Management of Steroid Resistant Acute and Chronic GVHD: Are We Making Progress?

Management of steroid resistant acute and chronic GVHD: Are we making progress?

Jose F. Leis, M.D., Ph.D. Associate Professor of Medicine Mayo Clinic Objectives

• Review initial management of acute GVHD • Discuss new and emerging therapies for steroid resistant acute GVHD • Understand the importance of biomarkers in risk stratification and clinical trial development for acute GVHD • Review current concepts in management of steroid-resistant chronic GVHD

General comments regarding management of acute GVHD

• Corticosteroids remain 1 st line of therapy • Suboptimal response rates 40-60% • Response decreases with increasing severity of disease • For steroid-resistant pts long-term prognosis is poor with mortality rates 70-80% • Response rates to 2 nd -line treatment is low • No 2 nd -line treatment has been proven to be superior to another

Hill, Ther Adv Hematol, 2018 Is GVHD always bad?

Horowitz , Blood 75, 555 (1990). GVHD helps control disease but at a cost!

GVHD Relapse or progression Overall mortality HR 95% CI p HR 95% CI p No GVHD 1.0 1.0

Acute 0.92 0.7-1.2 0.48 1.09 0.9-1.4 0.48 GVHD grade 2 Acute 0.63 0.4-1.0 0.06 3.0 2.3-3.9 <.0001 GVHD grade 3-4 Chronic 0.55 0.4-0.8 0.0002 1.10 0.9-1.4 0.42 GVHD after acute GVHD Denovo 0.46 0.3-0.7 <.001 0.88 0.7-1.1 0.32 chronic GVHD

R. Storb, J Clin Oncol 31, 1530 (2013) GVHD helps control disease but at a cost!

R. Storb, J Clin Oncol 31, 1530 (2013) Factors that influence initial management of acute GVHD • Prophylactic regimen used • Sites (organs) involved • Severity of symptoms • Concurrent infections • Underlying disease • aGVHD and GVT may be caused by same cells Stage and grade of acute GVHD Initial management of acute GVHD

• Optimize prophylactic agent • Grade I • < 50% skin involvement • High-potency topical steroids bid • Grade II-IV • Systemic oral/IV glucocorticoids • Methylprednisolone 1-2mg/kg/d • GI tract involvement • Oral non-absorbable steroids • Beclomethasone/budesonide

Martin, Recommendations of ASBMT, BBMT, 2012 Do higher doses of steroids improve outcome?

A: 6MPred dose 2mg/kg/d A: pts responding to 2mg/kg/d B: 6MPred 10mg/kg/d @ day5, taper B: required increased steroids

Van Lint, Blood, 1998 Does addition of other agents to steroids improve outcomes in acute GVHD

• BMT-CTN randomized 4 arm phase II trial

• A: day 56 CR rates; B: 9 month overall survival rates Alousi, Blood, 2009 Does addition of other agents to steroids improve outcomes in acute GVHD

• Mycophenolate (MMF) + MP 2mg/kg/d most promising combination • CTN 0802 trial: multicenter phase III, double blind • Steroids + placebo vs. steroids + MMF • Closed early due to futility

DFS OS

Bolanos-Meade, Blood, 2014 Addition of other agents to steroids generally do not improve outcomes in aGVHD

• Horse ATG + prednisone vs prednisone • Addition of horse ATG resulted in inferior overall response and 6 mo survival • Daclizumab (anti-CD25) + prednisone vs prednisone • No difference in response rates, 6 month survival was inferior with addition of antibody • Etanercept (TNF α blockade) + prednisone vs prednisone • Improved response rate, superior 6 mo survival • Infliximab (TNF α blockade) + prednisone • Equivalent response rates, equivalent 6 mo survival

Couriel, Blood. 2004; Patriarca, Haematologica, 2004; Pidala, BBMT , 2009; Lee, Blood, 2004; Cragg, BBMT, 2000; Levine, Blood, 2008 Use of non-absorbable steroids can spare use of prednisone and improve outcome in aGVHD of GI tract • 129 pts with biopsy-proven GVHD GI tract • Randomized 10 days prednisone + beclomethasone or placebo • Rapid prednisone taper if response at D10

Hockenbery, Blood, 2007 Initial management of acute GVHD

• Steroids remain standard initial therapy for grade II-IV aGVHD • Complete response rates 25-50% • Optimal dose 1-2mg/kg/day • Retrospective 1mg/kg/d does not compromise outcome (Mielcarek, Blood, 2009) • Randomized: no difference in toxicity, relapse, NRM, OS • Progressive disease by day 5 or failure to respond by day 7 defined as refractory/resistant disease

Martin, Recommendations of ASBMT, BBMT, 2012 Impact of response to first-line therapy on outcome

Treatment related mortality Overall survival

Van Lint, Blood, 2006 Agents used for treatment of steroid resistant aGVHD

• Mycophenolate (MMF) • Etanercept • Recombinant human TNF-a receptor • Pentostatin • Sirolimus • JAK1/2 inhibitors • Ruxolitinib, Itacitinib (selective JAK1) • Extracorporeal photopheresis (ECP) • Antithymocytic globulin (ATG) Agents used for treatment of steroid resistant aGVHD

• Interleukin-2 receptor antibodies • Daclizumab, basiliximab, inolimomab • Alemtuzumab • Tocilizumab • Mesenchmal stromal cells (MSCs) Response to select 2 nd line agents

Treatment Response Disadvantages rate Photopheresis 70-80% Time commitment, need for central line Alemtuzumab (anti- 50-83% High infectious risk CD52) Infliximab 15-63% Moderate infectious risk Daclizumab (anti- 50-54% High infectious risk CD25) Mycophenilate mofetil 49-76% GI toxicity, decreased blood counts Sirolimus 76% Elevated triglycerides Pentostatin 63% Increased risk of late infections Tocilizumab (anti-IL- 76% Hepatic toxicity, exacerbation of 6R)` viral infections Ruxolitinib • JAK signaling contributes of inflammation and tissue damage • Act as transcription factors for proinflammatory genes • JAK inhibition impairs differentiation and function of dendritic cells • JAK1/2 inhibition increases Tregs in mouse model • In MPD patients decreased Th1, Th17, Tregs, and NK cells reported • Increased risk opportunistic infections • CMV, toxoplasmosis, mycobacterial, crypto Ruxolitinib • Multicenter retrospective study • 54 pts SR-aGVHD (grades III/IV) • Dose 5-10 mg bid • ORR 81.5%, CR 46.3%, med time to response 1.5 weeks (1-11w) • 6 month OS 79%, only 3/44 relapsed • CMV reactivation (33%), cytopenias • Withdrawal syndrome (SIRS-like) seen in myelofibrosis • taper

Zeiser, Leukemia, 2015 Clinical response and decreased T cells and cytokines to ruxolitinib Fig1

Fig2

Zeiser, Leukemia, 2015 Extracorporeal photopheresis

• Apheresis collected PB lymphocytes incubated with 8-methoxypsoralen, UV-A irradiated and infused • Mechanism of action unclear: increases T regs, down regulates activated T cell clones and decreases circulating dendritic cells • Evidence limited to nonrandomized single- institution prospective trials, retrospective data, or small case series ECP is steroid sparing and can induce CR in acute GVHD

Cutaneous Only

Greinix, Blood, 1998 and 2000 Meta-analysis of ECP for GVHD

• nine studies, including 1 randomized controlled trial, met inclusion criteria, with a total of 323 subjects. • overall response rates (ORR) were .69 (95% confidence interval [CI], .34 to .95) and .64 (95% CI, .47 to .79) for acute and chronic GVHD • pooled ORR for cutaneous in 5 studies (103 patients) was .84 (95% CI, .75 to .92), gastrointestinal in 5 studies (45 patients) was .65 (95% CI, .52 to .78), and hepatic in 5 studies (38 patients) was .55 (95% CI, .35 to .74)

Abu-Dalle, BBMT, 2014 UK consensus statement on ECP

• aGVHD responds rapidly to an intense weekly treatment schedule for 8 weeks • allows steroids to be discontinued without relapse • maintenance ECP generally not required • responses are excellent in a subset of patients • not immunosuppressive and has no reported drug interactions • does not have a negative impact on the graft- versus-malignancy effect of the transplant

Das-Gupta, BMT, 2014 Antithymocyte globulin (ATG)

• Original report from Seattle suggested 60% pts with grade II improved with ATG • Randomized ATG vs. methyprednisolone • More responders in steroid group • ATG few responses in GI tract and liver • ATG + CSA +/- methylprednisolone • Triple therapy lower OS • Increased infectious complications • JHU group: SR-GVHD, median OS 4.1 months grade 2, 3.6 months grade 3, 2.7 months for grade 4 • Only 5% of the deaths were due to relapse, with the remaining deaths due to GVHD, infection, and/or organ failure

Storb, Blood, 1974; Doney, Am J Hematol, 1981; Deeg, Transplantation, 1985; Arai, BBMT, 2002 Antithymocyte globulin (ATG)

• Karolinska: 29pts, grade II(4), grade III(13), grade IV(12) • Different ATG preps • ORR skin 72%, GI and liver 38% • 12% alive at 1 year, most died GVHD and infection • “ATG adds nothing…” • U of Minn: 79 pts, 34 MRD, 45 URD (31 partially matched) • Defined SR-aGVHD: PD after 4 days, no improvement after 7 days • 43% Grade III/IV • ORR 54%, 20% CR (skin > GI, liver) • 1 year OS 32% • Early ATG improves outcome

Remberger, Clin Transplant, 2001; MacMillan, BBMT, 2002 Mycophenolate mofetil (MMF)

• prospective study of acute GVHD, 9 of 19 patients (47%) had response, 10 (53%) had no response • OS 6 and 12 months after the start of MMF was 37 and 16% • retrospective study of acute GVHD, 14 of 29 patients (48%) responded and 15 (52%) had no improvement • Survival at 6 and 12 months was 55 and 52%

Furlong, BMT, 2009 Potential of Biomarkers for GVHD

• Severity of symptoms at onset of GVHD does not accurately define risk • Allow for better risk stratification at the onset of the GVHD clinical signs • Identify patients at high risk for morbidity and mortality could permit tailored treatment plans and early initiation of additional immunosuppressive treatment • Identify low-risk patients who will respond well to steroid treatment and allow more rapid tapering of steroid regimens to reduce long-term toxicity, infections, and a loss of the graft versus tumor effect Levine, Lancet Haematol, 2015 Biomarkers for acute GVHD

• Ann Arbor GVHD Score: Used concentrations of 3 validated biomarkers (TNFR1, ST1, Reg3 aaa) to create an algorithm to compute NRM 6 months after SCT • Predicted response to primary GVHD treatment within 28 days: 86% score 1, 67% score 2, 46% score 3 • Cumulative incidence of 6 month NRM increased with score: 8% score 1, 27% score 2, 46% score 3 (p<0.0001)

Levine, Lancet Haematol, 2015 Ann Arbor Risk Score for aGVHD

Levine, Lancet Haematol, 2015 How are biomarkers being used

• BMT CTN 1501 • aGVHD Standard risk by refined Minnesota criteria and Ann Arbor 1 and 2 • Randomized between prednisone 2mg/kg/d vs. sirolimus • Natalizumab Plus Standard Steroid Treatment For High Risk Acute GVHD ( ClinicalTrials.gov: NCT02133924) • Early intervention with natalizumab + steroids in Ann Arbor 3 aGVHD • Humanized monoclonal antibody against aaa4- integrin (cell adhesion molecule) • Mediates homing of lymphocytes to GI tract. Management of steroid-resistant chronic GVHD Acute, late acute, chronic overlap, and classic chronic GVHD. The box sizes do not reflect prevalence.

Stephanie J. Lee Blood 2017;129:30-37

• Diagnosis based on clinical features not timing of onset • Single most important factor affecting long-term QOL in allogeneic transplant patients • skin, liver, gastrointestinal tract, and lungs are the principal target organs • Patients report adverse general health, mental health, functional impairments, activity limitation, and pain • 458 patients: Skin 67%, mouth 60%, liver 52%, lung 50%, eyes 48%, joints/fascia 48% GI 30%, genetalia 12% Jacobsohn, Blood, 2012

Chronic GVHD: Diagnostic Features • Skin: • Poikiloderma • Lichen planus like features • Sclerotic features • Morphea like features • Lichen sclerosus like features • Mouth: • Lichen type features • Hyperkerotitic plaques, restriction of mouth from opening from sclerosis

Filipovich, BBMT, 2005 Chronic GVHD: Diagnostic Features

Lichen Planus

Courtesy Dr. Jeanne Palmer Chronic GVHD: Diagnostic Features

Courtesy Dr. Jeanne Palmer Chronic GVHD: Diagnostic Features • Genitalia • Lichen planus like features • Vaginal stenosis • GI: • Esophageal web • Strictures or stenosis in the upper to mid third of the esophagus • Lungs: • Bronchiolitis obliterans syndrome diagnosed by lung biopsy • Muscles, fascia, joints • Fasciitis • Joint stiffness or contractures due to sclerosis

Filipovich, BBMT, 2005 Chronic GVHD: Diagnostic Features Band-like deep dermal Rippling and sclerosis presenting in a “cellulite” linear appearance in the pattern. axillae produced by subcutaneous septal fibrosis.

Courtesy Dr. Jeanne Palmer Scoring Chronic GVHD

• Mild disease • one or two organs (except lung) with score 1 • Moderate disease • 3 or more organs with score 1 or lung score 1, or one or more organs with score 2. • Severe disease • any organ with a score 3 or lung score 2 or progressive GVHD

Filipovich, BBMT, 2005 Initial Management of chronic GVHD

• Systemic corticosteroids for moderate to severe disease (0.5-1mg/kg/d) • Site directed therapy • Skin: sun protection, topical steroids, stretching exercises • Mouth: topical steroids, fluorides • Eyes: tear duct plugs, artificial tears, topical CSA/tacrolimus, gas permeable scleral lenses • Vaginal: topical steroids, estrogens, GYN eval • Pulmonary: bronchodilators, inhaled steroids, pulmonary rehab Majority of patients with cGVHD fail initial therapy

• 575 patients: prospective observational trial, clinician reported response

Palmer, Blood, 2016 Schematic overview of the cellular and molecular mediators, known and implicated, contributing to the continuum of aGVHD and cGVHD pathology.

Kelli P. A. MacDonald et al. Blood 2017;129:13-21

Cooke, BBMT, 2017 Mechanistic approach to treatment of chronic GVHD

Cutler, Blood, 2017 2nd line treatment of cGVHD

• After steroids fail, no current consensus on an optimal second-line treatment choice • Retrospective and prospective studies suggest high response rates with 2 nd -line treatment options • Few complete responses • Failure common • Treatment choice often based on: • Physician experience • Convenience • Toxicity profile Response to 2 nd line treatment of chronic GVHD

Therapy Response Comments CNI (tacrolimus, 35-40% Potential benefit if added to cyclosporine) steroids initially ECP 50-65% 30-35% CR, 25-35% taper mycophenolate 50-75% Oral, did not improve initial mofetil response vs. steroids alone Sirolimus 56-80% Oral Hydroxychloroquine 50% Oral

Pentostatin 55% 1 year OS 78% Low dose IL-2 50-61% Daily injection, no CR, Tregs

Imatinib 36-80% Few CR, 40-50% sparing Ritixumab 27-86% Best for skin, oral, MSK Ruxolitinib 50-85% Oral, 35/41 responded

Ibrutinib 67% Oral, 21% CR, bleeding/infection risk ECP may improve outcome of patients with bronchiolitis obliterans(BO)

• Meta-analysis showed 64% ORR for cGVHD • skin > GI tract > liver • Mayo Clinic 1261 consecutive allogeneic SCT • 75 developed BO • 28 received ECP, 47 treated without ECP • Multivariable model: higher FEV1 at onset ECP, slower decline FEV1 before ECP, and use of ECP associated with better OS • ECP stabilized FEV1 and associated with survival benefit independent of PFT responses • Infections and respiratory failure most common cause of death

Langer, ASBMT Tandem Meeting 2018, S48 Ruxolitinib for chronic GVHD

• Retrospective, multicenter survey of 95 patients who received ruxolitinib as salvage therapy for steroid-refractory GVHD • Included 41 patients with chronic GVHD (all moderate to severe) • ORR: 85.4% (35/41) • Rate of chronic GVHD relapse among responders: 5.7% • At 1-year follow-up: 36% (13/36) • 6-month survival: 97.4% (95% CI, 92.3%-100%) • 1-year OS: 92.7% (95% CI, 84.7%-100%) • 24% of patients have ongoing response and are free of any immunosuppression

Zeiser, Leukemia. 2015; Zeiser, Blood. 2016;128:4561 JAK inhibitors actively being studied in a & cGVHD

• JAK tyrosine kinases regulate signal transduction of multiple cytokines which modulate T cell function and GVHD • JAK2 (with JAK1, Tyk2) control proinflammatory IL-6, IL-12, IL-23, IFN-g • JAK1,3 regulate IL-2, IL-7, IL-15 required by Tregs, cytotoxic T cells, NK cells

MacDonald, BBMT, 2018 B cell role in development of chronic GVHD

• Acute GVHD mediated almost entirely by donor T cells • B cells and the production of autoantibodies appear to play key roles in chronic GVHD • critical breakdown in peripheral B cell tolerance in patients with cGVHD • failure of normal B cell tolerance checkpoints • due to high levels of BAFF • persistence of donor B cells reactive to a variety of recipient antigens • secretion of pathologic allo- and autoantibodies

Sarantopoulos, BBMT, 2015 Rituximab for treatment of cGVHD

• 21 patients steroid-refractory cGVHD • Rituximab 375 mg/m2/week for 4 weeks • Best responses skin and musculoskeletal

Cutler, Blood, 2006 Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD

• hypothesized that posttransplant B cell depletion could prevent the occurrence of chronic GVHD • 65 patient phase 2 trial of rituximab (375 mg/m(2) IV), administered at 3, 6, 9, and 12 months after transplantation • incidence of cGVHD and systemic steroid- requiring GVHD at 2 years from transplantation was 48% and 31% • concurrent control cohort (60%, P = .1, and 48.5%, P = .015) • TRM at 4 years lower (5% vs 19%, P = .02), and OS superior at 4 years (71% vs 56%, P = .05)

Cutler, Blood, 2013 Rituximab and imatinib yield low response rates in sclerotic chronic GVHD

• Highlights importance of conducting larger multicenter studies to evaluate promising results from smaller studies • higher percentage of activated B cells (CD27 +) before treatment in the rituximab patients who had treatment success

Aria, Clin Cancer Res, 2016 Ibrutinib for chronic GVHD

• irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) • inhibits the activation of B-cells, specific T- cell subsets, and certain myeloid cells that are implicated in cGVHD • selectively inhibits cGVHD pathogenic pre- germinal center B-cells and Tfh cells, while preserving immune memory and Th1 T-cells • FDA approved for various lymphoid malignancies (CLL, Mantle cell NHL, marginal zone NHL, Waldenstrom’s) and now chronic GVHD

Byrd, NEJM, 2013; Miklos, Blood, 2016;128: Abs LBA-3; Sahaf, Blood, 2017; 130: Abs 4481 Ibrutinib for chronic GVHD

• 42 patients steroid-dependent/resistant cGVHD • Received ibrutinib 420mg/d until progression • Ibrutinib resulted in clinically meaningful and sustained responses in patients who have failed at least 1 prior treatment for chronic GVHD • ORR of 67% • 71% had a sustained response at least 20 wk • response rates across all affected organs • Patients with multiple organ involvement generally showed responses in >2 organs • Reduction in steroids in 2/3 patients • Improved QOL Miklos, Blood, 2016;128: Abs LBA-3 Ibrutinib for chronic GVHD

Miklos, Blood, 2016;128: Abs LBA-3 Ibrutinib toxicity in chronic GVHD patients

• Fatigue 57% • Diarrhea 36% • Muscle spasms 29% • Nausea 26% • Bruising 24% • Serious AEs in 52% • > 3 in 40% • 2 deaths from multilobar pneumonia • No atrial fibrillation reported

Miklos, Blood, 2016;128: Abs LBA-3 Biomarkers for chronic GVHD

• Development for biomarkers for cGVHD has lagged behind • International workshop 3/2017 priorities • Development prognostic biomarkers for subsequent moderate/severe cGVHD • Development clinical-grade assays for biomarker quantification • Most promising prognostic biomarkers • Serum: CXCL9, ST2, matrix metalloproteinase-3, osteopontin, CXCL10, CXCL11, CD163 • Cellular subsets: CD4+ T-cell and NK cell subsets, CD19+CD21 low B cells

Wolff, BMT, 2018 BMT Tandem 2018 abstracts of note

• KD025 for steroid dependent cGVHD • Selective ROCK2 inhibitor, downregulates Th17, Tfh, and upregulates Tregs • ORR 57% and steroid/tacrolimus reduction (Lazaryan, S38) • Low-dose IL-2 induces Treg expansion and increases Treg reportoire diversity and clonality (no change in Tcon and CD8 T cells) (Whangbo, S39) • Low-dose IL-2 suppresses T follicular helper cells and induces expansion, activation, and function of T follicular regulatory cells (Kamihara, S40) • IL-2 promotes both B and T tolerance in cGVHD • Ibrutinib selectively inhibits cGVHD pathogenic pre-germinal center B-cells and T follicular helper cells while preserving immune memory and Th1 T-cells (Sahaf, S2)

Tandem abstracts, BBMT, 2018 Biology of GVHD will guide clinical trials of the future

Kelli P. A. MacDonald et al. Blood 2017;129:13-21 Conclusion • Responses to primary therapy with steroids for acute and chronic GVHD often suboptimal • High risk side effects • Second-line treatments have low response rates resulting in poor outcomes • Our understanding of the biology of a/c GVHD and biomarkers are allowing for better risk stratification and targeted treatments • Enrollment in clinical trials is essential Mayo Clinic

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