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Home , Denileukin diftitox, Filgotinib, Ruxolitinib

PRACTICE AID Mechanisms of Action of Emerging Agents in GVHD

Selected Mechanistic Interventions in Acute GVHD1,2

Antigen-presenting cell B cell

MHCII CD20 CD80/CD86

ALCAM Treg Itolizumab MSC α β IL-6 IL-2 CD6 Maraviroc IFNγ ATG IFNγR1 IFNγR1 α CD52 α α β IFNγR2 IFNγR2 IL-6 receptor IL-2 receptor JAK1 JAK2 JAK1 β β JAK2 β γ TNFR T cell receptor CD28 CCR5

Cyclosporine STAT iCASP9 IκBα FKBP12 Proteasome • Itacitinib (JAK1) AcetylCoA AcetylCoA CASP3 Bortezomib • Gandotinib (JAK2) • (JAK1 and JAK2) HMG-CoA Atorvastatin • (JAK1 and JAK2) reductase • (JAK1) ? Cholesterol NFATc mTORC

T-cell signaling inhibitors and trafficking modulators Depletion of T lymphocytes • Calcineurin blockade: Cyclosporine and tacrolimus • Antithymocyte globulin • JAK1/2 inhibition: Ruxolitinib, itacitinib, gandotinib, • Alemtuzumab baricitinib, and filgotinib • Proteasome inhibitors: Bortezomib • CCR5 inhibitors: Maraviroc and ixazomib • Alpha-4 inhibitors • T-cell costimulation blockade: Abatacept and itolizumab Cell cycle progression • DNA synthesis blockade: Mycophenolate mofetil, Epigenetic modulators , and pentostatin • DNA hypomethylating drugs • Histone deacetylase inhibitors: Cellular therapies Vorinostat and suberoylanilide Alloreactive hydroxamic acid T cells • Mesenchymal stem cells • Histone methyltransferase/ • Apoptotic cell therapy EZH2 inhibitors IL-6 signaling IL-2 upregulation • IL-6 receptor blockade: Tocilizumab • IL-2 receptor blockade: Daclizumab and basiliximab IL-2 signaling • IL-2–directed toxin: • mTOR blockade: Sirolimus

This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients. Access the activity, “Innovative Therapies in Post-Transplant GVHD: Personal Insights From the Patient CaseBook,” at www.peerview.com/GVHD19. PRACTICE AID Mechanisms of Action of Emerging Agents in GVHD

Mechanistic Interventions in Chronic GVHD3

Stem cell graft engineering • Antithymocyte globulin • Post-transplant Inhibit T-cell signaling cyclophosphamide • ITK inhibition: • CD34 selection Alloreactive • JAK1/2 inhibition: Ruxolitinib • Ex vivo pan–T-cell T cells • ROCK-II inhibition: KD025 depletion • T-cell costimulation • Ex vivo selective T-cell blockade: Abatacept depletion • Donor IL-2 therapy

Treg-sparing therapy • Sirolimus • Mycophenolate mofetil Adoptive Treg therapy CD4+ FoxP3+ • Ruxolitinib • Purified donor Treg regulatory • Bortezomib • Ex vivo expanded Treg • Antigen-specific Treg T cells In vivo Treg expansion • ECP • Low-dose IL-2

B-cell depletion in vivo Alloreactive Inhibit B-cell signaling • Rituximab and • BTK inhibition: Ibrutinib • • SYK inhibition: • autoreactive Fostamatinib B cells

α: alpha; ALCAM: activated leukocyte cell adhesion molecule; ATG: antithymocyte globulin; β: beta; BTK: Burton's tyrosine kinase; CASP: caspase; CCR5: C-C motif 5; CD: cluster of differentiation; CTLA-4: cytotoxic T-lymphocyte–associated protein 4; ECP: extracorporeal photopheresis; EZH2: enhancer of zeste homolog 2; FKBP: FK506 binding protein; FoxP3: forkhead box P3; HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA; iCASP: inducible CASP; IL: ; ITK: IL-2 inducible T cell kinase; IκBα: nuclear factor of kappa polypeptide gene enhancer in B cells inhibitor alpha; JAK: ; MHC: major histocompatibility complex; MSC: mesenchymal stem cell; mTOR: mammalian target of rapamycin; mTORC: mTOR complex; NFATc: nuclear factor of activated T cells cytoplasmic; ROCK-II: Rho associated coiled-coil containing protein kinase 2; STAT: signal transducer and activator of transcription; SYK: spleen tyrosine kinase; TNFR: tumor necrosis factor receptor; Treg: regulatory T cells; γ: gamma. 1. Choi SW, Reddy P. Nat Rev Clin Oncol. 2014;11:536-547. 2. Schroeder MA et al. Biol Blood Marrow Transplant. 2018;24:1125-1134. 3. Cutler CS et al. Blood. 2017;129:22-29. Access the activity, “Innovative Therapies in Post-Transplant GVHD: Personal Insights From the Patient CaseBook,” at www.peerview.com/GVHD19. PRACTICE AID Reducing GVHD Events A Patient CaseBook for Clinicians

Case 1: Leonard

25-Year-Old Caucasian Male; AML in CR2

• Sister, 32: HLA matched Possible • Brother, 22: HLA matched Donors • Brother, 24: HLA haplo-identical • More than eighty 10/10 HLA matches in the NMDP Registry

Donor choice Therapy q Brother, 22: HLA matched Considerations GVHD prophylaxis q CNI/Mtx Patient counseling on risks of transplant q Primary disease relapse (37%), GVHD (20%), and infections (17%) remain issues with an HLA-matched donor q Low risk of organ failure (6%)

Case 2: Lisa

60-Year-Old Mixed-Ethnicity Female; AML in CR2

• Sister, 48: HLA haplo-identical • One 9/10 URD in the NMDP Registry in South America Possible • Father, 80: HLA haplo-identical • No large enough cord blood units in the registry Donors • No 10/10 URD in the NMDP Registry

Donor choice Therapy q Sister, 48: HLA haplo-identical Considerations GVHD prophylaxis q Post-transplant cyclophosphamide vs α/β T-cell depletion ± T-cell add-back Patient counseling on risks of transplant q Relapse, infections, and slow immune reconstitution are all issues with haplo-identical donor; aGVHD remains a risk, but cGVHD is signicantly protected by both prophylactic strategies

Case 3: Moe

30-Year-Old Mixed-Ethnicity Male; AML in CR2

• No siblings; mother deceased • Ten 9/10 URD in the NMDP Registry Possible • Father, 75: HLA haplo-identical • Three cord blood units; would need a double cord to Donors • No 10/10 URD in the NMDP Registry obtain adequate cell dose

Donor choice Therapy q 9/10 URD or cord Considerations GVHD prophylaxis q For 9/10 URD: CNI/Mtx + ATG or CNI/Mtx + abatacept q For cord: Cyclosporine/MMF potentially + Tregs Patient counseling on risks of transplant q Both donor choices historically have high rates of aGVHD and cGVHD

The scenarios in this CaseBook are designed to illustrate patients that may be potential candidates for treatment with currently approved or investigational therapies in the management of GVHD. Access the activity, “Innovative Therapies in Post-Transplant GVHD: Personal Insights From the Patient CaseBook,” at www.peerview.com/GVHD19. PRACTICE AID Managing Steroid-Refractory aGVHD A Patient CaseBook for Clinicians

Case 4: Patty

69-Year-Old Woman With MDS

• Patient underwent RIC MRD PBSCT; CMV D+/R+ • At d 88 post-transplant, patient reported new-onset diarrhea and Patient abdominal tenderness History • Biopsy of the recto-sigmoid colon was consistent with aGVHD • She was started on methylprednisolone 1 mg/kg/d; no improvement in symptoms was noted after 1 wk of steroid therapy

Treatment q Increased dose of methylprednisolone, ECP, equine ATG, α1-antitrypsin, Options or ruxolitinib

Treatment Recommendations

ü Patient was enrolled in the REACH 1 trial ü Started ruxolitinib on d 97 post-transplant; ruxolitinib dose was escalated to 5 mg PO BID while tapering steroid dose to prednisone 40 mg QD in 1 wk (d 108)

For Date Re ll times

• Abdominal pain resolved with ruxolitinib therapy in 2 wk; patient continued to show improvement in q Follow-up on d 179 showed symptoms and prednisone dosage was reduced no active GVHD to 25 mg/d q Continued treatment with • After 5 wk of ruxolitinib therapy 5 mg BID, patient ruxolitinib 5 mg/d, prednisone developed in the setting of 10 mg/d, MMF 500 mg BID, CMV reactivation and tacrolimus (FK506) Response

Assessment/ Assessment/ • Ruxolitinib was held (d 137 post-transplant) and 1 mg am/0.5 mg pm BID prednisone dosage was reduced to 20 mg/d q At d 300, patient still in CR

Therapy Modi cations Therapy • 3 wk later, ruxolitinib was restarted at 5 mg/d to ruxolitinib (per protocol); prednisone continued at 10 mg/d

Access the activity, “Innovative Therapies in Post-Transplant GVHD: Personal Insights From the Patient CaseBook,” at www.peerview.com/GVHD19. PRACTICE AID Managing cGVHD A Patient CaseBook for Clinicians

Case 5: Barney

46-Year-Old Man With ALL

• Patient underwent myeloablative matched related donor PBSCT • Received GVHD prophylaxis with tacrolimus + Mtx Patient • Beclomethasone and budesonide administered for GI symptoms in rst History 100 d for nausea and anorexia • Patient was followed regularly and managed on tacrolimus, budesonide, beclomethasone, and prednisone with no cGVHD for ≈16 mo • On d 518, new onset of mild oral cGVHD was diagnosed (NIH grade 1), which worsened to cutaneous GVHD grade 2 and edema in the extremities by d 660

Treatment q Options Ibrutinib or clinical trial

Treatment Recommendations

ü Patient was started on ibrutinib 140 mg/d and dose increased to 280 mg/d at 4 wk

For Date Re ll times

• At 3-mo follow-up, no improvement in symptoms q Low-dose IL-2 noted with ibrutinib; patient was potentially getting q Patient counseling for worse (eyes NIH grade 2, mouth NIH grade 1, skin enrollment in a clinical trial NIH grade 3 [with sclerosis and fasciitis]) q Another JAK inhibitor • Patient was enrolled in a clinical trial of KD025, a (baricitinib or itacitinib) ROCK-II inhibitor; patient had progressive GVHD q Anti–CSF-1 MoAb

Assessment/ Assessment/ • Received sequential treatment with ECP, rituximab, (SNDX-6352) and ruxolitinib (increasing doses) with no q T-cell costimulation Therapy Modi cations Therapy improvement in symptoms blocker (abatacept) Further Treatment Options Treatment Further aGVHD: acute graft-versus-host disease; ALL: acute lymphocytic ; AML: acute myeloid leukemia; ATG: anti-thymocyte globulin; BID: twice a day; cGVHD: chronic graft-versus-host disease; CMV: cytomegalovirus; CNI: calcineurin inhibitor; CR: complete remission; CR2: second complete remission; CSF-1: colony-stimulating factor 1; D/R: donor/recipient; ECP: extracorporeal photopheresis; GVHD: graft-versus-host disease; HLA: human leukocyte antigen; IL-2: interleukin-2; JAK: Janus kinase; MDS: myelodysplastic syndrome; MMF: mycophenolate mofetil; MoAb: monoclonal ; MRD: minimal residual disease; Mtx: methotrexate; NIH: National Institutes of Health; NMDP: National Marrow Donor Program; PBSC: peripheral blood stem cell transplant; QD: every day; RIC: reduced intensity conditioning; ROCK-II: Rho-associated coiled-coil kinase 2; Treg: regulatory T cells; URD: unrelated donor. Access the activity, “Innovative Therapies in Post-Transplant GVHD: Personal Insights From the Patient CaseBook,” at www.peerview.com/GVHD19.