells_IFNgR KO Mon, Aug 23, 2010 14:29:49 Experiment: 8-23-10 Jaebok Mon, Aug 23, 2010 14:29:49 Experiment: 8-23-10 Jaebok Mon, Aug 23, 2010 14:44:24 Experiment: 8-23-10 Jaebok/sec/cm 13.4 72.8 3.12 4.15 Em filter=OpenEm filter=Open Comment1:0.20Comment1: 10sec,bin8 10sec,bin8 Em filter=Open Comment1: 10sec,bin8

Bin:M (8),Bin:M FOV15, (8), f1, FOV15, 10s f1, 10s Comment2:Comment2: Bin:M (8), FOV15, f1, 10s Comment2: Radiance Camera: Camera:IVIS 1354, IVIS SI620EEV 1354, SI620EEV Animal Number:Animal Number:B5 post mortem, B5 post open+spleen+intmortem,Camera: open+spleen+int IVIS 1354, SI620EEV Animal Number: C2 post mortem, open+spleen+int

103 103

IFN

0.15 photons 2 2 Post-

10 10

GI+body 2

0.10 / sr 1 1 activation

10 10

FL5-H: IFNgR bio_SAAPCCY7 IFNgR FL5-H:

FL5-H: IFNgR bio_SAAPCCY7 FL5-H: IFNgR

) 0.05 100 5.84 8100 62.1 30.6 0 1 2 3 4 0 1 2 3 4 Spleen/( 10 10 10 10 10 10 10 10 10 10 Photon Flux Ratio: Flux Photon FL4-H: CXCR3 APC FL4-H: CXCR3 APC 0.00 pan T cells_WT pan T cells_IFNgR KO WT T IFNγR-/-T CXCR3

1. Choi J et al. Blood. 2012;120:4093-4103. Emerging MOAs: Will JAK1/JAK2 Inhibitors Mitigate GVHD?

A Schematic Representation of the Interferon-g Receptor (IFNgR) and Its Signaling Pathway1

1. Newport M. Expert Rev Mol Med. 2003;5:1-13. Ruxolitinib for Steroid-Refractory GVHD1-2

• Europe and United States retrospective survey – N = 95

 54 steroid-refractory aGVHD, grades III-IV; median follow-up: 26.5 weeks

 41 steroid-refractory cGVHD, moderate or severe; median follow-up: 22.4 weeks • ORR for aGVHD: 81.5% (44/54) – 25 complete responses (46.3%) – Median time to response, 1.5 weeks (1-11 weeks) • ORR for cGVHD: 85.4% (35/41)

• Rate of GVHD relapse in ruxolitinib responders – aGVHD: 6.8% (3/44) – cGVHD: 5.7% (2/35) a During ruxolitinib therapy. 1. Zeiser R et al. Leukemia. 2015;29:2062-2068. 2. Zeiser R, Blazar BR. Blood. 2016;127:3117-3126. Ruxolitinib for Steroid-Refractory GVHD1-2

• Europe and United States retrospective survey aGVHD Outcome – N = 95 N = 54

 54 steroid-refractory aGVHD1-year, gradesoverall IIIsurvival-IV; median follow-up: 26.562.4% weeks  41 steroid-refractory cGVHDEstimated, moderate median or overall severe; median follow-up: 22.4 weeks 18 months survival • ORR for aGVHD: 81.5% (44/54) Duration of ruxolitinib, median 5 months – 25 complete responses (46.3%) Ongoing response/free of – Median time to response, 1.5 weeks (1-11 weeks) 41% (22/54) immunosuppression • ORR for cGVHD: 85.4% (35/41) GVHD relapse or progression 31% (14/45) • Rate of GVHD relapse in ruxolitinibafter responders PR/CR at 1 -year – aGVHD: 6.8% (3/44) Response to retreatment 78% (11/14) – cGVHD: 5.7% (2/35) Cytopenia (any grade)a 55.6% (30/54) a During ruxolitinib therapy. CMV reactivationa 33.3% (18/54) 1. Zeiser R et al. Leukemia. 2015;29:2062-2068. 2. Zeiser R, Blazar BR. Blood. 2016;127:3117-3126. Abstract #390: Presented at the 58th American Society of Hematology Annual Meeting; San Diego, CA, December 3-6, 2016

A Phase 1 Trial of Janus Kinase Inhibition With INCB039110 in Acute Graft-Versus-Host Disease

Mark Schroeder, MD1, H. Jean Khoury, MD, FACP2, Madan Jagasia, MD, MS3, Haris Ali, MD4, Gary Schiller, MD5, Michael Arbushites6, Patricia Delaite6, Ying Yan6, Kathleen Rhein6, Miguel-Angel Perales, MD7, Yi-Bin Chen, MD8, John F. DiPersio, MD, PhD9

1Washington University School of Medicine in St. Louis, St. Louis, MO, USA, 2Emory University School of Medicine, Atlanta, GA, USA, 3Vanderbilt-Ingram Cancer Center, Nashville, TN, USA, 4City of Hope, Duarte, CA, USA, 5UCLA David Geffen School of Medicine, Los Angeles, CA, USA, 6Incyte Corporation, Wilmington, DE, USA, 7Memorial Sloan Kettering Cancer Center, New York, NY, USA, 8Massachusetts General Hospital, Boston, MA, USA, 9Washington University School of Medicine, St Louis MO, USA Novel JAK1 Inhibitor INCB 039110 (Itacitinib): 28-Day Overall Response1

Itacitinib 200 mg 300 mg Total Steroid- Steroid- Steroid-

First-line refractory First-line refractory First-line refractory Response,a n (%) (n = 6) (n = 8) (n = 6) (n = 9) (n = 12) (n = 17) Complete response 4 (66.7) 1 (12.5) 4 (66.7) 2 (22.2) 8 (66.7) 3 (17.6) Very good partial 0 0 0 1 (11.1) 0 1 (5.9) response Partial response 1 (16.7) 4 (50.0) 1 (16.7) 3 (33.3) 2 (16.7) 7 (41.2) Mixed response 0 1 (12.5) 1 (16.7) 0 1 (8.3) 1 (5.9)

Progression of disease 0 0 0 2 (22.2) 0 2 (11.8)

No response 1 (16.7) 1 (12.5) 0 0 1 (8.3) 1 (5.9) Not applicable 0 1 (12.5) 0 1 (11.1) 0 2 (11.8) Overall responseb 5 (83.3) 5 (62.5) 5 (83.3) 6 (66.7) 10 (83.3) 11 (64.7) 90% CIc 41.8–99.1 28.9–88.9 41.8–99.1 34.5–90.2 56.2–97.0 42.0–83.4 Responses were graded according to CIBMTR response criteria. The treatment population was limited to patients who received study treatment a Last response data available on or before Day 28. b Patients with complete response, very good partial response, or partial response. c Calculated based on the exact method for binomial distributions. 1. Schroeder M et al. 58th American Society of Hematology Annual Meeting (ASH 2016). Abstract 390. Novel JAK1 Inhibitor INCB 039110 (Itacitinib): 28-Day Overall Response1

Itacitinib Itacitinib 200 mg (n = 14) Itacitinib 300 mg (n = 15) 200 mg 300 mg Total 600 600 Steroid- Steroid- Steroid- INCB039110-108- INCB039110-108- First-line refractory First-line refractory First-line refractory Response,a n (%) 001-003 001-001

500 (n = 6) (n = 8) (n = 6) 500 (n = 9) (n = 12) (n = 17)

INCB039110-108- INCB039110-108- Complete response 4 (66.7) 1 (12.5)001-005 4 (66.7) 2 (22.2) 8 (66.7) 001-0043 (17.6) Very good partial 400 0 0 INCB039110-108- 0 400 1 (11.1) 0 INCB039110-108-1 (5.9)

response

005-001 001-006 Partial response 1 (16.7) 4 (50.0) 1 (16.7) 3 (33.3) 2 (16.7) 7 (41.2)

, , mg INCB039110-108- INCB039110-108- 300 300

Mixed response 0 1 (12.5)008-002 1 (16.7) 0 1 (8.3) 008-0011 (5.9) Dose

Progression of disease 0 0 INCB039110-108- 0 Dose, mg 2 (22.2) 0 INCB039110-108-2 (11.8) 200 011-002 200 008-003 No response 1 (16.7) 1 (12.5) 0 0 1 (8.3) 1 (5.9)

INCB039110-108- INCB039110-108- Combined Corticosteroid Not applicable 0 1 (12.5)011-004 0 Combined Corticosteroid 1 (11.1) 0 011-0032 (11.8) 100 b 100 Overall response 5 (83.3) 5 (62.5)INCB039110-108- 5 (83.3) 6 (66.7) 10 (83.3) 11INCB039110-108- (64.7) 90% CIc 41.8–99.1 28.9–88.9018-004 41.8–99.1 34.5–90.2 56.2–97.0 42.0016-002–83.4 Responses0 were graded according to CIBMTR response criteria.INCB039110-108- The treatment population was limited0 to patients who received study treatment INCB039110-108- 0 14 28 42 56 70 84 98 112 126 021-001 0 14 28 42 56 70 84 98 112 126 018-002 a Last response data available on or before Day 28. Day Day b Patients with complete response, very good partial response, or partial response. c Calculated based on the exact method for binomial distributions. 1. Schroeder M et al. 58th American Society of Hematology Annual Meeting (ASH 2016). Abstract 390. Effect of Ruxolitinib on GVHD: ? Off-Target Effects1

100

75 IFNγR-/- T+DMSO (n = 10) 50 IFNγR-/- T+INCB (n = 10)

Survival, % Survival, P = .0117

0 0 20 40 60 After HSCT, d a b 4

BM+WSC+DMSO (n = 10) 2

Score BM+WSC+INCB (n = 10)

a P < .05. b P < .01. Clinical GVHD 0 0 20 40 60 After Allo-HSCT, d

1. Choi J et al. PLoS One. 2014;9:e109799. Agents Targeting the JAK1/JAK2 Pathways1-8

AMG 487 Many others in development

1. Quintás-Cardama A et al. Blood. 2010;115:3109-3117. 2. Rosenthal A et al. Expert Opin Pharmacother. 2014;15:1265-1276. 3. Gunerka P et al. Eur J Pharmacol. 2015;765:188-197. 4. Shi JG et al. J Clin Pharmacol. 2014;54:1354-1361. 5. Van Rompaey L et al. J Immunol. 2013;191:3568-3577. 6. Tawara I et al. Clin Cancer Res. 2011;17:77-88. 7. Tvedt THA et al. Front Immunol. 2017;8:667. 8. Choi J, DiPersio J et al. Submitted. 1. KennedyGA et al. IL6 Inhibition: Phase Phase Inhibition: IL6 No. at Risk No.at No.Risk at

Incidence of Incidence of Overall cGVHD, % 100 Grades 2-4 aGVHD, % 100 20 40 60 8 20 40 60 8

0 0 0 0

48 48 0 0

Lancet Oncol 20 48 40 6

AfterSCT,mo AfterSCT,d 40 47

. 2014;15:1451 12 29

60 47

14 18

8 47 0

- 1459. 24 100 5 44

Incidence of Incidence of

Extensive cGVHD, % Prophylaxis 100 Grades 3-4 aGVHD, % 100 20 40 60 8 20 40 60 8 0 0 1/2 Outcomes Outcomes 1/2 0 0

48 0 48 0

20 48 40

AfterSCT,mo AfterSCT,d 40 47

12 29

60 47

18 14 8 47

100 44 24 5

Incidence of

Overall Survival, % With Tocilizumab

100 Relapse, % 100 20 40 60 8 20 40 60 8 0 0 0 0

48 48 0 0

45 45 6 6

AfterSCT,mo AfterSCT,mo 12 12 34 34

18 18 18 18

24 24 6 6

Novel JAK 1/2 Inhibitor: Baricitinib Effect of CCR5 Inhibitor Maraviroc on GVHD1

a 35 patients undergoing reduced-intensity conditioning hematopoietic stem cell transplantation with maraviroc added to standard GVHD prophylaxis. 1. Reshef R et al. N Engl J Med. 2012;367:135-145. Effect of CCR5 Inhibitor Maraviroc on GVHD1

aGVHDa Moderate to Severe cGVHDa

100 100

80 80 60 60

40 Grades 2-4 40 20 20 Grades 3-4

0 0 Cumulative Cumulative Incidence, % 0 2 4 6 8 10 12 Cumulative Incidence, % 0 5 10 15 20 24 Months Months

Organ-Specific aGVHDa

Skin Liver Gut 100 100 100

80 80 80 60 60 60

40 40 40

20 20 20

0 0 0 Cumulative Cumulative Incidence, % 0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months Months Months

• CCR5-/- T cells associated with earlier death and more GVHD (pulmonary GVHD) • CCR5-/- x CXCR3-/- T cells associated with earlier death and more GVHD (pulmonary GVHD) • Expression of CCR5 and CXCR3 and ligands may be differentially expressed in MA vs RIC conditioning • Unknown effects on host tissues BMT CTN 1203 PROGRESS 1 Bolaños-Meade J. Abstract LBA 1 Sunday Feb 25 Failed to show a beneficial effect with Tac/MTX/Maraviroc Exploring Integrin Inhibitors in Allo-HSCT and GVHD

Type of Inhibitor Effect Agents b7-/- T cells and Less GVHD and less T cell Firategrast, natalizumab, and BOP anti-b7 Ab trafficking to the gut1 avb3 antibodies and Less GVHD due to less GI Peptidomimetics, small molecules, av-/- T cells neovascular proliferation2 and antibodies a4b1 inhibitors and Less GI GVHD3 Bio5192, firategrast, natalizumab, a4-/- T cells and vedolizumab aLb2 (LFA-1) inhibitors or Less GVHD4,5 Efalizumab (psoriasis) and lifitegrast b2 -/- T cells (dry eyes) aEb7 antibodies and Less GVHD6 Etrolizumab aE-/- T cells (in development for IBD)

1. Waldman E et al. Blood. 2006;107:1703-1711. 2. Leonhardt F et al. Blood. 2013;121:3307-3318. 3. Alahmari B et al. Blood. 2016;128:3344. 4. Wang Y et al. Biol Blood Marrow Transplant. 2009;15:1513-1522. 5. Liang Y et al. Blood. 2008;111:954-962. 6. Liu K et al. PLoS One. 2011;6:e21968. A 100 TCD BM Tie-2 cre+

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a P < .05. b P < .01. c P < .001. d P < .0001. 1. Alahmari B et al. Blood. 2016;128:3344.

Selected Ongoing Phase 3 Trials in aGVHD

Estimated Enrolling Patient Trial Estimated Arms Primary Endpoint Primary Enrollment Characteristics Identifier(s) Completion Date Itacitinib + corticosteroids New onset grades 1-4 436 NCT03139604 ORR based on CIBMTR vs placebo + aGVHD defined by April 2019 GRAVITAS-301 criteria at day 28 corticosteroids MAGIC criteria Incidence of severe Prophylaxis in patients (grades 3-4) mucositis based with hematologic Tacrolimus + mini-dose on WHO grade by day 28; 100 malignancies Methotrexate + MMF vs NCT01951885 time to neutrophil July 2018 undergoing BMT from tacrolimus + methotrexate engraftment; time to platelet matched unrelated engraftment; Incidence of donor aGVHD days 7-100

Ruxolitinib vs best 308 Steroid-refractory NCT02913261 ORR at day 28 November 2018 available therapy grades 2-4 aGVHD REACH-2 Methotrexate + low-dose New onset grades 2-4 NCT03371667 GVHD-free and corticosteroids vs placebo 102 December 2018 aGVHD MTX-aGVHD corticosteroids-free survival + low-dose corticosteroids New Directions in cGVHD Management: Will Emerging Therapies Make a Difference?

1. MacDonald KP et al. Blood. 2017;129:13-21. Three Biologic Phases of cGVHD1

1 2 3

TGFβ

1. Cooke KR et al. Biol Blood Marrow Transplant. 2017;23:211-234. Organ Involvement in Patients With cGVHD1

70% 60% 50% 40% 30% 20% 10% 0% Skin Oral Eye GI Liver Joint

1. Arora M et al. Biol Blood Marrow Transplant. 2016;22:449-455. Risk Factors for cGVHD1

aGVHD NIH cGVHD Matched unrelated donor 100 Matched related donor

80 Mismatched unrelated donor

Female donor/male recipient , % , 60 Mobilized blood cell graft

Diagnosis of CML cGVHD

40 Total body irradiation NIH NIH Conditioning with rabbit ATG 20 Patient age (per decade)

Donor age (per decade) 0 0 3 6 9 12 15 18 21 24 0.4 0.6 0.8 1.0 2.0 Months From Transplant Hazard Ratio

Acute GVHD ↑ Post-treatment cyclophosphamide ↓ Umbilical cord blood ↓

1. Flowers ME et al. Blood. 2011;117:3214-3219. The 2015 NIH Consensus Guidelines in cGVHD cGVHD Assessment1-2

• 0 – no clinical manifestations/symptoms • Performance Score • NIH Individual Organ Severity Score • 1 – clinical manifestations with no more than ─ Skin mild disability ─ Mouth • 2 – clinical manifestations with moderate disability ─ Eyes • 3 – clinical manifestations with severe disability ─ GI tract ─ Liver Number Maximum ─ Lungs Category of Organs Severity ─ Joints and fascia ─ Genital tract Mild ≤2 1 (0 for lung) • Other indicators, clinical features, or Moderate (a) ≥3 1 (0 for lung) complications Moderate (b) Any 2 (1 for lung) • Overall severity Severe Any 3 (2 for lung)

1. Filipovich AH et al. Biol Blood Marrow Transplant. 2005;11:945-956. 2. Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21:389-401. Treatment Strategy for cGVHD1

• Local symptoms  local treatment – Early identification crucial – Supportive vs local immunosuppressive

 Can be accessed through the ASBMT website: http://asbmt.org/practice-resources/nih- chronic-gvhd-consensus-project

1. Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21:1167-1187. Initial Therapy of cGVHD1

Agent Recommendation Evidence Evidence from ≥1 properly randomized, Steroids Should always be offered controlled trial Evidence for efficacy is insufficient to support for or against, or evidence might not Evidence from >1 well-designed clinical trial without outweigh adverse consequences or randomization, from cohort or case-controlled analytic CNI cost of the approach. studies (preferable from >1 center) or from multiple time Use in first-line treatment justified and/or use series or dramatic results from uncontrolled experiments in equal to or greater than second-line treatment justified.a Moderate evidence for lack of efficacy or for Evidence from >1 well-designed clinical trial without MMF in adverse outcome supports a recommendation randomization, from cohort or case-controlled analytic triple-agent against use. studies (preferable from >1 center) or from multiple time combinations Should generally not be offered. series or dramatic results from uncontrolled experiments Moderate evidence for lack of efficacy or for Evidence from >1 well-designed clinical trial without adverse outcome supports a recommendation randomization, from cohort or case-controlled analytic Azathioprine against use. studies (preferable from >1 center) or from multiple time Should generally not be offered. series or dramatic results from uncontrolled experiments Moderate evidence for lack of efficacy or for Evidence from >1 well-designed clinical trial without adverse outcome supports a recommendation randomization, from cohort or case-controlled analytic Thalidomide against use. studies (preferable from >1 center) or from multiple time Should generally not be offered. series or dramatic results from uncontrolled experiments a Only applied for topical treatment of cGVHD. 1. Wolff D et al. Biol Blood Marrow Transplant. 2010;16:1611-1628. Phase 3 Studies of Initial Treatment of cGVHD

Double Author Arms Compared Blind N Results Prednisone Sullivan1 Yes 179 Decreased survival  azathioprine Prednisone Koc, 20022 No 287 Limited benefit  cyclosporine (CSP) CSP/prednisone Koc, 20003 Yes 51 Toxicity  thalidomide CSP/prednisone Arora4 No 54 No benefit  thalidomide CNI/ Martin5 Yes 151 No benefit prednisone  MMF CNI/ Gilman6 prednisone  No 54 Terminated early hydroxychloroquine Sirolimus/ Carpenter7 No 151 Terminated early prednisone  CNI

1. Sullivan KM et al. Blood. 1988;72:546-554. 2. Koc S et al. Blood. 2002;100:48-51. 3. Koc S et al. Blood. 2000;96:3995-3996. 4. Arora M et al. Biol Blood Marrow Transplant. 2001;7:265-273. 5. Martin PJ et al. Blood. 2009;113:5074-5082. 6. Gilman AL et al. Biol Blood Marrow Transplant. 2012;18:84-91. 7. Carpenter PA et al. Biol Blood Marrow Transplant. 2016;22(suppl):S50-S52. Novel Mechanistic Interventions for the Prevention or Treatment of cGVHD1

Stem cell graft engineering Inhibit T cell signaling • Antithymocyte globulin • ITK inhibition: Ibrutinib • Post-transplant • JAK1/2 inhibition: Ruxolitinib cyclophosphamide Alloreactive • ROCK2 inhibition: KD025 • CD34 selection T cells • Bortezomib • Ex vivo pan–T cell depletion • Ex vivo selective T cell Treg-sparing therapy depletion • Sirolimus • Donor IL2 therapy • Mycophenolate CD4+ FoxP3+ mofetil • Ruxolitinib Adoptive Treg therapy Regulatory • Purified donor Treg • Bortezomib • Ex vivo expanded Treg T cells • Antigen-specific Treg In vivo Treg expansion • ECP B cell depletion in vivo • Low-dose IL2 • Rituximab Alloreactive Inhibit B cell signaling • Ofatumumab and • Obinutuzumab • BTK inhibition: autoreactive Ibrutinib B cells • SYK inhibition: • Fostamatinib 1. Cutler CS et al. Blood. 2017;129:22-29. Randomized Phase 2 Trials for Initial Therapy of cGVHD1-2

Sirolimus Plus Prednisone vs Rituximab vs Imatinib: Sirolimus/CNI Plus Prednisone: cGVHD Consortium CTN 0801

1.0

0.8 0.8

0.6 P = .14 Rituximab

0.6 Sirolimus/CNI plus prednisone, 12.9% Imatinib Sirolimus plus prednisone, 13.9% 0.4

Failure 0.4

Incidence of Secondary ofSecondary Incidence 0.2 P = .855

0.2 Immunosuppressive Therapy Immunosuppressive

0.0 0.0 0 30 60 90 120 150 180 0 1 2 3 4 5 6 7 Post Randomization, d Months 1. Carpenter PA et al. 2016 BMT Tandem Meetings. Abstract 42. 2. Arai S et al. Clin Cancer Res. 2016;22:319-327. Options for Steroid-Refractory cGVHD1

Treatment Overall Response Survival Extracorporeal 65%-70% 70%-78% at 1 year photopheresis Rituximab 66%-86% 72% at 1 year Imatinib 22%-79% 75%-84% at 1.5 year Other Therapies Pentostatin 53%-56% 34%-60% at 1-3 year Calcineurin inhibitor Mesenchymal stem cell 50%-74% 78% at 2 year High-dose methylprednisolone Mycophenolate mofetil 26%-64% 67%-96% at 1 year Methotrexate Thalidomide 20%-82% mTOR inhibitor 76% 72% at 3 year Hydroxychloroquine overall Interleukin-2 52% Not reported Clofazimine response Thoracoabdominal irradiation rates Alefacept reported Infliximab Etanercept JAK1/2 inhibitors

1. Flowers ME, Martin PJ. Blood. 2015;125:606-615. Low-Dose IL2: Clinical Response1-2

• Rationale: Impairment of Treg function is associated with cGVHD • IL2 is critical for normal Treg development, expansion, activity, and survival

Patients with extensive steroid- Daily IL2 1 x 106 IU/m2 refractory cGVHDa given SC for 12 weeks followed (N = 35) by a mandatory 4-week hiatus

Responses: CR: 0 PR: 20 (61%) SD: 10 (30%) PD: 3 (9%) Response sites: Liver: 6/13, 46% Lung: 3/15, 20% Skin: 9/27, 33% Joint/fascia: 4/23, 17% Gl: 3/10, 30%

• 23 patients with PR or SD with minor responses chose to continue daily IL2 after a mandatory 4-week treatment hiatus a Active cGVHD despite ≥4 weeks of immunosuppressants with ≥0.25 mg/kg/d prednisone prior 12 months. 1. Koreth J et al. Blood. 2016;128:130-137. 2. Koreth J et al. N Engl J Med. 2011;365:2055-2066. B Cells Contribute to Immune Pathology of cGVHD

• B cells are important in disease process – Immune complexes in patient’s skin1 – Murine studies demonstrate a role for B cells in pathogenesis2,3 – Rituximab (anti-CD20) efficacious for steroid-refractory cGVHD patients4,5

1. Tsoi MS et al. J Immunol. 1978;120:1485-1492. 2. Zhang C et al. Blood. 2006;107:2993-3001. 3. Srinivasan M et al. Blood. 2012;119:1570-1580. 4. Cutler C et al. Blood. 2006;108:756-762. 5. Zaja F et al. Bone Marrow Transplant. 2007;40:273-277. Second-Line cGVHD Treatment Options: Rituximab1

• Rationale: B cell role in the pathogenesis of cGVHD  allo-antibody, BAFF • Hypothesis: B cell depletion may be effective cGVHD therapy

Rituximab 375 mg/m2/week for 4 weeks Patients with extensive 1 additional cycle permitted for patients with no steroid-refractory cGVHD response or an incomplete response 8 weeks after (N = 21) first cycle

Clinical Parameter Study Entry 1 Year P Overall response rate, % NA 70 Complete response rate, % NA 10 Median prednisone dose, mg/d 40 10 Discontinued prednisone, % NA 21 <.001 Prednisone dose reduction of ≥50%, % NA 68 No change or higher dose, % NA 32

Reported significant changes for: Skin involvement (sclerodermatous and lichenoid), oral pharyngeal score, ocular Schirmer's test, and rheumatologic symptoms

1. Cutler C et al. Blood. 2006;108:756-762. Agents Targeting B Cell Signaling Pathways Second-Line cGVHD: Efficacy With Ibrutinib1-2

PCYC-1129-CA Multicenter Open-Label Phase 2 Study of Ibrutinib in cGVHD After Failure of Corticosteroids

Patients who have failed Ibrutinib 420 mg orally continued until progression frontline cGVHD therapy of cGVHD or unacceptable toxicity (N = 42) -Recommended phase 2 dose identified in phase 1

100% Eligibility criteria 100 Best chronic GVHD • Steroid dependent/refractory cGVHD response 80%80 (N = 42) CR • >25% body surface area erythematous rash PR 60%60 or >4 total mouth score defined by NIH criteria 9

40%40 Primary endpoint % Responders, 19 7 • cGVHD response per NIH 2005 20%20 response criteria 2 0%0 SD PD 1. Miklos D et al. Blood. 2016;128:LBA-3. 2. Miklos D et al. Blood. 2017;130:2243-2250. Ibrutinib: Safety1-2

PCYC-1129-CA Multicenter Open-Label Phase 2 Study of Ibrutinib in cGVHD After Failure of Corticosteroids

Fatigue Diarrhea Muscle spasms Nausea Grade 1 Tendency to bruise Grade 2 Upper respiatory tract infection Grade 3 Pneumonia Grade 4 Pyrexia Grade 5 Headache Fall 0.0 0.1 0.2 0.3 0.4 0.5 0.6

1. Miklos D et al. Blood. 2016;128:LBA-3. 2. Miklos D et al. Blood. 2017;130:2243-2250. Ibrutinib Inhibition Selectively Targets and May Preserve Cytotoxic T Cells and Regulatory T Cells1-2

B Cell and Monocyte and Th2 and Th17 Th1, Treg, and Leukemia Macrophage T Cells CD8 T Cells

BCR TLR TCR TCR

Ibrutinib Ibrutinib Ibrutinib MYD88

BTK ITK ITK RLK

Ibrutinib

PLCγ IRAK4

BTK PLCγ PLCγ

NFκB AP1 NFAT NFκB NFκB AP1 NFAT NFκB AP1 NFAT B cell proliferation and survival Antigen presentation, B cell stimulation and antibody Immunity against malignancy, inflammation, and response to production intracellular pathogens, and danger signals autoimmune protection 1. Shinners NP et al. J Immunol. 2007;179:3872-3880. 2. Dubovsky JA et al. Blood. 2013;122:2539-2549.

JAK1/2 Inhibition: Summary of Studies With Ruxolitinib in cGVHD

Study GVHD Patients, n Prior Treatment/Follow- Response Overall Survival Type Severity Treatments, up Duration, (95% CI) Median Median (range) (range) Retrospective1 Moderate or 19 ≥2 18 (6-27) mo ORR, 100% NA severe (CR, 95%)

Retrospective2,3 Moderate or 41 3 (1-10) 22.4 (3-135) wk ORR, 85% 6 mo, 97% severe 24 (NA) mo (CR, 7%) (92%-100%) Ongoing, 12 mo, 93% 24% (85%-100%) Pilot4 Grade 3 2 4 (3-5) 23.5 Response, NA (10-37) wk 100%

Retrospective5 Severe 3 2 (1-2) NA ORR, 100% NA (CR, 57%)

1. Khoury HJ et al. Biol Blood Marrow Transplant. 2018 Jan 24 [Epub ahead of print]. 2. Zeiser R et al. Leukemia. 2015;29:2062-2068. 3. Zeiser R et al. ASH 2016. Abstract 4561. 4. Spoerl S et al. Blood. 2014;123:3832-3842. 5. Mori Y et al. Bone Marrow Transplant. 2016;51:1584-1587. Ruxolitinib for Steroid-Refractory GVHD1-2

• Europe and United States retrospective survey cGVHD Outcome – N = 95 N = 41  54 steroid-refractory aGVHD,1-year grades overall III-IV; survival median follow-up: 26.592.7% weeks  41 steroid-refractory cGVHD, moderate or severe; median follow-up: 22.4 weeks Estimated median overall NR • ORR for aGVHD: 81.5% (44/54) survival – 25 complete responses (46.3%) 10 months – Median time to response, 1.5 weeksDuration (1-11 of weeks) ruxolitinib, median • ORR for cGVHD: 85.4% (35/41) Ongoing response/free of 24% (10/41) immunosuppression • Rate of GVHD relapse in ruxolitinib responders GVHD relapse or progression 36% (13/36) – aGVHD: 6.8% (3/44) after PR/CR at 1-year – cGVHD: 5.7% (2/35) Response to retreatment 86% (11/13) Cytopenia (any grade)a 17.1% (7/41) CMV reactivationa 14.6% (6/41) a During ruxolitinib therapy. 1. Zeiser R et al. Leukemia. 2015;29:2062-2068. 2. Zeiser R, Blazar BR. Blood. 2016;127:3117-3126. Selected Ongoing Phase 3 Trials for Initial Prophylaxis or Treatment of cGVHD

Estimated Trial Estimated Enrolling Patient Primary Identifier(s) Arms Enrollment Characteristics Primary Endpoint Completion Date

iNTEGRATE Prednisone ± ibrutinib New onset moderate or Response rate at 24 186 March 2020 NCT02959944 vs placebo ± ibrutinib severe GVHD weeks

REACH-3 Ruxolitinib vs best Steroid-refractory Response rate at 324 July 2019 NCT03112603 available therapy moderate or severe GVHD cycle 7

CD34-selected T cell Prophylaxis in patients BMT CTN 1301 depletion in PBSC grafts with hematologic cGVHD-free relapse- PROGRESS-II vs post-transplant PTCy 345 malignancies undergoing free survival at 2 Sept 2020 NCT02345850 vs tacrolimus + HSCT from matched years methotrexate related- or unrelated donor

Tacrolimus + Prophylaxis in patients with AML, ALL, or MDS cGVHD incidence at 1 NCT03066466 methotrexate 207 Feb 2020 undergoing BMT from year ± atorvastatin matched unrelated donor iNTEGRATE1

PCYC-1140: A Randomized, Double-Blind Phase 3 Study of Ibrutinib in Combination With Corticosteroids Versus Placebo in Combination With Corticosteroids in Subjects With New Onset cGVHD

R • Population a Ibrutinib + ─ Frontline moderate and severe cGVHD n prednisone ─ NIH 2014 cGVHD criteria ─ Age ≥12 years old d • International study, n = 186 subjects o 1:1 ratio • Primary endpoint m ─ cGVHD response rate at 24 weeks • Secondary endpoints i Placebo + ─ Safety z prednisone ─ Overall survival e ─ Steroid dose reduction ─ Time to withdrawal of immunosuppressants

1. https://clinicaltrials.gov/ct2/show/NCT02959944. Accessed January 11, 2018. Phase 3 REACH-31

Phase 3 Randomized Clinical Trial for Steroid-Refractory cGVHD Comparing Ruxolitinib vs Best Available Therapy

Key eligibility criteria Ruxolitinib • ≥12 years old with moderate to severe BID at protocol-defined starting steroid-refractory classical cGVHD dose • Myeloid and platelet engraftment R • Only prior treatments, corticosteroids ± CNI N = 324 for cGVHD • If prior JAK inhibitor for aGVHD, CR or PR, Best available treatmenta and off for >8 weeks Optional crossover after cycle 6 Key endpoints • Primary: ORR • Secondary: Change symptom scale score, DOR, OS, reduction of steroid use, QOL, toxicity a ECP, methotrexate, MMF, mTOR inhibitor, infliximab, rituximab, pentostatin, imatinib. 1. https://clinicaltrials.gov/show/NCT03112603. Accessed January 11, 2018. BMT CTN 1203 (PROGRESS I) GVHD Prophylaxis Protocol1

Age 18-75 years, controlled malignant disease, RIC, related • Phase 2 or unrelated Primary outcome PBSC donor • PIs: Bolaños- • Rate of GVHD- Meade, Koreth, and relapse-free Reshef survival 1 year Tac/MTX/ Tac/MTX/ Tac/MMF/ after transplant • NCT02208037 bortezomib maraviroc PTCy

Tac/MTX CIBMTR controls

CIBMTR controls eligibility Transplants performed in the US Centers not participating in BMT CTN 1203 and agree to provide supplemental information Age 18-75 years Transplants for malignant disease using RIC and a PBSC graft GVHD prophylaxis with Tac/MTX without additional agents

1. Bolaños-Meade J et al. 2018 BMT Tandem Meetings. Abstract LBA1. BMT CTN 1203 (PROGRESS I): Primary Outcomes1

Controls Tac/MTX/bortezomib Tac/MTX/maraviroc MMF/Tac/PTCy (N = 224) (N = 89) (N = 92) (N = 92) GRFS Adjusted 1 yr KM estimates 0.32 (0.26-0.39) 0.42 (0.33-0.54) 0.32 (0.23-0.43) 0.46 (0.37-0.57) HR (90% CI) 1 0.82 (0.62-1.08) 1.02 (0.79-1.32) 0.72 (0.54-0.94) P .24 .86 .04 aGVHD III-IV Cumulative at 180 days 13 (9-16)% 8 (4-13)% 9 (4-14)% 2 (0-5)% (90% CI) HR (90% CI) 1 0.51 (0.25-1.04) 0.58 (0.29-1.15) 0.13 (0.03-0.44) P .12 .19 .006 cGVHD requiring Cumulative at 1 yr (90% CI) 32 (27-37)% 22 (16-30)% 27 (20-35)% 19 (12-26)% immunosuppression HR (90% CI) 1 0.70 (0.45-1.07) 0.85 (0.57-1.26) 0.57 (0.36-0.89) P .17 .5 .04 Treatment-related Cumulative at 1 yr (90% CI) 16 (12-21)% 17 (11-24)% 17 (11-24)% 11 (6-17)% mortality HR (90% CI) 1 1.06 (0.63-1.78) 0.97 (0.57-1.65) 0.62 (0.34-1.11) P .84 .93 .17 GVHD-free survival Adjusted 1 yr estimates 0.39 (0.33-0.46) 0.46 (0.37-0.58) 0.40 (0.31-0.51) 0.56 (0.47-0.67) (90% CI) HR (90% CI) 1 0.83 (0.62-1.11) 0.98 (0.75-1.28) 0.63 (0.46-0.85) P .3 .91 .01 1. Bolaños-Meade J et al. 2018 BMT Tandem Meetings. Abstract LBA1. BMT CTN 1301(PROGRESS II) CNI-Free GVHD Prophylaxis Protocol1

≥1 year and <66 years, controlled acute leukemia and MDS, • Phase 3 myeloablative conditioning, related or Primary outcome • PIs: Luznik, unrelated 8/8 HLA-matched bone marrow, or • Chronic GVHD-free peripheral blood stem cell donor Perales, Pasquini relapse-free survival • NCT02345850 N = 345

CD34 selected BM BM/PTCy PBSC Tac/MTX

Estimated primary completion date: cGVHD/relapse-free survival (CRFS) Sep 2020

1. https://web.emmes.com/study/bmt2/protocol/1301_protocol/BMT%20CTN%20Protocol%201301%20Synopsis%20v4.0.pdf. Accessed January 11, 2018. How Are Physicians Choosing cGVHD Therapies?

• Clinical efficacy – NIH response, durability, composite endpoints – Organs involved – Retrospective analysis vs prospective rigor – Single institution vs multicenter trials • Toxicity profile • Mechanism of action • Mode of delivery – Hickman access, IV infusion, injection, pill • Patient compliance • Cost

Shared Decision-Making: SHARE Approach1-3

• SHARE Approach – 5-step process for shared decision-making – Includes exploring and comparing the benefits and risks of each management option through meaningful dialogue about what matters most to the patient:  Seek your patient's participation  Help your patient explore and compare treatment options  Assess your patient's values and preferences  Reach a decision with your patient  Evaluate your patient's decision

1. ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/tools/tool-1. Accessed January 11, 2018. 2. Kane HL et al. CA Cancer J Clin. 2014;64:377-388. 3. Eliacin J et al. Qual Health Res. 2015;25:688-678. QOL of Patients With GVHD1-2

• QOL inversely correlates with severity of disease (NIH global severity score and organ-specific severity) • QOL may vary by tissue-specific affectation – Mild symptoms in the lungs, GI, and/or joints and fascia cause clinically meaningful deterioration of physical QOL • Physicians frequently underestimate changes in QOL – Especially for patients with no or mild GVHD symptoms

1. Fiuza-Luces C et al. Bone Marrow Transplant. 2016;51:13-26. 2. Kurosawa S et al. Biol Blood Marrow Transplant. 2017;23:1749-1758. QOL of Patients With GVHD1

• Physicians frequently underestimate changes in QOL

VAS by Patients P < .001 No GVHD Mild Moderate Severe

40 50 60 70 80 90 100

VAS by Physicians P < .001 No GVHD Mild Moderate Severe

40 50 60 70 80 90 100

1. Kurosawa S et al. Biol Blood Marrow Transplant. 2017;23:1749-1758. Psychosocial and Sexual Function1-5

Sexual Dysfunction and Satisfaction from • Fatigue Pre-HCT (T1) to One Year Post-HCT (T4) 80 • Adherence to treatment/assessment . T1

. T4 • Sleep disorders 60 • Body image disturbance 40

• Anxiety disorders, depression Percentage 20 • Post-traumatic stress disorder 0 • Post-traumatic growth • Positive changes in quality of life; new appreciation for life • Sexual function: Assess (dryness, narrowing), vaginal moisturizer and dilator, and referral Symptom

1. Tierney DK et al. Oncol Nurs Forum. 2015;42:488-497. 2. Neumann J. Hematol Oncol Stem Cell Ther. 2017 Jun 28 [Epub ahead of print]. 3. Bishop MM, Wingard JR. Expert Rev Pharmacoecon Outcomes Res. 2004;4:111-123. 4. Lee S et al. Biol Blood Marrow Transplant. 2003;9:215-233. 5. Kydd S, Rowett D. Intimacy After Cancer: A Woman’s Guide. Mountain View, CA: Big Think Media, Inc; 2006. Resources for GVHD: Doctors, Nurses, Patients

• National Marrow Donor Program Additional links: – www.cancer.org – www.bethematch.org – www.cancer.gov – Smartphone app (excellent) – CIBMTR.org – www.cancercare.org • BMT InfoNet – www.livestrong.org – www.bmtinfonet.org – www.lls.org – www.nbmtlink.org

– www.oncofertility.northwestern.edu • nbmtLink – www.resolve.org – www.nbmtlink.org – www.vitaloptions.org – www.youngsurvival.org

Take-Home Messages

Acute versus chronic GVHD  Not time frame specific but depends on presence of specific signs and symptoms  Pathologic changes of aGVHD may contribute to cGVHD GVHD prophylaxis Calcineurin inhibitor plus methotrexate versus Tac/MMF/PTCy  Should results from PROGRESS 1 change practice? aGVHD primary therapy: Steroids  New strategies: Chemotaxis influencers and JAK inhibitors Steroid-refractory cGVHD Has FDA approval of ibrutinib changed practice?  There are multiple promising agents being tested in randomized trials  Shared decision-making should be an integral part of GVHD care Abbreviations

α: alpha BLNK: B cell linker Ab: antibody BM: bone marrow AcetylCoA: acetyl coenzyme A BMT: bone marrow transplant aGVHD: acute graft-versus-host disease BO: bronchiolitis obliterans allo-HCT: allogeneic hematopoietic cell transplantation BOOP: bronchiolitis obliterans organizing pneumonia allo-HSCT: allogeneic hematopoietic stem cell transplant BTK: Bruton’s tyrosine kinase ALP: alkaline phosphatase Ca2+: calcium ions AP1: activator protein 1 CASP3: caspase 3 APC: antigen-presenting cell CCR5: C-C motif chemokine receptor 5 ASBMT: American Society for Blood and Marrow Transplantation CD: cluster of differentiation AST: aspartate aminotransferase cGVHD: chronic graft-versus-host disease ATG: antithymocyte globulin CI: confidence interval BAFF: B cell activating factor CIBMTR: Center for International Blood and Marrow Transplant Research BAFF-R: B cell activating factor receptor CK-18: cytokeratin-18 BCR: B cell receptor CLL: chronic lymphocytic leukemia BID: twice a day Abbreviations

CLP: common lymphoid progenitor DMSO: dimethyl sulfoxide CML: chronic myeloid leukemia DOR: duration of response CMV: cytomegalovirus ECP: extracorporeal photopheresis CNI: calcineurin inhibitors ERK: extracellular signal-regulated kinases CR: complete response EZH2: enhancer of zeste homolog 2 CRFS: chronic graft-versus-host disease relapse-free survival FDA: Food and Drug Administration CSP: cyclosporine FOXP3: forkhead box P3 CTLA4: cytotoxic t-lymphocyte associated protein 4 GI: gastrointestinal CTLA4Ig: cytotoxic t-lymphocyte associated protein 4 immunoglobulin Gp130: glycoprotein 130 CXCR3: C-X-C motif chemokine receptor 3 GRFS: graft-versus-host disease–free/relapse–free survival CY: cyclosporine GVHD: graft-versus-host disease d: day GvL: graft-vs-leukemia DAG: dystroglycan Gvt: graft-versus-tumor DC: dendritic cell haplo: haploidentical DLI: donor lymphocyte infusion HCT: hematopoietic cell transplantation DLL4: delta-like protein 4 HGF: hepatocyte growth factor Abbreviations

HLA: human leukocyte antigen ITK: IL2 inducible kinase HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA IV: intravenous HR: hazard ratio JAK: Janus kinase HSC: hematopoietic stem cell KM: Kaplan-Meier HSCT: hematopoietic stem cell transplant LN: lymph node IBD: inflammatory bowel disease MA: myeloablative iCASP9: inducible caspase 9 MAGIC: Michigan Appropriateness Guide for Intravenous Catheters IFNƴ: interferon gamma MAPK: mitogen-activated protein kinase IFNƴR: interferon gamma receptor MCL: mantle cell lymphoma iJAK: Janus kinase inhibitor MDS: myelodysplastic syndromes IL: interleukin MHC: major histocompatibility complex IL2Rα: interleukin 2 receptor alpha MiR: MicroRNA iNKT: invariant natural killer T cell mm: mismatch

InSP3: inositol trisphosphate MMF: mycophenolate mofetil IRAK4: interleukin 1 receptor associated kinase 4 Abbreviations

mo: month NK: natural killer

MOA: mechanism of action NKreg: regulatory natural killer MSC: mesenchymal stem cells NR: not reached MSD: matched sibling donor NRM: nonmyeloablative MRD: matched related donor OMRS: oral mucosa rating scale mTORC: mammalian target of rapamycin complex ORR: objective response rate MTX: methotrexate OS: overall survival mMUD: mismatched unrelated donors PB: peripheral blood MUD: matched unrelated donor PBL: peripheral blood leucocytes MZL: marginal zone lymphoma PBSC: peripheral blood stem cell MYD88: myeloid differentiation primary response 88 PD: progressive disease NA: not applicable PDGFα: platelet-derived growth factors alpha NFAT: nuclear factor of activated T cells PI: principal investigator NFATc: nuclear factor of activated T cells cytoplasmic PKC: protein kinase C NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells PLCγ: phospholipase C gamma NIH: National Institutes of Health PMN: percentages of neutrophilic Abbreviations

PR: partial response SLL: small lymphocytic lymphoma PTCy: post-transplant cyclophosphamide ST2: suppression of tumorigenicity 2 QOL: quality of life STAT: signal transducer and activator of transcription R: randomized sTNFR1: TNF receptor superfamily member 1 RD: related donor SYK: spleen associated tyrosine kinase REG3α: regenerating islet-derived protein 3α Tac: tacrolimus

RIC: reduced intensity conditioning Tallo: alloreactive T cells RLK: receptor-like protein kinase TCD BM: T cell depleted bone marrow

ROCK2: rho associated coiled-coil containing protein kinase 2 TEFF: effector T cell

Rux: ruxolitinib TFH: follicular helper T cell sBAFF: soluble B cell activating factor TGFβ: transforming growth factor-beta SC: subcutaneous Th: T helper cell SCT: stem cell transplantation TIM-3: T cell immunoglobulin and mucin domain 3 SD: stable disease TKI: tyrosine kinase inhibitor sec: second TLR: toll-like receptors shRNA: short hairpin RNA TN: naive T cells Abbreviations

TNF: tumor necrosis factor TNFR: tumor necrosis factor receptor TRAIL: TNF-related apoptosis-inducing ligand Treg: regulatory T cell UCB: umbilical cord blood UGI: upper gastrointestinal URD: unrelated donor VAS: visual analogue scale VP: vaginal penetration WHO: World Health Organization wk: week Please remember to complete and submit your Post-Test and Evaluation for CME credit. Missed anything?

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