Treatment Of Graft-versus-host Disease Research Articles

Inflammation-induced tissue damage mimicking GvHD in human skin models as test-platform for immunotherapeutics_suppl

Due to the rapidly increasing development and use of cellular products, there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin models from human biopsies by isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells and seeding these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. We then were able to induce inflammation-mediated tissue damage by adding pre-stimulated, mismatched allogeneic lymphocytes and/or inflammatory cytokine-containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. This could be prevented by the addition of immunosuppressants to the models. Consequently, these models harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. They also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells, which would otherwise be limited to animal models. Thus, the current test platform, developed with the limitation that no professional antigen presenting cells are in place, could greatly reduce animal testing for investigation of novel immune therapies.

Inflammation-induced tissue damage mimicking GvHD in human skin models as test-platform for immunotherapeutics.

With cellular products being on the front run there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin models from human biopsies isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells finally allowing to seed these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. Afterwards, we were able to induce inflammation-based tissue damage by pre-stimulated mismatched allogeneic lymphocytes and/or inflammatory cytokine containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. The effects could be prevented by the addition of immunosuppressants to the models. Consequently, these models would harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. This would also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells which would otherwise be limited to animal models. Thus, the current test platform developed with the limitation given that no professional APC are in place could highly reduce animal testing for investigation of novel immune therapies.

Graft-versus-host disease: new insights into disease pathogenesis

Graft-versus-host disease (GVHD) is a potentially life-threatening complication associated with allogeneic hematopoietic stem cell transplantation (allo-SCT). Although prophylaxis and GVHD treatment using immunosuppressants are essential for a successful allo-SCT, profound immunosuppression could lead to an infection and/or the recurrence of malignant diseases. Recently, the concept of tissue tolerance has emerged. This concept has been identified as a means to suppress GVHD by relying on tissue-intrinsic mechanisms that are independent from those underlying immune tolerance. Thus, GVHD prophylaxis and treatments targeting the mechanisms that promote tissue tolerance could help suppress GVHD and maintain leukocyte-mediated immune responses against tumors and infectious pathogens. Epithelial regeneration from LGR5-positive intestinal stem cells and epithelial maintenance mediated by metabolites from the intestinal microbiota are representative mechanisms that promote tissue tolerance in the gut. However, these protective mechanisms are weakened by GVHD and conditioning regimens. This review focuses on the pathophysiology of acute GVHD and tissue-intrinsic mechanisms that promote tissue tolerance.

Adverse events in second- and third-line treatments for acute and chronic graft-versus-host disease: systematic review.

Background:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased risk of graft-versus-host disease (GvHD), a strong prognostic predictor of early mortality within the first 2 years following allo-HSCT. The objective of this study was to describe the harm outcomes reported among patients receiving second- and third-line treatment as part of the management for GvHD via a systematic literature review.Methods:A total of 34 studies met the systematic review inclusion criteria, reporting adverse events (AEs) across 12 different second- and third-line therapies.Results:A total of 14 studies reported AEs across nine different therapies used in the treatment of acute GvHD (aGvHD), 17 studies reported AEs of eight different treatments for chronic GvHD (cGvHD) and 3 reported a mixed population. Infections were the AE reported most widely, followed by haematologic events and laboratory abnormalities. Reported infections per patient were lower under extracorporeal photopheresis (ECP) for aGvHD (0.267 infections per patient over 6 months) relative to any of the therapies studied (ranging from 0.853 infections per patient per 6 months under etanercept up to 1.998 infections per patient on inolimomab).Conclusion:The reported incidence of infectious AEs in aGvHD and grade 3–5 AEs in cGvHD was lower on ECP compared with pharmaceutical management.

Treatment of graft-versus-host disease

Graft-versus-host disease (GVHD) is one of the most important complications after an allogeneic hematopoietic stem cell transplantation (allo-SCT). The current National Institutes of Health's (NIH) consensus is that clinical manifestations, and not the time to symptomatic onset after transplantation, determine whether the clinical syndrome of GVHD is considered acute or chronic. In the past decade, peripheral blood stem cell transplantation from an unrelated donor can be performed in Japan. Furthermore, poor-risk patients without human leukocyte antigen (HLA)-matched donor can receive allo-SCT from HLA haploidentical donor. Therefore, severe or steroid-refractory GVHD would be increased. Corticosteroid, at a dose of 2 mg/kg, is a standard first-line therapy for acute GVHD. If there is no improvement after the first-line therapy, second-line therapy should be administered immediately. Although anti-thymocyte globulin and mesenchymal stem cells are covered by health insurance in Japan, another treatment options should be determined for steroid-refractory acute GVHD. Furthermore, severe chronic GVHD increases patients' mortality and decreases their quality of life. A number of novel drugs targeting specific biological pathways for GVHD are under development. Currently, more than 60 clinical trials are carried out for the treatment of steroid-refractory GVHD worldwide for drug approval. The accumulation of novel evidence for GVHD treatment is expected to be established.

Post-Transplant Cyclophosphamide and Thymoglobulin, a Graft-Versus-Host Disease Prophylaxis in Matched Sibling Donor Peripheral Blood Stem Cell Transplantations

Post-transplant cyclophosphamide (PTCy) has been explored in several types of stem cell transplantations (SCTs) and it proved highly effective in controlling graft-versus-host disease (GvHD) without aggravating relapsed disease. However, PTCy alone has resulted in inferior outcomes in matched sibling donor (MSD) employing peripheral blood (PB) SCTs. We hypothesized that adding thymoglobulin to PTCy would be able to control GvHD effectively. We retrospectively compared the use of standard GvHD prophylaxis encompassing a combination of PTCy and thymoglobulin (ATG) in patients with myeloid malignancies in a myeloablative conditioning MSD PBSCT. Forty-two patients underwent PBSCT using either methotrexate and cyclosporine (MTX/CSA, 21 patients) or PTCy and ATG (21 patients) as a GvHD prophylaxis. With median follow-ups of 71 months, the 1-year GvHD-free, relapse-free survival rates and chronic GvHD-free survival rate of the standard and PTCy/ATG groups were similar: 24% versus 37% (P = 0.251) and 29% versus 43% (P = 0.095), respectively. When focusing on chronic GvHD we observed that 17/35 patients (48.6%) suffered from this, 5/18 (27.8%) treated with MTX/CSA had extensive chronic GvHD, but 0/17 PTCy/ATG did. Twenty-one patients required additional GvHD treatment; 7/21 in the PTCy/ATG received only corticosteroid, while 8/14 MTX/CSA required at least 2 drugs. The 5-year overall survival rates were 52% and 52% (P = 0.859), and the 5-year disease-free survival rates were 52% and 52% (P = 0.862) for the MTX/CSA and PTCy/ATG groups, respectively. We conclude that PTCy in combination with ATG without immunosuppression of a calcineurin inhibitor can effectively control GvHD.

The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease

AbstractThe Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP), derived from 2 serum biomarkers, measures damage to crypts in the gastrointestinal tract during graft-versus-host disease (GVHD). We hypothesized that changes in MAP after treatment could validate it as a response biomarker. We prospectively collected serum samples and clinical stages of acute GVHD from 615 patients receiving hematopoietic cell transplantation in 20 centers at initiation of first-line systemic treatment and 4 weeks later. We computed MAPs and clinical responses and compared their abilities to predict 6-month nonrelapse mortality (NRM) in the validation cohort (n = 367). After 4 weeks of treatment, MAPs predicted NRM better than the change in clinical symptoms in all patients and identified 2 groups with significantly different NRM in both clinical responders (40% vs 12%, P < .0001) and nonresponders (65% vs 25%, P < .0001). MAPs successfully reclassified patients for NRM risk within every clinical grade of acute GVHD after 4 weeks of treatment. At the beginning of treatment, patients with a low MAP that rose above the threshold of 0.290 after 4 weeks of treatment had a significant increase in NRM, whereas patients with a high MAP at onset that fell below that threshold after treatment had a striking decrease in NRM that translated into clear differences in overall survival. We conclude that a MAP measured before and after treatment of acute GVHD is a response biomarker that predicts long-term outcomes more accurately than change in clinical symptoms. MAPs have the potential to guide therapy for acute GVHD and may function as a useful end point in clinical trials.

The MAGIC Algorithm Probability (MAP): A Novel Laboratory Biomarker for the Response to Treatment of Acute Graft-Versus-Host Disease

The MAGIC Algorithm Probability (MAP): A Novel Laboratory Biomarker for the Response to Treatment of Acute Graft-Versus-Host Disease

A Case Report of the Benefit of Cannabidiol (Cannabidiol (CBD)-Predominant Medical Cannabis Preparation) in the Management of Refractory Skin Graft Vs Host Disease (GVHD)

Cannabis sativa contains numerous cannabinoids, with D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) the primary cannabinoids of medical interest. Both THC and CBD possess potent anti-inflammatory and immunosuppressive properties, but THC has significant psychoactive properties. In a phase 2 study of CBD plus standard GVHD prophylaxis,, Yeshrun et al found low rates of grade II - IV acute GVHD, and compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II - IV acute GVHD was .3 (P =.0002)1. Also, Kalytera Therapeutics announced promising results in a Phase 2a study evaluating the safety and efficacy of CBD, for the treatment of acute Grade III-IV GVHD, including 9/ 10 responses, of which 7 were complete remission (CR)2. We report a case of steroid refractory eczematous GVHD successfully treated with a CBD-predominant medical cannabis product. A 35 year old woman with T-cell Acute Lymphoblastic Leukemia (T-ALL) was treated on an MSKCC pediatric -inspired ALL protocol. She developed CNS involvement during induction therapy treated with intrathecal therapy with persistent CNS disease. She then received salvage therapy with HyperCVAD part B with high dose methotrexate, high dose cytarabine, with CR and underwent matched related donor (sister) stem cell transplant conditioned with Etoposide, TBI 1200 cGy. GvHD prophylaxis was Alemtuzumab, Tacrolimus. She developed a rash on day 126 post transplant involving face and scalp which spread to chest and back and within 1 week involved 100% of BSA with itching, facial and orbital swelling, ankle/feet swelling. Skin biopsy revealed an eczematous variant of GvHD which is considered to be very aggressive, difficult to control with immunosuppression3, and carries a poor prognosis. Phototherapy and steroid ointment was initiated with initial benefit and regression of rash but then rash and edema returned within 6 months. Ruxolitinib was given on expanded access protocol with no benefit. Systemic steroids were again initiated at 1 mg/kg/ day with minimal benefit. Insurance denied tociluzumab. Extracorporeal photopheresis was started with only minimal response and eventually ibrutinib was initiated. With steroids, photopheresis and ibrutinib she had marginal response but ongoing severe skin GvHD. She had numerous infectious complications including soft tissue skin infections requiring multiple admissions. At 16 months post transplant, the patient began a medical cannabis product manufactured by VIREO HEALTH, consisting of a high CBD:THC ratio (19:1) oral solution containing CBD 47.5mg/ml and THC 2.5mg/ml. A daily dose of 6 ml provided 285 mg CBD and 15mg THC daily comparable to the 300 mg CBD product in the Kalytera product. Toxicity was sleepiness; thus the patient took the dose in the evening. There was a definite response within 3 months, allowing discontinuation of ibrutinib and photopheresis. By 2 years post transplant, her skin issues had resolved with only mild itching and flakiness. She remains on this product at a dose of 6 ml daily. This case adds to the developing evidence regarding the potential anti- inflammatory and immunosuppressive effects of medical cannabis and its activity for the treatment of active GVHD. Both THC and CBD are anti-inflammatory via CB2 receptors and THC inhibits T-lymphocyte expansion in a murine BMT model.1 The THC component may have contributed therapeutic benefit but also explains the toxicity and was dose limiting. Further studies are warranted to explore the role of medical cannabis, the optimal dose of CBD and THC, in the prevention and management of GVHD. 1 Yeshurun, Moshe, et al. "Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study." Biology of Blood and Marrow Transplantation, vol. 21, no. 10, 2015, pp. 1770-1775., doi:10.1016/j.bbmt.2015.05.018. 2. Kalytera Therapeutics Announces Encouraging Results of a Phase 2a Clinical Study for the Treatment of Acute Graft versus Host Disease. Source: Kalytera Therapeutics, Inc.VANCOUVER, British Columbia, Feb. 22, 2017 (GLOBE NEWSWIRE) 3. Creamer D, Martyn-Simmons CL, Osborne G, et al. Eczematoid Graft-vs-Host Disease: A Novel Form of Chronic Cutaneous Graft-vs-Host Disease and Its Response to Psoralen-UV-A Therapy. Arch Dermatol.2007;143(9):1157-1162. doi:10.1001/archderm.143.9.1157 Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: This is a medical cannabis product manufactured by VIREO HEALTH, consisting of a high CBD:THC ratio (19:1) oral solution containing CBD 47.5mg/ml and THC 2.5mg/ml. The drug was used to treat refractory graft versus host disease.

Adoptive Therapy with Cord Blood Regulatory T Cells Can Treat Graft Vs Host Disease

Background Adoptive therapy with regulatory T cells (Tregs) has already been established as a promising strategy for prevention of graft vs. host disease (GVHD) in clinical trials. Our group at MD Anderson Cancer Center has previously shown that a significantly lower dose of cord blood (CB) Tregs as compared to conventional T cells (Tcon) in the donor graft is able to prevent GVHD while preserving the graft vs. leukemia (GVL) effect. Therefore, we now examined the efficacy of using CB Tregs in the treatment of GVHD. Method: Xenogenic GVHD mouse model was established using NOD/SCID/IL2Rgnull (NSG) mice were sublethally irradiated at 300 cGy followed by injection of 1x107 peripheral blood (PB) mononuclear cells on day 0, as previously described. Ex vivo expanded CB Tregs were injected on day -1 (for prophylaxis) or at different days post PBMC injection for treatment. Mice were serially examined for appearance, weight, posture, GVHD score and survival. Serial peripheral blood sampling for flow cytometry and serum cytokine analysis. CB Tregs were also analyzed by flow cytometry. In order to understand the impact of the routine immunosuppressive agents on the function of CB Tregs, we incubated the CB Tregs in culture with cyclosporine (200ng/ml) or sirolimus (20 ng/ml) from day 8 to day 14. Cells were harvested on day 14 and analyzed by flow cytometry and CellTrace Violet suppression assay. Result: A single dose of 1x107 CB Tregs injected at day +7 did not result in a survival difference compared to the control arm (data not shown). Therefore, we froze multiple aliquots of expanded CB Tregs to be injected at different intervals post-transplant. Thawed CB Tregs showed stable phenotype of CD4+25+127lo: 94.7%; intracellular Helios+: 98.5% and intracellular FOXP3+: 99.4% and were able to suppress 87% of the proliferating conventional T-cells (Tcons). In order to compare the efficacy of the CB Tregs for GVHD treatment, we set up 3 arms: i) Control: PBMC alone; ii) Prophylaxis: 1x107 CB Tregs injected on day -1 and iii) Treatment: 1x107 CB Tregs injected on day +4, +7, +18 and +25. The mice in the prophylaxis and treatment arm retained their weight as compared to the control arm (p&lt;0.003) (Fig 1A) and showed significantly better overall survival (P=0.01) (Fig 1B), which correlated with the decrease in circulating inflammatory cytokines including TNFa (Fig 1C). Since the standard of care for acute GVHD still remains high dose steroids, we evaluated the effect of continued exposure to steroids (prednisone-100ug/ml) for a period of 96 hours on the viability of CB Tregs. When compared to CB Tcons, 90.3% CB Tregs remained alive and viable compared to 64.7% of Tcons (Fig 1D). No differences were observed in the intracellular expression of FOXP3 or Helios in the control vs. cyclosporine or sirolimus exposed cells (Fig 1E). Similarly, no significant impact was observed on their suppressor function (Fig 1F). Conclusions: Multiple injections with CB Tregs can effectively treat GVHD. Combination therapy of CB Tregs with the commonly used GVHD treatments can be explored. Figure 1 Disclosures Iyer: Genentech/Roche: Research Funding; Incyte: Research Funding; Seattle Genetics, Inc.: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Arog: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Blocking JAK1/JAK2 While Sparing JAK3 Not Only Prevents GvHD but Also Promotes Damaged Tissue Repair

The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are primarily derived from graft-versus-leukemia (GvL) that is mediated by mature T cells in donor grafts. Unfortunately, graft-versus-host disease (GvHD) results from immune reactions of these same donor T cells against host tissues and organs after allo-HSCT. Due to this strong association between GvHD and the beneficial GvL, our lab and others have been working on developing effective therapeutic strategies to selectively prevent and treat GvHD without abrogating GvL. Recently we have reported that pharmacologic inhibition of Janus kinases 1/2 (JAK1/JAK2) prevents GvHD by blocking IFNGR and IL6R signaling. Although baricitinib (BARI) and ruxolitinib (RUX) are both JAK1/JAK2 inhibitors with similar potency, BARI was found to be superior to RUX in prevention of GvHD in our mouse models of allo-HSCT. One of our proposed mechanistic pathways by which BARI prevents GvHD is via a robust increase in regulatory T cells (Tregs) which play a pivotal role in controlling GvHD. Since the proliferation and survival of Tregs are mediated through the IL2-JAK1/JAK3-STAT5 signaling pathway and that RUX is a more JAK3 inhibitor, we hypothesized that sparing JAK3 by BARI is critical for this increase of Tregs. To test this hypothesis, we administered BARI to allo-HSCT recipient mice with or without JAK3-specific inhibitor and monitored them for GvHD signs. The mice treated with BARI and iJAK3 had significantly lower Tregs and overall survival rates compared to the mice treated with BARI alone. This data suggests that BARI prevents GvHD by retaining JAK3, thereby increasing Tregs. We have also previously reported that BARI treats established GvHD. However, the mechanisms by which BARI reverses ongoing GvHD remain unclear. Consequently, we hypothesized that BARI not only modulates immune cell functions as we previously reported, but also promotes restoration of GvHD damaged tissues. To test our hypothesis, we delayed the administration of BARI until mice developed clinically apparent GvHD and treated them starting on days 10, 17, or 24 after allo-HSCT. Despite this latency, the day 10 group showed significantly better overall survival (p&lt;0.001, n=14) and lower histopathological grades (p&lt;0.001, n=5) in comparison with all other groups (Fig. A). Since the gastrointestinal (GI) tract is the one of most frequently diagnosed and severely damaged GvHD target organs, we tested the possible mechanistic pathways by which BARI reverses GvHD in the GI tract. We found that Paneth cells and intestinal stem cells which are both involved in maintaining the intestinal barrier integrity are substantially increased in day 10 (p&lt;0.0001, n=13) and 17 (p&lt;0.001, n=29) groups compared to the vehicle control (Fig. B). To understand the molecular mechanisms underlying BARI-mediated reversal of established GvHD, we treated human intestinal organoids with BARI and RUX. Upon observing an increased proliferation in organoids treated with BARI and RUX, we then performed RNA-seq analyses on them to determine the specific genes that are differentially regulated by the treatment of BARI and RUX. Thirteen genes were found to be significantly upregulated in the RUX and BARI treated samples and three of these genes (TFF1, ABCB1, and IGFBP3) have been shown to be positively associated with EGFR signaling while negatively associated with TNFR signaling. Once we confirmed the expression levels of these genes in the human organoids using real-time PCR, we then generated an in vitro established GvHD model by treating mouse intestinal organoids with inflammatory cytokines (IFNγ, TNFα, and IL-1β). Two days later, we treated these organoids with BARI and RUX to evaluate expressions of IGFBP3, TFF1 and ABCB1 (Fig. C). We found that BARI significantly upregulates expression of TFF1, ABCB1, and IGFBP3 RNA levels in those cytokine damaged intestinal organoids compared to RUX. Collectively, these data suggest that BARI possibly reverses established GvHD by promoting damaged tissue repair by activating EGFR signaling while inhibiting inflammation and crypt apoptosis by TNFR1 signaling through TFF1, IGFBP3, and ABCB1. Lastly, the increase of Tregs by sparing JAK3 and the upregulation of these three genes in BARI-treated groups may explain the superiority of BARI over RUX in both prevention and treatment of GvHD. Figure Disclosures DiPersio: Karyopharm Therapeutics: Consultancy; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Macrogenics: Research Funding, Speakers Bureau; WUGEN: Equity Ownership, Patents &amp; Royalties, Research Funding; Magenta Therapeutics: Equity Ownership; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline Rx: Research Funding, Speakers Bureau; NeoImmune Tech: Research Funding. Choi:Daewoong Pharmaceuticals Co., Ltd: Consultancy.

Phase I Study of Cord Blood Transplantation with Intra-Bone Marrow Injection of Mesenchymal Stem Cells

Phase I Study of Cord Blood Transplantation with Intra-Bone Marrow Injection of Mesenchymal Stem Cells

Time to Change Our Practice: Experience in the Treatment of Steroid Refractory Graft Versus Host Disease in a Universitary Hospital in Chile

Introduction Steroids refractory (SR) acute (a) or chronic (c) graft versus host disease (GVHD) carries morbidity and lethality. Treatment algorithms varies widely among institutions meaning that the most effective treatment is not yet established. Extracorporeal photopheresis (ExP) and Ruxolitinib have shown in retrospective studies a hopeful efficacy in the treatment of this disease. Moreover, prolonged corticoid or immunosuppressant drugs are associated with opportunistic infection and mortality. Consequently our GVHD algorithm consider 7 days of high dose steroids before moving on to the second line treatments mentioned above to avoid prolonged infectious risk. Because of quick availability and reported benefit, without adding more immunosuppression, we have prefered ExP over other treatments. However this apparent advantages are contrasted with its great cost, as each session exceeds $US 2000. Ruxolitinib in the other hand, is less expensive, but since it is only administered orally, doubts regarding its absorption frequently appear in situations of intestinal GVHD. Hence we used Ruxolitinib as third line therapy after ExP. To know real outcomes of our patients we analyzed all patients with SR-GVHD of our adult hematopoietic transplantation program. Methodology Since 1993 we prospectively performed a registry of all transplanted patients. For this analysis we reviewed all allogeneic transplantated patients and data of those who developed SR-GVHD was extracted. In 2013, ExP was available in our center and was included in our algorithm. SR-GVHD was defined as patients that did not respond despite 5-7 of high dose steroids. As some patients suffer from aGVHD and cGVHD we analyse them separately for global response purpose. Considering that some events can affect more than one organ, when less than 3 organs were affected, we also analyse responses to each one of them separately. When 3 or more organs were affected we consider it as multisystemic affectation Results Until 2013 150 allogeneic transplants were performed; of those, 14 patients (9%) developed SR-GVHD, with 90% mortality. Unsuccessful treatmens included ATG, high doses of methylprednisolone, etanercept, and cyclosporine adjustment. Since 2013 we performed 135 allogeneic transplants and 20 patients (14,8%) developed SR-GVHD. Twelve patients presented with SR-aGVHD, 5 patients with SR-cGVHD and 4 patients with acute and chronic SR-GVHD in different time. For analysis of global response, then, we consider 16 SR-aGVHD patients and 9 SR-cGVHD patients (patients characteristics are shown in table 1). All 16 SR-aGVHD patients were treated with ExP with a median of 5,3 sessions. Among SR-aGVHD patients 37% responded to ExP, all being complete responses. When including ruxolitinib addition, final responses reached 56,3%. Mortality was high in this group (56,3% died, 66% of them because of aGVHD). In patients with no response to ExP and Ruxolitinib, mortality rate was 85,7%. Most affected organs were small intestine and skin, affecting 43,7% of patients each. Responses to therapy by organ affectation are shown in table 2. In SR-cGVHD, ExP was used in 7/9 patients, and 85,7% responded. In this case most patients only achieved partial response (71,4%) and ruxolitinib did not improved response any further. Among SR-cGVHD, skin affectation was the most common, 66% of SR-cGVHD patients presented with skin affectation either exclusively or combine with other organ affectation. Conclusions SR-GVHD remains a challenging disease, and no standard treatment exist. Beyond the high mortality rate, cost associated with treatment, procedures and hospitalization makes this patients even more difficult to manage. Therefore it is imperative that every center analyse their own data and treatment pathways to optimize both, GVHD treatment results and hospital resources. As a matter of fact, after reviewing our own data, we switched to a combined modality of ExP and Ruxolitinib for affectation other than skin, in SR- aGVHD. We hope this new algorithm overcomes, specially, the bad results of monotherapy in intestinal SR-aGVHD seen in our center, as these patients are exposed to high risk of malnutrition, dehydration, prolonged hospitalization and death. In SR-cGVHD we found a consistent tendency of partial responses with ExP. Keywords: Steroids refractory graft versus host disease, Extracorporeal Photopheresis, Ruxolitinib. Disclosures No relevant conflicts of interest to declare.

A Phase IB Study of Blinatumomab (blina) in Patients with B Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (allo-BMT) Remission Maintenance

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, long term survival is limited by transplant-related toxicity and particularly by disease relapse. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates the use of alternative allograft sources. Moreover, following PTCy, cellular immune reconstitution is favorable for the integration of strategies to augment anti-tumor immunity. Blina, a CD19/CD3 bispecific T cell engager antibody construct, is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance established posttransplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. Thus, we have undertaken a phase Ib trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL. Methods: Patients ³18 years-old with high risk CD19+ B ALL or NHL who underwent alloBMT using PTCy were eligible including those with prior blina exposure. Patients had to be 60-180 days from transplant with documented count recovery and no evidence of disease progression. Patients had to be off all post-transplant immunosuppression including steroids for the treatment of GVHD for ≥4 weeks prior to treatment initiation, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Patients could receive two cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received only one cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28. Results: As of July 23, 2019, 12 adults (10 males/2 females) have enrolled including 4 patients with B ALL and 8 patients with NHL. Among the B ALL patients, two with known TP53 mutations were transplanted in CR1, while two with relapsed disease were transplanted in CR3. Among the NHL patients, five had large cell transformation (3 from follicular and 2 from CLL); one had relapsed primary CNS lymphoma (PCNSL); one had relapsed mantle cell lymphoma (MCL); and one had diffuse large B cell lymphoma (DLBCL). The median age was 53 (range, 30-73). All patients underwent alloBMT using a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation (TBI). Eight patients received allografts from haploidentical donors, three from matched-unrelated donors, and one from a matched-related donor. Five patients received peripheral blood allografts, and seven bone marrow. Two patients were enrolled after a second alloBMT, and 3/4 ALL patients previously received blina. Baseline characteristics are presented in Figure 1. Patients started blina a median of 144 days post-transplant (range, 90-180). One patient stopped treatment on day 5 due to a grade 2 tremor, and one patient required dose reduction on day 25 due to grade 4 neutropenia. Toxicities were otherwise mild and are presented in Figure 2. There were no exacerbations of GVHD. At a median follow-up of 13.7 months after BMT (range 3.8-23 months), ten patients remain in remission, while one patient suffered a third CNS relapse of ALL at 20.6 months after his 2nd transplant and another had relapse of his transformed lymphoma. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented. Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity. 83% of the very high risk patients treated on study remain in CR at a median of 13.7 months post-transplant. Based on promising safety and efficacy data from the phase IB, the plan is to proceed to the phase II portion of the study. Disclosures Webster: Amgen: Consultancy; Genentech: Research Funding; Pfizer: Consultancy. Wagner-Johnston:Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents &amp; Royalties: Patent holder. Gojo:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Research Funding; Jazz: Consultancy, Honoraria; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Amphivena: Research Funding. OffLabel Disclosure: Blinatumomab is not labeled for use as post-transplant maintenance therapy or for use in the non-Hodgkin lymphoma.

Peri-Transplant Administration of Ruxolitinib Is Safe and Feasible in Patients with Myelofibrosis: Primary Results of a Pilot Open-Label Study of Ruxolitinib Administration in Combination with Reduced Intensity Conditioning

Peri-Transplant Administration of Ruxolitinib Is Safe and Feasible in Patients with Myelofibrosis: Primary Results of a Pilot Open-Label Study of Ruxolitinib Administration in Combination with Reduced Intensity Conditioning

Maintaining the Cellular Anti-Viral and Anti-Leukemic Activities in GvHD Patients Undergoing Extracorporeal Photophoresis Therapy

Introduction: Systemic steroids with their strong immunosuppressive and anti-inflammatory effects are the current gold standard for initial treatment of the graft-versus-host disease (GvHD). But, the effectiveness of high-dose steroids comes along with an increased susceptibility to infections and other secondary malignancies. Extracorporeal photophoresis (ECP), an immunotherapeutic therapy, is currently being used as a clinically well-established second-line treatment for GvHD. Contrary to steroid treatment, there is no clinical data showing that ECP is associated with an increased risk of infection. However, the exact mechanism of action how ECP preserves the anti-viral and anti-leukemic effects on the cellular level has not been discovered yet. Materials and methods: Thirty-four patients with steroid-refractory/resistant aGvHD ≥ II and moderate to severe cGvHD were treated with ECP at the University Hospitals in Heidelberg, Greifswald in Germany and Chaim Sheba Medical Center in Israel. A comprehensive analysis of cell subsets was performed using multi-parametric flow cytometry. Additionally, the quantity and quality of CMV-specific T cells was determined by tetramer staining and interferon-γ enzyme-linked immunospot assay. The NK activity in terms of killing functionality and cytokine release was analyzed by intracellular cytokine staining and chromium-51 release assay, respectively. The proliferative capacity of effector cells was determined by carboxyfluorescein succinimidyl ester (CFSE) staining. Results: ECP therapy was effective with an overall response rate of 75% for patients with aGvHD (x/y) and 78% (x/y) for patients with cGvHD. Of note, all patients showed neither the increased susceptibility to infections nor the reactivation of CMV nor the tumor relapse. Overall, the frequency of well-established protective cell subsets in terms of cytotoxic CD8+ T cells, CD4+CD8+ T cells, γδ T cells, NK cells and NKT cells remained constant under the ECP therapy. Specifically, no significant influence of ECP therapy on the CD56dimCD57+NKG2C+ NK cells, a specialized anti-viral/tumor population, and the CMV+CD8+ T cells could be observed. The further phenotyping of CMV+CD8+ T cells showed that CD45RA+CCR7-CMV+CD8+ TE cells and CD45RA-CCR7-CMV+CD8+ TEM cells could keep stable under the ECP therapy. Besides these, priming, differentiation and maturation of NK cells through upregulation of CD57 by ECP therapy bridged the T-cell-deficient period after HSCT in order to control the viral infections and eliminate the residual malignant cells. Moreover, ECP could reduce the CD62L expression on TE population which not only facilitates the hematopoietic engraftment and contributes to the phenotypic and functional T cell reconstitution after transplantation without causing GvHD, but also enhances the functional immune reconstitution against tumor and viral antigens. Functionally, neither IFN-g released by virus specific T cells nor production of TNF-a and IFN-g by NK cells in response to K562 cells was hampered by ECP. Of note, the functions of NK cells in terms of the MFI of cytokines and the polyfunctionality of NK cells were stable under ECP treatment. Additionally, the proliferation of NK cells, CD4+ T cells and CD8+ T cells providing an expanded pool of effector cells against the pathogens was not hampered by ECP therapy as well. Conclusions: ECP therapy constitutes an effective strategy to treat GvHD. In addition, ECP appears to be a safe therapy compared to continued steroid use. Our current results suggest that ECP allows to maintain immunity against infections and tumors. Disclosures Schönland: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Dreger:Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Schmitt:Therakos Mallinckrodt: Other: Financial Support .

Fast CMV and EBV Reactivations after Ruxolitinib for Graft-Versus-Host Disease Treatment

Introduction: Corticosteroid-refractory graft-versus-host disease (GVHD) remains a serious complication of hematopoietic stem cell transplantation (HSCT) with high morbidity and mortality rates. Unfortunately, no standard therapy exists for this setting. Ruxolitinib (ruxo), an oral selective Janus-associated kinase (JAK) inhibitor, achieved good results for corticoresistant acute and chronic GVHD in preclinical and clinical studies, with 80% overall response rates. Recent studies showed an increased risk of infections in patients treated with ruxo, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations. Patients and methods: In order to assess the efficacy and the safety of ruxo, we reviewed here the outcome of 57 patients who received ruxo for corticosteroid-refractory GVHD (in case of digestive tract involvement or in the absence of available ongoing clinical trials) or as a steroids-sparing medication. EBV and CMV reactivation risks were also assessed in the 137 consecutive patients received HSCT between January 1, 2012 and December 31, 2017 and who presented acute or chonic GVHD (57 of whom received ruxo). For this purpose, each reactivation were analyzed separately as a competing risk with death in a cause specific Cox model of survival after the first GVHD occurrence and the onset of ruxo therapy was coded as time dependent covariate. Results: The median age of 57 patients with ruxo was 55 years (range, 49 to 61). Indication for HSCT was acute myeloid leukemia for 25% patients, lymphoma for 30%, acute lymphoblastic leukemia for 11%, myeloproliferative neoplasm for 14% and myelodysplastic syndrome for 7%. Only 9% of this patients received ruxo before HSCT. Unrelated donor was used for 60% patients and main source of hematopoietic stem cells was peripheral stem cells (93%). T cell depletion with polyclonal anti-thymocyte globulin was performed for 89% of patients. Conditioning with high doses cyclophosphamide was used for 21% patients. A lymphopenia &lt;1G/L persisted at day 100 for 42/51 patients evaluated. In these 57 patients, ruxo was given for 62 episode of GVHD (acute: 21 [which 95% for an acute grade III-IV GVHD]; chronic: 36; overlap syndrome: 5). Response rates to ruxo were 48% for acute GVHD, 60% for overlap syndrom and 58% for chronic GVHD. The overall GVHD related-death rate was 33% (19% for acute GVHD and 14% for chronic GVHD). Our median follow-up was 30 months (range, 9 to 42) after HSCT. Main non-infectious adverse events were cytopenias (17/57) and hepatic cytolysis (6/57) leading to discontinuation or tapering of ruxo in 12 patients. EBV reactivation (&gt; 4 log or increasing viral charge of 0.5 log) occurred in 19 patients after ruxo with a 6-weeks cumulative incidence (6WCuI) of 22% (95CI [95% confidence interval]: 15-34). It was the first reactivation in 13 patients. CMV reactivation (&gt; 3 log) occurred in 8 patients after ruxo with a 6WCuI of 4% (95CI: 7-25). It was the first reactivation in 3 patients (Figure 1). The distribution of first reactivation before ruxo and in the remaining 80 patients is shown in Table 1. Thus, 6WCuI of first EBV and CMV reactivation after the first episode of GVHD was 24% (95CI: 19-31) and 20% (95CI: 15-25) respectively. Finally, onset of ruxo coded as time dependent covariates retained a significant adverse prognostic value for the competing risks of death and first episode of EBV reactivation (HR [Hazard Ratio]: 2,657, p&lt;0,05) as well as first episode of CMV reactivation (HR: 1,747, p&lt;0,05) after first episode of GVHD. Discussion /Conclusion: Ruxo initiation coded as a time-dependent covariate was significantly associated with the overall risk of viral reactivation after the first episode of GVHD and the viral reactivations incidences after ruxo were similar with the incidence of reactivation at the onset of GVHD. Thus, it might be linked to the immuno-compromised state induced by both HSCT and GVHD. Furthermore, as we used ruxo for serious gastro intestinal GVHD, we could have selected patients with a more severe GVHD, requiring multiple immunosuppressive therapy, worsening immune reconstitution. To our knowledge it is the first study to assess the competing risk of CMV and EBV reactivation during ruxo treatment for GVHD. Given its effectiveness in corticoresistant GVHD, ruxo use must not be limited by the fear of viral reactivation at the light of our data, conditioned upon a close monitoring of viral loads in the first weeks. Disclosures No relevant conflicts of interest to declare.

Plasma Biomarker Predicts Lethal Acute Graft Versus Host Disease and Non-Relapse Mortality in Japanese Patients

Introduction Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative treatment option for hematopoietic malignancies. In addition to relapse mortality, non-relapse mortality (NRM) such as severe graft-versus-host disease(GVHD) is a major cause of aHSCT. Pre-transplant clinical risk factors for acute GVHD include the degree of human leukocyte antigen (HLA) match between donor and recipient, recipient age, donor type, and conditioning regimen intensity. Although GVHD prophylaxis is usually decided by these risk factors, excessive immunosuppression induces opportunistic infection. Laboratory test cannot predict the risk of NRM or severe GVHD after aHSCT prior to the onset of GVHD symptoms; however, 2-biomarker (ST2 and REG3α) algorithm, namely MAGIC algorithm, may predict severe GVHD as has been shown recently (Hartwell et al. JCI Insight 2017). We retrospectively analyzed these 2 biomarkers in our patients to try whether the 2-biomarker algorithm is available to identify high risk of lethal GVHD and non-relapse mortality in Japanese patients. Patients and Methods We retrospectively analyzed consecutive 47 patients who received aHSCT for hematologic malignancies at Kansai Medical University Hospital from January 1, 2010 until April 30, 2016.Overall survival (OS), non-relapse mortality, cause of death, and GVHD clinical staging were investigated. Non-relapse deaths were considered related to GVHD if the patient died from either GVHD itself or from an infection that developed while receiving systemic steroids (at least 10 mg prednisone daily or equivalent) for the treatment of GVHD. Bloodsamples were obtained 7 days after transplantation. ST2 and REG3α concentrations were analyzed by ELISA, and were used for the 2-biomarker algorithm (Hartwell et al. JCI Insight 2017). Results Of the 47 patients (male 24, female 23), median age was 52 years (range, 22-69 years). Eleven patients received PBSCT, 27 patients received bone marrow transplantation, and 9 patients received cord blood transplantation. Of 27 patients who received bone marrow transplantation, 3 patients were transplanted allografts from HLA mismatched donor. Twenty-seven patients underwent reduced intensity conditioning regimen. The median survival time and 1-year OS rate were 375 days (range, 7-3236 days) and 53.2 %, respectively.The overall cumulative incidences of 6-month NRM was 23.4%. The incidence of grade II-IV and III-IV acute GVHD were 17.0%, and 13.2%, respectively. Twelve patients were identified as high risk (HR), and 35 patients were identified as low risk (LR) by the MAGIC algorithm. OS was 33.3% in HR and 71.4% in LR (p&lt;0.05). Six-month cumulative incidence of NRM in HR patients was significantly higher than that of LR (58.3% vs. 11.4%, p&lt;0.001) (Figure), whereas the relapse rate did not differ between risk groups. Four and three patients died from GVHD in HR and LR patients, respectively (33.3% vs. 8.6%, p&lt;0.05). Severe gastrointestinal GVHD was greater in HR patients (18.7 % vs. 8.6%). Conclusion The biomarker algorithm based on blood sample taken 7 day after aHSCT can identify HR patients of lethal GVHD and NRM in Japanese patients as well. Figure Disclosures Ito: Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding.

Incidence and Risk Factors of De Novo Skin Cancer in a Contemporary Cohort of Hematopoietic Cell Transplantation Survivors

Introduction: Hematopoietic cell transplantation (HCT)-related factors, such as total body irradiation (TBI) used for conditioning, graft-versus-host disease (GvHD), and prolonged exposure to calcineurin-inhibitors, can result in high risk for subsequent skin cancers in long-term survivors. Previous studies examining skin cancers after HCT have largely focused on patients transplanted in earlier eras (&lt;2000), which may not be as informative for providers caring for survivors treated with contemporary conditioning (e.g. less myeloablative) approaches or GvHD treatment regimens, and do not account for newer stem cell sources (e.g. cord, haploidentical) with their evolving immunosuppression risk. Additionally, due to registry reporting, past studies have largely focused on melanoma, which underestimates the burden due to more common skin cancers such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). The current study describes the incidence and risk factors of melanoma and non-melanoma skin cancer in a large contemporary cohort of HCT survivors. Methods: 2338 consecutive patients who underwent a first HCT between 2005 and 2014 at City of Hope (COH) and survived ≥1 year, were included in the study. Patients with a history of skin cancer prior to HCT were excluded from the cohort. All skin cancers were validated using pathology reports, and physician notes (20%) whenever the former was not available. Skin cancers included SCC, BCC, melanoma, atypical fibroxanthoma, and merkel cell carcinoma. Patients were followed from HCT to death, second HCT, last known alive date, or December 31, 2018, whichever occurred first. Cumulative incidence of skin cancer was estimated taking into consideration competing risk of death. Fine-Gray sub-distributional hazard regression was used to calculate hazard ratio (HR) estimates, adjusted for relevant covariates. Results: Median age at HCT was 51.8y (range: 0.7-78.7); 57.6% were male; 56.5% were non-Hispanic white (NHW); 4.4% had a history of Pre-HCT cancer (antecedent to primary diagnosis); 47.7% underwent allogeneic HCT; 22.0% received myeloablative TBI (≥1200 cGy)-based conditioning. Among survivors of allogeneic HCT, 57.2% developed ≥moderate chronic GvHD (84% involving the skin); the most common immunosuppressive agents used for the management of ≥moderate chronic GvHD were tacrolimus (84.6%), followed by sirolimus (76.5%), and cyclosporine (28.4%). Burden of skin cancer over time: 179 survivors developed a total of 450 skin cancers after HCT; median time from HCT to first skin cancer was 2.8 years (range: 0.2-13.6). SCC was the most common subtype (59.1%), followed by BCC (31.3%), melanoma (5.1%), and other (4.4%); 43.4% of patients with SCC had invasive or high grade disease at presentation. The cumulative incidence of de novo skin cancer after HCT was 8.3% at 5 years, and 14.8% at 10 years (figure). Eighty-nine patients with skin cancer had a second skin cancer at a median of 0.5 years (range: 0.2 to 7.2) from the first; 55.1% were of a different histology. The cumulative incidence of a second skin cancer was 41.9% at 5-years (figure). Risk factors: Multivariate analysis revealed male sex (HR=1.7, p=0.0008), NHW race/ethnicity (HR=9.0, p&lt;0.0001), older age HCT (≥50years at HCT, HR=2.4, p&lt;0.0001), allogeneic HCT (HR=2.2, p&lt;0.0001), and a history non-skin cancer prior to HCT (HR=1.7, p=0.04) to be significant and independent predictors of post-HCT skin cancer risk. Among allogeneic HCT patients, neither severity of chronic GvHD, location (e.g. skin), nor duration of post-HCT immunosuppression were associated with risk of de novo skin cancer, irrespective of skin cancer histology. Conclusions: This study confirms the higher risk of skin cancer by sex, race/ethnicity, and age at HCT, and highlights the greater than two-fold risk of skin cancer among allogeneic HCT survivors compared to autologous patients, a finding that is not entirely explained by GvHD and its treatment. Further, we identified a previously unreported association between pre-HCT (non-skin) cancer and post-HCT cancer risk, and describe the very high burden of multiple histologically distinct skin cancers over time. Taken together, these data set form the basis for implementation of updated risk-based screening and prevention practices in survivors at highest risk of skin cancer after HCT. Disclosures Abdulla: Johnson &amp; Johnson: Research Funding; Elorac: Research Funding; Trillium: Research Funding; Stemline: Research Funding; MiRagen: Research Funding; Bionz: Research Funding; Mallinckrodt: Research Funding; Mallinckrodt: Consultancy; Mallinckrodt: Speakers Bureau. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan.

201 Efficacy of Fecal Microbiota Transplantation for Acute Graft Versus Host Disease in the Gut: A Systematic Review and Meta-Analysis

INTRODUCTION: Graft versus Host disease (GVHD) is a major cause of mortality and morbidity in allogenic hematopoietic stem cell transplant recipients (HSCT). Gut microbiome dysbiosis secondary to conditioning regimens (which include antibiotics) in HSCT, appears to play a significant role in gut GVHD development through its interaction with the immune system. Fecal Microbiota Transplantation (FMT) has been explored for the treatment of gut GVHD owing to its ability to restore the gut microbiome. We performed a systemic review and meta-analysis to review the efficacy and safety of FMT for gut GVHD. METHODS: A systematic search of Medline, Embase, and Web of Science was performed from January 2000 through May 2019. Articles included for meta-analysis were observational studies which included patients with steroid-dependent or resistant gut GVHD after HSCT who underwent one or more FMTs. The main outcomes were pooled proportions of patients achieving response defined as a decrease in gastrointestinal symptoms including stool volume and frequency or reduction of steroid or immunosuppressant dose. Partial response was defined as a decrease of gastrointestinal symptoms followed by recurrence of symptoms. RESULTS: Five studies (4 prospective single arm pilot studies and 1 retrospective case series) including 37 patients were included with follow up ranging from 1–13 months. Three studies used naso-duodenal route, one used oral capsules and one used colonoscopy for FMT. Median number of FMTs per study was 2 (range, 1–6). Unrelated donors were used in 4 studies. A total of 23/37 patients achieved complete response with a pooled proportion of 61.0% (95% confidence interval [CI] 46–76.0), with no heterogeneity (I2 = 0%). Partial response was seen in 3 patients. Hence, the overall response rate was 74.0% (95% CI 49–93, I2 53%). FMT was generally well tolerated. No treatment-related mortality was reported by any study. Serious adverse events were reported in 3 patients (hypoxia in one patient and bacteremia in two patients) but were not directly attributed to FMT. CONCLUSION: FMT is a promising modality for management of gut GVHD and appears to be safe as a salvage therapy based on the current limited data. Ongoing placebo-controlled prospective clinical trials will help to further establish its safety and efficacy.