The International Congress of BMT 2017 COI disclosure Name of author : Byong Sik Cho I have no personal or financial interests to declare: I have no financial support from an industry source at the current presentation.
Novel therapeutic approaches to GVHD prophylaxis The International Congress of BMT 2017 Catholic BMT Center Byoung Sik Cho, MD & PhD Aug-25-2017 Catholic BMT Center Catholic BMT Center
Introduction Graft-versus-host disease (GVHD) syndrome after allo-hsct Acute GVHD: rash, GI, liver Chronic GVHD: skin, eyes, mouth, GI liver, musculoskeletal, lungs, GU
Introduction Occurrence of GVHD Catholic BMT center: 2002~2012, AML with CR1, Intermediate & adverse-risk N=457 GVHD prophylaxis ATG agvhd grade II agvhd grade III-VI cgvhd cgvhd Mod, Sev MSD (n=252) CS/MTX No 34.6 8.7 55.2 34.4 WM-UD (n=112) FK/MTX 0 ~ 2.5 mg 47.3 6.3 45.8 27.8 PM-UD (n=41) FK/MTX 2.5 mg 48.8 29.3 41.5 22 FMT (n=52) FK/MTX 5.0 mg 35.6 15.4 56.3 27.3 P value - 0.021 <0.001 NS NS agvhd grade III-IV cgvhd Mod & Sev by Yoon JH
Introduction GVHD significantly impacts on non-relapse mortality EBMT data: a large homogeneous group of 14,403 patients transplanted for early leukemia from an HLA-identical sibling donor Nonrelapse mortality Gratwhol A et al. 2005 BMT
Introduction agvhd pathophysiology (3 step model) Phase 1 : Transplant conditioning and inflammation Phase 2 : Donor T-cell priming and differentiation Phase 3 : The effector phase Markey et al. Blood 2014
Introduction Factors contributing to the continuum of agvhd & cgvhd pathology Kelli P et al. Blood 2017
Potential new therapeutics Introduction Potential new therapeutics for GVHD prevention T cells Stem cell graft engineering - CD34 selection - Ex vivo naïve-t or -T cell depletion ATG or Post-transplant cyclophosphamide (PTCy) Inhibit T cell signaling - abatacept, bortezomib Tregs Adoptive transfer of Tregs - Purified donor Treg, ex vivo expanded Treg, Ag-specific Treg Treg-sparing therapy - sirolimus, MMF, ruxolitinib, bortezomib In vivo Treg expansion: low-dose IL-2 or ECP B cells B cell depletion in vivo - rituximab, ofatumumab, obinutuzumab Inhibiting B cell activation - Syk, BTK, Rho-associated kinase, JAK-1 - Final stage of aberrant B-cell response (proteosome inhibition)
I. Standard strategies Calcineurin inhibitor (CNIs) based regimen Backbone of most T-cell replete transplantation CNIs+ MTX or MMF (NMT or UCB) Cyclosporin (Vogelsang et al. Medicine 1988) Interfering calcium-dependent signal transduction pathway downstream of the TCR Tacrolimus (Ratanatharathorn et al. Blood 1998) Methotrexate (MTx, Thomas et al. Blood 1971) Interfering with purine synthesis Inhibition of IL-2 and other cytokine Reduced function of T cells Choi and Pavan. Nat Rev Clin Oncol 2014, Holtan et al. Blood 2014
I. Standard strategies Sirolimus Feasibility Phase I-II trial (Antin JH et al. Blood 2003) Sirolimus+Tacrolimus+MTX Phase II trial (Cutler C et al. BBMT 2004) Sirolimus+Tacrolimus Phase III trial (Cutler C et al. ASH 2012; a739) Sirolimus+Tacrolimus vs. MTX+Tacrolimus Failed to show benefit, but less mucositis Sources #NCT01428973 #NCT02728700 #NCT01251575 #NCT03018223 Currently active trials Minitransplants With HLA-matched Donors : Comparison Between 2 GVHD Prophylaxis Regi mens: FK/MMF vs. FK/Sirolimus Sirolimus and Mycophenolate Mofetil in Preventing GVHD in Patients With Hematologic Malignancies Undergoing HSCT Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients With Hematologic Malignancies Undergoing Donor Peripheral Blood Stem Cell Transplant Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT (PTCy+Sirolimus+MMF)
II. T-cell depletion Ex vivo T-cell depletion (TCD) Role of Donor T cells Pros Promoting the establishment of donor hematopoiesis Transferring pathogenspecific immunity Mediating GVL effects Cons Central to the development of GVHD Im HJ et al. Blood Res 2016, Vadakekolathu J et al. Biomedicines 2017
II. T-cell depletion Ex vivo T-cell depletion: TCR- /CD19 depletion Mostly in pediatric haplo HSCT setting Different additional prophylaxis regimens against GVHD Blood BBMT EBMT BMT ASH Hematology ASBMT Different strategies for post-hsct GVHD prophylaxis in all studies: italian group[83]: no post-hsct GVHD prophylaxis ATG used as a part of conditioning in all studies Abdelhakim J et al. Biomedicines 2017
II. T-cell depletion Ex vivo T-cell depletion: TCR- /CD19 depletion Prospective phase II Italian study: Children with acute leukemia, haplo HSCT with MAC (n=80) MAC, Haplo (n=80) ATG at D-5 to D-3 (12 mg/kg) & no post-hsct GVHD prophylaxis Rituximab (200 mg/m2) at D-1 Graft failure: 2% (2/80) agvhd: 30% - grade I or II, only skin cgvhd: 5% - only limited type Locatelli F et al. Blood 2017
II. T-cell depletion Ex vivo T-cell depletion techniques: TCR- /CD19 depletion Mainly European centers, and a few pediatric USA centers Mostly pediatric haplo setting Lack of comparative studies with other approaches or in other settings Abdelhakim J et al. Biomedicines 2017
II. T-cell depletion Ex vivo T-cell depletion: naïve T cell depletion Naïve: CD45RA+CD62L+: severe GVHD Effector: short lived Memory subsets: less or no GVHD - transfer antipathogen immunity and GVL activity i) central memory (CD45RO+CD62L+): milder GVHD ii) effector memory (CD45RO+CD62L-): no GVHD iii) tissue-resident memory (CD45RO+CD62L-CD69+) Paul JM. Blood 2013
II. T-cell depletion Ex vivo T-cell depletion: naïve T cell depletion Prospective phase II: the first human trial for naïve T cell depletion Adults, MAC, MRD (n=35) No ATG Tacrolimus monotherapy CD34+ enriched cell followed by CD45RA-depleted cells Graft failure: no, preserve immune reconstitution Bleakley M et al. JCI 2015
II. T-cell depletion ATG (Anti-thymocyte globulins) Rabbit ATG ATG-Fresenius (T-lymphophoblastic Jurkat cell line) ATG-Sangstat (human thymus lymphocytes) Horse ATG: ATGAM (human thymus lymphocytes) The polyclonal nature of Thymoglobuline: diverse effects on the immune system: 1 2 3 T-cell depletion in blood and peripheral lymphoid tissues Apoptosis in all B-cell lineages Modulation of key cell-surface molecules (adhesion and chemokine receptors) that mediate leukocyte/endothelium interactions 1 2 Interference with dendritic cell functional properties Induction of Tregs / NKT cells Thymoglobuline provides multifaceted immunomodulation Mothy. Leukemia 2007
II. T-cell depletion ATG Some progress in preventing agvhd, but not cgvhd Bacigalupo et al. Blood 1991;77:1423 Kansu et al. Blood 2001;98:3868 Sullivan et al. BBMT 1996;2:44 Reduction of severe agvhd and cgvhd: unrelated donor ATG-Fresenius: Finke et al Lancet Oncol 2009;10:855 ATG-Sangstat: Bacigalupo et al. Blood 2001;98:2942 Reduction of agvhd and cgvhd: unrelated donor, MA/NMA ATG-Sangstat: Walker et al. Lancet Oncol 2016;17:164 Reduction of severe agvhd and cgvhd: sibling donor, MA, PB ATG-Fresenius: Kroger et al. NEJM 2016;374:43 ATG-Sangstat:?
II. T-cell depletion ATG: Meta-analysis of 9 RCTs (n=1089) No difference in relapse, infection, 1-year OS, 1-year DFS Less 100-day NRM in ATG group (P=0.05) agvhd cgvhd Yuan et al. Oncotarget 2017
II. T-cell depletion ATG: Matched sibling, MA, PBSC, acute leukemia at remission (RCT) ATG-Fresenius at a dose of 10 mg/kg on D-3, D-2, and D-1 (n=168) No difference in relapse, NRM, OS and DFS Kroger at al. NEJM 2016
II. T-cell depletion ATG: Matched sibling, MA(Flu/Bu4), AML CR1, EBMT (n=566) ATG (n=145) vs. no ATG (n=421) Mainly PB (83%), ATG-Sangstat [95%, mean 5 (2.5~15.8) mg/kg] Rubio at al. J Hematol Oncol 2017
II. T-cell depletion ATG: Matched sibling, MAC(Flu/Bu4), AML CR1, EBMT (n=566) ATG group: Improving Leukemia-free and overall survival Rubio at al. J Hematol Oncol 2017
II. T-cell depletion ATG dosing & schedule: MAC, FMT (n=224), RCT ATG-Sangstat (D-5 to D-2) : 6 mg (n=112) vs. 10 mg (n=112) Primary endpoints: occurrence of grade III to IV agvhd: no difference Comparable NRM, CIR, and DFS Infection-related deaths: 7.1% vs. 14.3% (P=0.084) Chang at al. Cancer 2017
II. T-cell depletion PTCy (post-transplantation cyclophosphamide) Induction of tolerance by PTCy: 3-step scheme Selective destruction of proliferating alloreactive donor and recipient T cells Increased Tregs (through the expression of aldehyde dehydrogenase) Delayed but long-lasting intrathymic clonal deletion of anti-host T cells Al-Homsi at al. BBMT 2015, Roberto et al. Blood 2015
II. T-cell depletion PTCy (post-transplantation cyclophosphamide), ongoing trials Al-Momsi at al. BBMT 2015
II. T-cell depletion T cell co-stimulatory blockade Abatacept (CTLA4-Ig): approved for rheumatoid arthritis In vivo CD28:CD80/86 costimulation blockade Adding abatacept to CS/MTX for URD Koura DT et al. BBMT 2013;19:1638 Significant inhibition of early CD4+ T cell proliferation and activation Grade II-IV agvhd: 20% (2 of 10) Phase II multicentre, randomized, double blinded RCT (#NCT01743131) is ongoing Choi and Pavan. Nat Rev Clin Oncol 2014
III. Regulatory T cells Adoptive transfer of Treg Preclinical data Regulator of self-tolerance & critical in immune tolerance to alloantigen Edinger M et al. NEJM 2003;9:1144 Clinical trials Suppress the early expansion of alloreactive donor T cells and limit the capacity to induce GVHD without an effect on GVL effect Feasibility Treg from umbilical cord unit (Phase I study) Brunstein CG et al. Blood 2011;117:1061 URD setting, Treg from umbilical cord unit, ex vivo expansion Grade II-IV agvhd: 43% (vs. 61% in historical controls) Co-infusion with conventional T cells DL lanni M et al. Blood 2011;117:3921 Haplo setting, co-infusion with conventional T cells Minimized lethal agvhd, no cgvhd, but 4 infection deaths
III. Regulatory T cells Adoptive transfer of Treg Hurdles for clinical applications Complex methods for cell purification and expansion Functional stability of transferred Tregs Persistence of adoptively transferred Tregs Sources Blood 2015;125:1502 #NCT02423915 #NCT01795573 Currently active trials Treg fucosylation to improve engraftment and homing of Tregs Fucosylated T cells for GVHD prevention Phase I Trial of Ex-vivo Expanded Donor Regulatory T Cells for Prevention of Acu te Graft-Versus-Host Disease (coculture with dentritic cells) #NCT02991898 Treg Cell With IL-2 to Suppress agvhd Umbilical Cord Blood Transplantation
IV. Targeting B cells Rituximab Meta-analysis (3 prospective, 7 retrospective, n=111) Response rates Skin: 13%~100% Oral: 0~83% Liver: 0~66% Lung: 0~38% Dose reduction of IST Prospective, multicenter, phase II (n=37) 375 mg/m 2 weekly 4 doses monthly 4 doses ORR 86% Musculoskeletal (100%), skin (77%), oral (71%), liver (44%), eyes (43%) Kharfan-Dabaja et al. BBMT 2009, Kim et al. Haematologica 2010
IV. Targeting B cells Rituximab prophylaxis Pre- or peri-transplant rituximab in B-cell malignacies agvhd: a prophylactic effect for agvhd cgvhd: not conclusive Blood 2008;111:5530, BJH 2009;145:816, BBMT 2009;15:671, Exp Hematol 2011;39:892, BMT 2012;47:101 Stanford Group (Arai et al. Blood 2012) Rituximab 375 mg/m 2 two months after transplantation (n=33) Lymphoid malignancies received TLI and ATG agvhd 6%, cgvhd 20%, NRM 3% Complete prevention of alloreactive H-Y Ab development
IV. Targeting B cells Rituximab prophylaxis, phase II (n=65) 375 mg/m 2 at 100 days, and 6, 9, 12 months after PBSCT Various malignancies, compared to historical controls Safe, not associated with excess infections Reduction in requirement of systemic corticosteroid and NRM Cutler at al. Blood 2013
V. Chemo-cytokine antagonists Emerging therapies for GVHD prophylaxis Inhibition of IL-2 and other cytokine Choi and Pavan. Nat Rev Clin Oncol 2014
V. Chemo-cytokine antagonists CCR5 inhibition (Maraviroc) CCR5: HIV-1 co-receptor, Lymphocyte migration to target tissues Maraviroc: CCR5 antagonist (FDA approved for HIV) Blocks lymphocyte chemotaxis while preserving effector functions Reshef et al. NEJM 2012;367:135 (phase 1/2, RIC, n=38) Maraviroc+Tacrolimus/MTX Grade II-IV agvhd: 14.7% (at day 100) and 23.6% (at day 180)
V. Chemo-cytokine antagonists IL-6 inhibition (tocilizumab) IL-6: increased during GVHD and IL-6 blockade reduce GVHD severity Blood 2009:114:891, Clin Cancer Res 2011:17:77 Steroid refractory GVHD (BBMT 2011:17:1862) : 4/6 of agvhd, 1/2 of cgvhd Kennedy et al. Lancet Oncol 2014;15:1451 (phase 1/2, n=48) Day-1 and CS/MTX Grade II-IV agvhd (12%), grade III-IV agvhd (4%) Suppression of known pathogenic STAT3-dependent pathways NCT02206035: phase II, tocilizumab+fk/mtx
VI. Epigenetic modulators Histone deacetylase inhibition Accumulation of acetylated histone- modification in DNA accessibility Altering the patterns of gene expression At lower and noncytotoxic concentration: anti-inflammatory, immunomodulatory effect (PNAS 2002;99:2995) Preclinical studies Suppress proinflammatory cytokine production, reduce GVHD, preserve GVL modulating IDO dependent innate immune and allo-stimulating function of APCs in a STAT-3-dependent manner (JCI 2008;118:2562, JI 2009;182:5899) Enhance natural Treg function (Nat Med 2007;13:1299) Choi et al. Lancet Oncol 2014;15:87 (phase 1/2, RIC) Vorinostat: tolerogenic effects on APC and apoptotic effects on alloreactive T cells D-10~D+100 to tacrolimus and MMF-based prophylaxis Grade II-IV agvhd: 22%
VI. Epigenetic modulators Histone deacetylase inhibition Choi et al. Blood 2017, e-pub (phase 2, MAC-mURD) Vorinostat (D-10~D+100 ) to tacrolimus and MTX-based prophylaxis Grade II-IV agvhd: 22%, cgvhd 29% Clinical trials NCT02588339: Panobinostat+sirolimus+tacrolimus, phase 2 NCT02848105: Valproic acid+methylprednisolone, phase 2
VII. Novel molecular regulators Bortezomib Proteasome inhibitors (FDA approved MM and mantle-cell lymphoma) NF-kB-inhibiting immunomodulator Preclinical studies block T-cell activation, proliferation, and survival within alloreactive T cells (PNAS 2004;104:8120, Blood 2006;107:3575, 827) Increased GI-related GVHD mortality (Blood 2005;106:4293) Koreth et al. JCO 2012;30:3202 (phase 1/2, RIC-mismatch-unrelated) Days+1, +4, and +7 to standard tacrolimus/mtx, mismatched unrelated Grade II-IV agvhd: 22% / cgvhd at 1 year: 29% Following studies Bortezomib+PTCy (phase 1): Al-Homsi et al. BBMT 2015;21:1315 Bortezomib+Tacrolimus/MTX (phase 2): Koreth et al. BBMT 2015;21:1907 Bu/Flu MAC (n=34) Grade II-IV agvhd: 32% (grade III-IV 12%) / cgvhd at 1 year: 50% Clinical trials: NCT01926899 phase 1, pediatric allo-hsct
VII. Novel molecular regulators GVHD prophylaxis BMT CTN trials for optimal prophylaxis approaches Part of PROGRESS (Prevention and Reduction of GVHD and Relapse and Enhancing Survival after Stem Cell Transplant) initiative BMT CTN 1203 (phase 2) 3 novel approaches» Maraviroc + tacrolimus/mtx» Bortezomib + tacrolimus/mtx» PTCy followed by tacrolimus/mmf Reduced-intensity conditioning, murd or 1 Ag mmurd BMT CTN 1301 (3-arm phase 3) 2 approaches without calcineurin inhibitors» CD34+ cell selection» PTCy» Comparison with tacrolimus/mtx Myeloablative, HLA-matched Holtan et al. Blood 2014
Summary Developing safer strategies to prevent and treat GVHD Will expand allo-hsct to higher-risk transplant population CNIs remain the mainstay of GVHD prophylaxis, but improved understating of biology of GVHD Newer approaches are being evaluated Published studies; mostly, single center, phase I/II or II A number of ongoing studies on an international-scale In the next few years Well-designed multi-center RCTs will be imperative Necessity of comparison between promising strategies
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