Chronic Graft-versus-host Disease Symptoms Research Articles

Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease

BackgroundColony-stimulating factor 1 receptor (CSF1R)–dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD.MethodsIn this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%.ResultsA total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.ConclusionsTargeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. (Funded by Syndax Pharmaceuticals and Incyte; AGAVE-201 ClinicalTrials.gov number, NCT04710576.)

Disability Associated with Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: Analysis of a Cross-Sectional US Patient Survey.

Chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT) is associated with poor health-related quality of life (HRQoL) and functional status. However, few studies have evaluated chronic GVHD-related disability and specific activity limitations from a patient perspective. The objective of this analysis was to assess physical, cognitive, and work disability, and describe factors predictive of disability in patients with chronic GVHD in the potentially employable general workforce. The cross-sectional, online, Living With Chronic GVHD Patient Survey was administered in 2020 to adult US patients who reported an active chronic GVHD diagnosis (i.e., within the previous 5years) following HSCT. Data included demographics, diagnosis, work status, chronic GVHD symptoms per the Lee Symptom Scale (LSS), and effects on daily living activities. Descriptive and correlational analyses informed composite disability definitions: (1) severe cognitive disability, (2) severe physical disability, and (3) work disability. Of 137 respondents with GVHD included in this analysis, 47.0% reported severe cognitive disability, and approximately two-thirds each reported severe physical disability (67.4%) and work disability (62.8%). Chronic GVHD severity/duration, symptoms (Lee Symptom Scale), and number of transplant specialists consulted were associated with all types of disability (univariable analyses). Severe cognitive disability was associated with the number of transplant specialists consulted, severe physical disability with female sex, and work disability with nonwhite race. In this analysis, we found that the presence of specific symptoms and the number of transplant specialists consulted were associated with all types of severe disability; female sex was predictive of severe physical disability and nonwhite race of work disability. These findings add to the understanding of chronic GVHD-associated disability, suggest a need for improved social support for patients, and highlight potential indicators for those most in need.

Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.

A boy with primary immunodeficiency, caused by a tyrosine kinase 2 (TYK2) mutation, presented with immune defects and a lifelong history of severe infections. Our aim was to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) could restore the patient's immune defenses and reduce susceptibility to infection. In the absence of a suitable HLA-matched blood relative to act as a donor, the patient received an allogeneic HSCT from unrelated donors. The patient's clinical data were analyzed in the Children's Hospital of Chongqing Medical University (Chongqing, China) before transplantation and during the 4-year follow-up period using a combination of western blotting (e.g., TYK2 and STAT levels), qRT-PCR (e.g., T cell receptor rearrangement excision circles, kappa deletion element recombination circles, and TYK2 transcript levels), and flow cytometry (e.g., lymphocyte subpopulations and CD107α secretion). We found that HSCT significantly reduced the incidence of severe infections, restored normal TKY2 levels, and reversed defects such as impaired JAK/STAT signaling in response to interferon-α or interleukin-10 treatment. Although the patient did not develop acute graft-versus-host disease (GVHD) after transplantation, he did experience chronic GVHD symptoms in a number of organs, which were effectively managed. Our findings suggest that HSCT is a feasible strategy for reconstituting the immune system in TYK2-deficient patients; however, the factors associated with GVHD and autoimmune thyroiditis development in TYK2-deficient patients undergoing HSCT warrant further investigation.

Patient-Reported Outcomes of BMT CTN 1703: A Randomized Phase III Study for Gvhd Prophylaxis - a Quality of Life Evaluation

Introduction A randomized phase III trial of post-transplantation cyclophosphamide (PTCy), tacrolimus, (Tac), and mycophenolate mofetil (MMF) versus tacrolimus/methotrexate (Tac/MTX) for graft-versus-host disease (GVHD) prophylaxis showed superior graft-versus-host disease-free, relapse-free survival (GRFS) in the PTCy-containing arm (NEJM, 2023). Here, we report the effect of GVHD prophylaxis on patient-reported outcomes and impact on quality of life (QOL). Methods The QOL study component of BMT CTN 1703 employed four primary endpoints: Lee Chronic GVHD Symptom Score and the PROMIS subscales of physical function, gastrointestinal symptoms, and satisfaction with participation in social roles. Secondary endpoints included hemorrhagic cystitis symptoms and Lee symptom subscale differences, with questionnaires to English and Spanish-speaking participants at enrollment and on Days 100, 180, and 365 post-transplant. Given the risk of missing assessments, an inverse probability weighted-independent estimating equations (IPW-IEE) model was applied for score comparison between arms, adjusting for baseline score, assessment time, age, donor type, disease risk index (DRI), planned conditioning regimen, and planned use of post-transplant maintenance therapy. Significance was declared at a 1.25% level for score comparisons between arms after Bonferroni correction for multiple testing. The analysis approach classified patients according to the intention-to-treat principle. Results QOL survey completion rates for patients at each timepoint were similar, exceeding 70% in each study arm. With the Lee Chronic GVHD Symptom Scale, higher scores indicate more severe symptoms. The IPW-IEE models indicated that the Lee Chronic GVHD Symptom Scale total scores were significantly lower in the PTCy arm compared to Tac/MTX at day 100 (mean difference [MD] -2.22, 99% confidence interval [CI] -5.05 to 0.61) and day 365 (MD -1.84, 99% CI -5.13 to 1.45, p=0.01 for overall treatment effect across all timepoints, Figure 1). Nutrition subscores were significantly better with PTCy at day 100 (MD -2.41, 99% CI -5.06 to 0.24, p=0.0014). Mouth scores were significantly better in the PTCy arm at day 365 (MD -7.09, 99% CI -13.21 to -0.98, p=0.0035). Patients over 65 years of age had better psychological subscores across the study population (MD -4.80, 99% CI -8.91 to -0.69, p=0.0026); no interaction was found between age and study treatment. Patient-reported hemorrhagic cystitis symptoms showed no significant difference between the study arms at any post-transplant time point. There was no significant treatment effect observed on the 3 PROMIS subscales. Across the entire study population, both relapse and acute GVHD were associated with worse scores on the Lee Symptom Scale, and PROMIS physical function, gastrointestinal symptoms, and social functions subscales. Chronic GVHD was associated with worse scores on the Lee Symptom Scale only, not the PROMIS subscales. No associations were found between patient-reported QOL at baseline and 1-year GRFS, disease-free survival, or overall survival. Conclusions The PTCy arm of BMT CTN 1703 showed superior GRFS, and this study confirms better patient-reported outcomes with PTCy. Patients who received PTCy showed better nutrition and mouth subscores on the Lee Chronic GVHD Symptom Scale compared to those who received Tac/MTX, possibly due to lower observed rates of severe acute and chronic GVHD in the PTCy arm. No association was found between patient-reported baseline quality of life and survival endpoints, suggesting the necessity of further research to elucidate the interplay of treatment strategies, patient factors, and their impact on long-term outcomes.

Predictors of post traumatic growth in allogeneic hematopoietic stem cell transplantation survivors: a cross-sectional survey

AimsGiven the increasing number of Hematopoietic Stem Cell Transplantations (HSCT) performed world-wide, the increasing likelihood of survival following HSCT, and the profound physical, psychosocial, and emotional impact of HSCT on survivors, their carers and families, it is important to identify factors that may contribute to or support post-traumatic growth (PTG) after transplant. In this study, we aimed to investigate the prevalence of PTG in an Australian cohort of long-term allogeneic HSCT survivors and describe associations between PTG and relevant clinical, sociodemographic and psychological variables.MethodsThis was a large, multi-centre, cross sectional survey of Australian HSCT-survivors inviting all those transplanted in New South Wales between 2000 and 2012. Respondents completed the PTG Inventory (PTGI), the Sydney Post-BMT Survey, FACT-BMT, DASS 21, The Chronic Graft versus Host Disease (GVHD) Activity Assessment–Patient Self-Report (Form B), the Lee Chronic GVHD Symptom Scale, and the Fear of Cancer Recurrence Scale. Data was analysed using independent t-tests, one-way analysis of variance, and pearson’s correlations, and hierarchical multiple regression adjusted for potential confounders and to ascertain independent associations of explanatory variables with PTG.ResultsOf 441 respondents, 99% reported some level of PTG with 67% reporting moderate to high levels of PTG. Female gender, younger age, complementary therapy use, anxiety, psychological distress and psychosocial care, and higher quality of life were associated with higher levels of PTG. Importantly, we also found that PTG was not associated with either chronic GVHD or post-HSCT morbidity.ConclusionsIn this study – the largest study of PTG in long-term allogeneic HSCT survivors - we found that growth appears ubiquitous, with 99% of survivors reporting some degree of PTG and 67% reporting moderate-high levels of PTG. Importantly, we found no association with GVHD or chronic physical post-HSCT morbidity, or adverse financial, occupational or sexual impacts. This suggests that it is the necessity for and experience of, HSCT itself that foments personal growth. Accordingly, healthcare professionals should be alert to the profound and wide-ranging impact of HSCT - and the degree to which survivor’s may experience PTG. Identifying interventions that may assist HSCT survivors cope and building their resilience is of utmost importance.

Patient-reported symptom burden and impact on daily activities in chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) treatment for hematologic malignancies. There are limited patient-reported data concerning symptom burden and effects on activities of daily living (ADL). The cross-sectional Living With Chronic GVHD Patient Survey was administered online in the United States (May-August 2020) to participants aged ≥18 years who underwent allogeneic HSCT, were diagnosed with chronic GVHD by a healthcare provider, and self-reported active chronic GVHD (within past 5 years). Information on patient demographics, disease characteristics, symptom burden, and ability to perform ADL was collected. Symptom burden was assessed using the validated Lee Symptom Scale (range from 0-100 with higher scores indicating greater burden). All data were summarized using descriptive statistics; no formal statistical comparisons were conducted. Out of 580 participants who entered the survey screener, 165 participants (28.4%) across 33 states fulfilled all study eligibility criteria, completed the entire survey, and were included (age: mean [SD], 53.7 (13.8) years; median [range], 57.0 [18-78] years; female, n= 105 [63.6%]; White, n= 137 [83.0%]). Respondents described their chronic GVHD severity primarily as moderate (n= 54 [32.7%]) or severe (n= 102 [61.8%]) at the time when symptoms were at their worst. One-third of respondents (33.9%) indicated that their chronic GVHD symptoms were at their worst for ≥1year in duration. Mean (SD; range) Lee Symptom Scale score was 44.8 (19.4; 2-100); 44% of respondents considered "dry eye" the most burdensome symptom. Almost half of respondents (n= 73 [44.2%]) rated their overall quality of life (QoL) as poor. Participants reported a detrimental impact of symptoms on ADL, including basic activities (eg, eating, personal hygiene, dressing). Survey respondents self-reported high chronic GVHD symptom burden and felt that their symptoms severely interfered with physical function and ADL. Effective strategies to mitigate chronic GVHD symptoms are needed to improve QoL among HSCT survivors.

Patients Reported Outcomes (PROs) Are Still Unsatisfactory Among AML Long-Term Survivors: The Impact of Chronic GvHD in a Prospective Study on 15 Years Transplant Activity

Background Acute myeloid leukemia (AML) represents the main indication to allogeneic hemopoietic stem cell transplantation (HSCT) and improvement of overall survival (OS) has been a major achievement provided by this treatment option. Unfortunately, graft-versus-host disease (GvHD) still represents the main complication affecting HSCT, increasing transplant related mortality (TRM) and worsening quality of life (QoL). While the mortality impact of GvHD is well recognized, the impact on QoL is still poorly characterized. The collection of patients reported outcomes (PROs) in routine practice is limited. The most common PRO measures used are the Lee chronic GvHD (cGvHD) symptom scale, the FACT-BMT and the NIH Form B. We aimed to analyze the perception of QoL in AML long-term survivors after HSCT according to the FACT-BMT scale. Methods Our analysis consisted of a prospective single-center study in a cohort of 510 patients affected by either de novo AML or secondary AML and treated with HSCT between January 2004 and December 2019 at our Institute. Data were censored April 1st, 2022. The follow-up was performed according with our Long Term Follow Up institutional program. The FACT-BMT questionnaire was administered as a paper questionnaire. A written consent was given in accordance with the Declaration of Helsinki. Results Overall, the 2-year OS was 51% and the 5-year OS for patients alive at 2 years was 80% (95% CI - 74-85%). For patients alive and in complete remission at 2 years post-HSCT the probability of 5-year OS was 84.5% (95% CI - 78-89,2%), the 5-year TRM 6.3% (95% CI - 0.5-23.3%) without evidence of a "plateau” effect, while the 5-year relapse incidence was 12.91% (95% CI - 4.91-24.91%) reaching a plateau. Both univariate and multivariate analysis showed that age and status of disease at transplant have a significant impact on long-term survival; univariate analysis instead did not show any impact of the year of treatment and of GvHD prophylaxis. Overall, among 195 patients alive and in complete remission at last follow-up, 70 patients completed the questionnaire. PROs analysis confirmed a better perception of QoL for patients that did not experience cGvHD versus patients affected by cGvHD; no difference emerged according to age and time after transplant. Of note, patients affected by cGvHD showed worst functional well-being (p 0.0293), worst physical well-being due to side effects (p <0.0001), less satisfaction about the appearance of their body (p 0.0152) and less satisfaction about their sexual life (p 0.0445 - 10 patients preferred not to answer). Overall, among patients without cGvHD, other side effects after HSCT were not perceived worse than they had imagined, while among those with cGvHD, most patients complained about this perception (p 0.0009). Conclusion QoL in patients cured from AML by HSCT is still far from being satisfactory, most of all among patients with cGvHD. Dedicated counselling and support to address QoL is a relevant unmet medical need. Systematic evaluation of PROs will optimize the care of HSCT survivors, potentially enhancing patient-provider communication and allowing the development of measure for both prevention and treatment of GvHD.

Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor Ameliorates Acute Graft-versus-Host Disease by Inhibiting Effector T Cell Differentiation while Sparing Regulatory T Cells.

Graft-versus-host disease (GVHD) remains to be a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). IL-2-inducible T cell kinase (ITK), a TEC cytoplasmic tyrosine kinase, has an essential role in T cell development and receptor signaling. The ITK/Bruton tyrosine kinase inhibitor ibrutinib has been shown to improve chronic GVHD symptoms; however, the effect of ITK selective inhibition on acute GVHD remains unclear. In this study, we evaluated the pharmacological effects of an ITK selective inhibitor (ITKsi) on acute GVHD using murine bone marrow transplantation models. First, we found that CD4+ T cell differentiation toward Th1, Th2, or Th17 was inhibited following ITKsi treatment in a dose-dependent manner while maintaining regulatory T cells in the presence of alloantigens both invitro and invivo. ITKsi preferentially inhibited inflammatory cytokine production and invivo proliferation of alloreactive T cells. We then demonstrated that short-term exposure of donor graft cells to ITKsi significantly delayed the onset of GVHD-associated mortality without compromising the donor cell engraftment and the graft-versus-tumor effect, indicating the potential of ITK selective inhibition in the setting of clinical allogeneic HSCT. These findings suggest that ITK is a potential therapeutic target against GVHD, and the pharmacological ITK inhibitor may serve as a novel strategy for immune regulation after HSCT.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIb. The 2020 Preemptive Therapy Working Group Report

Chronic graft-versus-host disease (GVHD) commonly occurs after allogeneic hematopoietic cell transplantation (HCT) despite standard prophylactic immune suppression. Intensified universal prophylaxis approaches are effective but risk possible overtreatment and may interfere with the graft-versus-malignancy immune response. Here we summarize conceptual and practical considerations regarding preemptive therapy of chronic GVHD, namely interventions applied after HCT based on evidence that the risk of developing chronic GVHD is higher than previously appreciated. This risk may be anticipated by clinical factors or risk assignment biomarkers or may be indicated by early signs and symptoms of chronic GVHD that do not fully meet National Institutes of Health diagnostic criteria. However, truly preemptive, individualized, and targeted chronic GVHD therapies currently do not exist. In this report, we (1) review current knowledge regarding clinical risk factors for chronic GVHD, (2) review what is known about chronic GVHD risk assignment biomarkers, (3) examine how chronic GVHD pathogenesis intersects with available targeted therapeutic agents, and (4) summarize considerations for preemptive therapy for chronic GVHD, emphasizing trial development, including trial design and statistical considerations. We conclude that robust risk assignment models that accurately predict chronic GVHD after HCT and early-phase preemptive therapy trials represent the most urgent priorities for advancing this novel area of research.

Successful and Safe Treatment of Intestinal Graft-Versus-Host Disease (GvHD) with Pooled-Donor Full Ecosystem Microbiota Biotherapeutic: Results from a 29 Patient-Cohort of a Compassionate Use/Expanded Access Treatment Program

Introduction Intestinal graft-versus-host disease (GvHD), following allogeneic hematopoietic stem cell transplantation (allo-HSCT), has a high mortality rate and a reduced life-expectancy. In this context, failure to respond to steroid therapy is associated with limited further therapeutic options, thereby representing an unmet medical need. Aiming at restoring microbiome functions, fecal microbiota transfer (FMT) has proved to be a promising treatment modality in this challenging clinical setting, with recent studies reporting favorable results in steroid refractory-acute GVHD (SR-aGvHD) patients. Here we report on the use of a next-gen FMT product "MaaT013", a standardized, pooled-donor, high-richness microbiota biotherapeutic, used to treat 29 patients with intestinal aGvHD as part of a compassionate use/expanded access treatment program. Patients and methods Twenty-nine allo-HSCT recipients with steroid-dependent or SR intestinal GvHD (classical aGVHD n=22, late-onset aGVHD n=2; aGvHD with overlap syndrome n=5) were treated with MaaT013 biotherapeutic as part of a compassionate use/expanded access treatment program of the developer MaaT Pharma. These patients had previously received and failed 1 to 5 lines (median 3; 22/29 received ruxolitinib) of GvHD systemic treatments. Each patient received 1 to 3 doses (median: 3; total doses administered: 71) of MaaT013, a 150 mL bag, by enema (n=28) or nasogastric tube (n=1). GI-GvHD response was evaluated 7 days after each administration and 28 days after the first dose. Prepared under Good Manufacturing Practices, MaaT013 biotherapeutics are characterized by a highly consistent richness of 455 ±3% Operational Taxonomic Units and an Inverse Simpson index greater than 20. Batch release specifications are based on potency (viability), identity (diversity), and purity (microbiological safety testing and proportion of proinflammatory species), ensuring the desired consistency across batches. Results We observed a GI overall response rate of 59% (17/29) at day 28 after first dosing, including 9 complete response (CR), 6 very good partial response (VGPR), and 2 partial response (PR). Considering the best GI response achieved, 20/29 patients (69%) achieved at least a PR, with 9 CR, 8 VGPR and 3 PR. Among the 29 treated patients, 16 were still alive at last follow-up (median follow-up (FU): 131.5 days; range [28; 413]) and 6 months overall survival was 54%. Among the 9 patients achieving CR, all were still alive at last follow-up (median FU: 197 days; [49; 301]) and were able to taper or stop steroids and immunosuppressants. Among these 9 patients, three patients presented GI symptom recurrence between 2 and 3 months after dosing. In 2 patients, this recurrence occurred after heavy antibiotic treatment, one of them received an additional MaaT013 dose and achieved a second CR. Of note, among these 9 patients, mild chronic mucosal GvHD symptoms persisted in one patient, and molecular relapse of hematologic malignancy was observed in another. The safety of the MaaT013 microbiota biotherapeutic was satisfactory for all patients. One patient developed "possibly related" sepsis one day after the third dosing but no pathogen was identified in blood cultures, and the patient recovered after a course of antibiotics. Another patient developed C. difficile diarrhea 24 hours post-administration. This was not causally related to MaaT013, as C. difficile testing was negative in the MaaT013 lot. Nosocomial transmission was suspected as the cause as several patients with C. difficile infection were hospitalized in the same unit during this period. Conclusions We herein report for the first time the treatment of 29 patients with steroid-dependent or SR intestinal aGvHD using a full ecosystem, standardized, pooled-donor, high-richness biotherapeutic. The overall response rate was 59% with the off-the-shelf MaaT013 product, which was shown to be safe and effective in these heavily pre-treated and immunocompromised patients, warranting further exploration of the full ecosystem microbiota restoration approach. Disclosures Malard: Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Keocyt: Honoraria; Theralos/Mallinckrodt: Honoraria; Biocodex: Honoraria. Plantamura:MaaT Pharma: Current Employment. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Phase 1 Study of Alvelestat, an Oral Neutrophil Elastase Inhibitor, in Patients with Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation

Introduction Bronchiolitis Obliterans Syndrome (BOS) is a rare but devastating complication of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and is associated with a high morbidity and mortality. There is a dearth of treatment options for BOS and new strategies are needed. Airway neutrophilia is a hallmark of BOS, even in the absence of infection, and neutrophil elastase (NE) is an enzyme that has been implicated in the pathogenesis of BOS. We conducted a phase 1 study of an oral NE inhibitor, alvelestat, in patients with BOS after HCT. Methods Patients age ≥18 years with BOS and chronic GVHD after HCT were recruited to the National Cancer Institute protocol (NCT02669251). Patients had stable systemic immunosuppression and FEV1 ≥30% on pulmonary function tests (PFTs). This phase 1 study had 2 parts: 8-week intra-patient dose escalation period, followed by a continuation period that allowed for up to 6 months of treatment. Alvelestat was given orally starting at 60mg twice daily (the dose previously used in patients with chronic lung disease) and increased every 2 weeks as tolerated to 120mg twice daily, 180mg twice daily, and finally 240mg twice daily. Patients continued this dose until completion of the continuation phase, or occurrence of unacceptable toxicity, dose interruption &amp;gt;28 days, or progression of GVHD or BOS. Primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities. Secondary objectives included determining pharmacokinetics, markers of NE activity, and markers of inflammation in blood and sputum. PFTs and chronic GVHD evaluations were performed at baseline, 4 weeks and 8 weeks during the dose escalation period, and at 3 months and 6 months during the continuation period. Results Between 2016 and 2018, 7 patients were enrolled (3 men and 4 women). Median FEV1 after bronchodilator at time of enrollment was 44% (range 38-74). All 7 patients were able to tolerate dose escalation of alvelestat up to the maximum dose 240mg twice daily; MTD was not reached. The most common adverse events (AEs) that were possibly related to study treatment were all grade 2, and included increased creatinine (3 patients), ALT or AST elevation (3 patients), and upper respiratory infection (3 patients). The only grade 3 AEs that were possibly related to study drug were gastroenteritis and vomiting requiring hospitalization in 1 patient and pneumonia in 1 patient. Three patients completed the study with 8 weeks + 6 months of treatment. Four patients required dose interruptions, and only 1 of those required dose reduction for grade 3 gastroenteritis (resulting in dehydration and elevated creatinine). Four patients discontinued treatment prior to end of study: 2 patients had dose interruption of &amp;gt;28 days due to adverse events, 1 patient had a decline in FEV1 after pneumonia, and treatment was stopped in 1 patient due to investigator discretion. The median duration of treatment was 6.4 months. Based on NIH chronic GVHD consensus criteria, 6 patients had unchanged disease and 1 patient had progressive disease (decline in FEV1 after pneumonia). Although patients did not achieve the 10% improvement in FEV1 required for an organ response, 2 patients had improvement of 9% in FEV1 and 4 patients had improvement in the Lee chronic GVHD symptom scale lung score. Preliminary pharmacokinetic analyses of the 7 patients showed a linear dose-dependent increase in each exposure metric (steady-state trough and steady-state peak), despite some inter-patient variability. Bronchoalveolar lavage fluid and induced sputum samples are being analyzed for NE activity. Conclusion In this phase 1 study of the oral NE inhibitor, alvelestat, in patients with BOS after HCT, MTD was not reached and the study drug was well tolerated. Six patients had stable disease, while 1 patient had progression in the setting of pneumonia. Two patients notably had improvement in FEV1 of 9%, and 4 patients experienced improvement in symptoms. We have demonstrated that NE inhibition is well tolerated and shows a signal of stabilizing disease in patients with advanced BOS. Further study of the clinical efficacy of alvelestat in BOS after HCT is warranted, especially at an earlier stage of disease and longer duration of drug administration. Disclosures No relevant conflicts of interest to declare.

Anti-ICOS mAb Targets Pathogenic IL-17A-expressing Cells in Canine Model of Chronic GVHD.

Chronic graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality in transplant patients. We have previously shown that 3 doses of an anti-inducible costimulator (ICOS) mAb transiently ameliorated symptoms and extended survival of dogs affected by chronic GVHD over that of control dogs. The purpose of this study was to specifically correlate changes in T-cell populations in the peripheral blood with anti-ICOS treatment and chronic GVHD progression and regression to reach a better understanding of the mechanism of the disease and prioritize future studies. Peripheral blood cells from canines transplanted with DLA-mismatched bone marrow and peripheral blood mononuclear cells to generate chronic GVHD were analyzed by flow cytometry using a panel of antibodies specific to helper and cytolytic T cells. Chronic GVHD was specifically associated with an increase in CD4+ICOS+ cells, ICOS+ cells expressing IL-17A, and CD8+ cells generating granzyme B. Treatment with anti-ICOS mAb at onset of chronic GVHD symptoms specifically targeted IL-17A+-expressing cells, transiently relieved symptoms, and lengthened survival but was unable to reduce the percentage of CD8+ T-cells expressing granzyme B. These studies suggested a role for both CD4+ and CD8+ T cells in pathogenesis of chronic GVHD in the canine model. We propose that future studies should focus on further extending survival by developing a treatment that would control both CD4+ and CD8+ T cells.

Pretransplant Short-Term Exposure of Donor Graft Cells to ITK Selective Inhibitor ONO-7790500 Prevents Acute Gvhd in Mouse BMT Model

Introduction and Objectives Graft-versus-host disease (GVHD) triggered by activated donor graft cells still remains a major complication and course of non-relapse mortality after HSCT. Interleukin-2-inducible T-cell kinase (ITK) is a TEC family cytoplasmic tyrosine kinase of crucial importance for T cell development and TCR signaling. Recent studies demonstrated that ITK-deficient CD4+ T cells easily differentiated into regulatory T cells (Tregs) and ITK/BTK inhibitor ibrutinib could improve chronic GVHD symptoms in mouse model and human clinical study, suggesting that ITK may have important roles in post-transplant immune tolerance. In this study, we examined the effects of ITK-selective inhibitor (ITKsi; ONO-7790500) on acute GVHD by using murine BMT model. Methods Allogeneic response of ITKsi-treated CD4+ T cells from B6 was evaluated by in vitro system and murine BMT model. In BMT experiments, lethally irradiated 10-week old B6D2F1 recipient mice were transplanted with 5 × 106 TCD BM together with 1.5 × 106 CD4+ T cells from B6 donors. Survival and GVHD severity were clinically monitored, and T cell subset reconstitution and serum cytokine profile were also examined. Results First, to examine the influence of ITKsi on alloreactive T cell to the corresponding antigens in vitro, CD4+ T cells isolated from B6 mice were exposed to ITKsi for 3 hours and then cultured with irradiated Balb/c stimulators. Proliferation and IFN-gamma production of ITKsi-treated T cells in response to allogeneic stimulators were significantly reduced in comparison to those from controls (P Conclusion Taken together, these data showed that pretreatment of CD4+ T cells with ITKsi efficiently regulated alloreactive T cell and improved the symptoms of acute GVHD. ITKsi inhibited both Th1 and Th2 response but spared the expansion of donor-derived Tregs. Our findings suggest that graft manipulation with short-term culture with ITKsi just before transplant could provide a simple but efficient strategy to modulate alloreactive T cell response and clinical GVHD.

Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial

Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative-reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed. Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·60–7·60]; p=0·0016). At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·9–23·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·9–25·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·2–29·2) versus 31·3% (21·9–40·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·5–35·1) in the anti-thymocyte globulin group and 41·3% (31·3–51·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 70·6% (95% CI 60·6–78·6) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 53·3% (42·8–62·8) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·35–0·90]; p=0·017). Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient in the anti-thymocyte globulin plus GVHD prophylaxis group died of Epstein-Barr virus hepatitis, but no deaths were attributable to anti-thymocyte globulin. The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including decreases in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-thymocyte globulin should be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. Canadian Institutes of Health Research and Sanofi.

Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

Successful and Safe Treatment of Intestinal Graft-Versus-Host Disease (GvHD) with Pooled-Donor Full Ecosystem Microbiota Biotherapeutics

Introduction Intestinal Graft-versus-Host Disease (GvHD), following allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), comes with a high mortality rate and a reduced life-expectancy. In this context, failure to respond to steroid therapy is associated with an absence of further therapeutic options, thereby representing an unmet medical need. A marked reduction in gut microbiota diversity leading to loss of functions was strongly associated with reduced overall survival in GvHD, while a high gut microbiota diversity appears to be protective. Aiming at restoring microbiome functions, Fecal Microbiota Transfer proved to be a promising treatment modality in this challenging clinical situation, with recent studies reporting favorable results in steroid refractory-acute GVHD (SR-aGvHD) patients. Here we report on the use of "MaaT013", a standardized, pooled-donor, high-richness microbiota biotherapeutic, used to treat 8 patients with intestinal-predominant aGvHD. Patients and methods Eight allo-HSCT recipients with steroid-dependent or steroid-refractory gastrointestinal GvHD (classical aGVHD n=3, late-onset aGVHD n=2; aGvHD with overlap syndrome n=3) were treated with the MaaT013 biotherapeutic as part of a compassionate use program. These patients had previously received and failed 1 to 5 lines (median 2.5) of GvHD systemic treatments. MaaT013 microbiota biotherapeutics were provided as a pharmaceutical preparation to hospitals by the developer, "MaaT Pharma". Each patient received 1 to 3 doses (median: 3; total doses administered: 21) of MaaT013, a 150 mL bag, by enema (n=7) or nasogastric tube (n=1). GvHD response was evaluated 7 days after each administration and 28 days after the first dose. Prepared under Good Manufacturing Practices, MaaT013 biotherapeutics are characterized by a highly consistent richness of 455 +/- 3% Operational Taxonomic Units (OTUs) and an Inverse Simpson index greater than 20. Batch release specifications are based on potency (viability), identity (diversity), and purity (microbiological safety testing following regulatory guidelines and proportion of proinflammatory species), ensuring the desired consistency between batches. Results We observed 6/8 positive responses at D28 after first dosing, including 3 Complete Responses (CR), one Very Good Partial Response (VGPR), and 2 Partial Responses (PR). Considering the best GI response achieved, all (8/8) patients experienced at least a PR, with 3 CRs, 2 VGPRs and 3 PRs. The 3 patients with CR were still alive at last follow-up (60 to 192 days after last dosing; median: 115 days) and were able to taper and stop steroids and immunosuppressants without relapse of GI symptoms. Of note, among these 3 patients, mild mouth chronic GvHD symptoms persisted in one patient, and relapse of hematologic malignancy was observed in another patient. Among the 8 treated patients, 5 were still alive at last follow-up (60 to 232 days after last dosing; median: 125 days). The safety of the MaaT013 microbiota biotherapeutic was satisfactory in all patients. One patient developed a possibly related sepsis one day after the third MaaT013 administration. In the latter case, no pathogen was identified in blood cultures, and the patient recovered after a course of antibiotics. Conclusions We herein report for the first time the treatment of 8 patients with steroid-dependent or steroid-refractory intestinal aGvHD using a full ecosystem, standardized, pooled-donor, high-richness biotherapeutic. Overall, 3/8 patients attained a complete response following treatment with the off-the-shelf MaaT013 product, shown to be safe and effective in these immunocompromised patients with severe conditions, warranting further exploration of the full ecosystem microbiota restoration approach. Disclosures Malard: Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria; Therakos/Mallinckrodt: Honoraria; Keocyte: Honoraria; Janssen: Honoraria. Plantamura:MaaT Pharma: Employment. Carter:MaaT Pharma: Employment. Chevallier:Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Anti-Thymocyte Globulin for Patients Undergoing Hematopoietic Cell Transplantation from Unrelated Donors: A Randomized, Controlled, Open-Label, Phase 3, Multicentre Trial from Cell Therapy Transplant Canada

Background: We previously reported that pretreatment with anti-thymocyte globulin (ATG) decreases the use of immunosuppressive therapy (IST) and the occurrence of chronic graft versus host disease (CGVHD) at 12 months after haematopoietic cell transplantation. We have now examined whether these benefits would persist at 24 months. Methods: This was a phase 3, multicentre, open-label, randomized controlled trial at 10 centres in Canada and one in Australia. Patients were eligible if they had a hematological malignancy and were to receive an unrelated donor graft. They could receive myeloablative or non-myeloablative/ reduced intensity conditioning, Patients were randomized to receive, or not receive, ATG 4·5 mg/kg as part of conditioning. The primary endpoint was freedom from all systemic immunosuppressive therapy (IST) without resumption up to 24 months after transplantation. Findings: Thirty-eight (38·3%) of 99 patients in the ATG group were free from IST at 24 months compared with 18 (18·6%) of 97 patients in the No ATG group (adjusted OR 3·49 [ 95 CI 1·60 - 7·60]; p = 0·002). Most patients retained the same IST status from 12 to 24 months, 74 (74·7%) and 79 (81·4%) in the ATG and No ATG and groups respectively. The cumulative incidence of relapse was 16 (16·2%) of 99 patients in the ATG group compared with 17 (17·5%) of 97 patients in the No ATG group (p=0·73). The cumulative incidence of CGVHD at 24 months was 26 (26·3%) of 99 patients in the ATG group compared with 40 (41·2%) in the No ATG group (p=0·032). Symptoms of CGVHD were more prevalent in the No ATG, the scores by Lee scale being 13·57 (SE 1·47) and 19.90 (SE 2·15) in the ATG and No ATG groups respectively; (p=0·017). The cumulative incidence of non-relapse mortality was 21 (21·2%) of 99 patients in the ATG group compared with 30 (30·9%) in the No ATG group (p=0·14). Overall survival at 12 months was 74·8% (SE 4·4) compared with 64·9% (SE 4·8) in the ATG and No ATG groups respectively (adjusted HR 0·56 [95% CI [0·35-0·90]; p=0·017)). At 24 months follow up of all patients, 70 (71%) patients out of 99 in the ATG group and 52 (53.6%) out of 97 in the No ATG group were alive (p=0·018). Both acute and chronic graft versus host disease- and relapse free-survivals (GRFS and CRFS) were significantly higher in the ATG group (p=0·0034 and p=0·01 respectively). Depressive symptoms were more prominent in the No ATG group, the mean CES-D scores being 10·39 (SE 1·29) in the ATG group compared with 14·63 (SE 1·48) in the No ATG group (p=0·034). Interpretation: Pretreatment with ATG provides long term benefits consisting of decreases in CGVHD and its symptoms, depressive symptoms, use of IST and improvement in survival. This trial is the first to demonstrate both a survival advantage and a decrease in depressive symptoms for patients receiving ATG. ATG should be included in the preparative regimens of all transplants that use unrelated donors. Clinical Trial Number: This trial was registered at ISRCTN, number 29899028 and at clinicaltrials.gov, number NCT01217723. Funding Statement: The Desroches Bone Marrow Transplant Fund, McMaster University (ON, Canada) provided funding for protocol development. Declaration of Interests: SJL reports personal fees from Pfizer, personal fees and non-financial support from Mallinckrodt, personal fees and non-financial support from Incyte, personal fees from Pfizer, personal fees from Kadmon, grants from Takeda, grants from Amgen, grants from Kadmon, grants from Syndax, grants from Pfizer, grants from AstraZeneca, outside the submitted work. GP and IW report consulting fees from Sanofi. TN and IW report financial grant support from Sanofi. GD, DS and TN report grants from Canadian Institutes of Health Research. All other authors declare no competing interests. Ethical Approval Statement: This study was approved by the Research Ethics Boards of all participating transplant centres.

2018 update on chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) occurs in 30-40% of patients who undergo allogeneic hematopoietic cell transplantation. The symptoms of chronic GVHD resemble those of autoimmune diseases, and many sites, including the eyes, mouth, skin, gastrointestinal tract, liver, lungs, joints, and fascia, can be affected. Severe chronic GVHD increases patients' mortality and decreases their quality of life. The 2014 National Institutes of Health (NIH) Consensus has proposed a three-step model for classification of the mechanisms of chronic GVHD: early acute inflammation, chronic inflammation with dysregulated immunity, and tissue fibrosis. Many drugs targeting specific biological pathways for treating chronic GVHD are under development. The NIH Consensus has also clarified objective response measures, optimal endpoints, and clinical trial designs to be used for drug approval. More than 30 novel drugs for GVHD treatment are currently being tested in over 80 clinical trials worldwide.

Association of Socioeconomic Status with Chronic Graft-versus-Host Disease Outcomes

Chronic graft-versus host disease (GVHD) is a chronic and disabling complication after hematopoietic cell transplantation (HCT). It is important to understand the association of socioeconomic status (SES) with health outcomes in patients with chronic GVHD because of the impaired physical health and dependence on intensive and prolonged health care utilization needs in these patients. We evaluated the association of SES with survival and quality of life (QOL) in a cohort of 421 patients with chronic GVHD enrolled on the Chronic GVHD Consortium Improving Outcomes Assessment study. Income, education, marital status, and work status were analyzed to determine the associations with patient-reported outcomes at the time of enrollment, nonrelapse mortality (NRM), and overall mortality. Higher income (P = .004), ability to work (P < .001), and having a partner (P = .021) were associated with better mean Lee chronic GVHD symptom scores. Higher income (P = .048), educational level (P = .044), and ability to work (P < .001) also were significantly associated with better QOL and improved activity. In multivariable models, higher income and ability to return to work were both significantly associated with better chronic GVHD Lee symptom scores, but income was not associated with activity level, QOL, or physical/mental functioning. The inability to return to work (hazard ratio, 1.82; P = .019) was associated with worse overall mortality, whereas none of the SES indicators were associated with NRM. Income, race, and education did not have statistically significant associations with survival. In summary, we did not observe an association between SES variables and survival or NRM in patients with chronic GVHD, although we found some association with patient-reported outcomes, such as symptom burden. Higher income status was associated with less severe chronic GVHD symptoms. More research is needed to understand the psychosocial, biological, and environmental factors that mediate this association of SES with major HCT outcomes.

JAK1/2 Inhibition As a Salvage Therapy for Steroid Refractory Acute and Chronic Graft Versus Host Disease in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients

Introduction: The Jak1/2 inhibitor, ruxolitinib, is effective as a salvage therapy for steroid refractory (SR) graft versus host disease (GVHD) in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. The effectiveness of ruxolitinib for the salvage of SR-GVHD in pediatric HSCT patients has not been studied.Objective: To evaluate ruxolitnib as a salvage therapy for SR- acute GVHD (aGVHD) and chronic GVHD (cGVHD) in pediatric HSCT recipients.Methods: We conducted a retrospective review of pediatric HSCT recipients who received ruxolitinib for treatment of SR-GVHD at our center. SR aGVHD and cGVHD were defined as lack of response to high dose corticosteroids (1-2 mg/kg/day) for 1 and 3 weeks, respectively. Ruxolitnib was administered orally at 5 mg twice daily for patients weighing ≥ 25 kg or 2.5 mg twice daily if < 25 kg. The dose was halved if azoles were concurrently administered, and increased to a maximum of 10mg twice daily if the initial dose was tolerated. A complete response (CR) was defined as resolution of acute and chronic GVHD symptoms. Partial response (PR) in aGVHD was defined as improvement in at least 1 stage in 1 organ without worsening of other organ stages, and in cGVHD by at least 50% reduction of current immune suppressive doses, lasting for 4 weeks. No response (NR) was defined as worsening of GVHD or need for escalation of immune suppression. Responses were assessed from the initiation of ruxolitinib until either escalation of immune suppression or ruxolitinib discontinuation. The best response in the above specified time was assessed. Durable response was defined as CR or PR lasting for 3 weeks or greater.Results: Fifteen patients of median age 8.5 years (range 1.6-16.5 years) received ruxolitinib for acute (n=13) and chronic (n=2) GVHD. Transplant characteristics are shown in table 1.aGVHD patients: Grades of aGVHD at time of ruxolitinib administration were grade II (n=2), III (n=9) and IV (n=2). Forty-seven percent (n=6) of patients had acute gastrointestinal (GI) GVHD, 6% (n=1) had acute skin GVHD and the remaining 47% (n=6) had multiple organ involvement. aGVHD was diagnosed at a median of 41 days (20-169 days) and ruxolitinib was started at a median of 147 days (range 55-538 days) after HSCT. Patients received a median of 4 immune suppressive medications (range 1-6) prior to starting ruxolitinib. The median initial dose of ruxolitinib was 5 mg twice daily (range 2.5 mg daily- 5 mg twice daily). Doses were escalated in 11/15 patients, and 9/15 patients reached a maximum dose of 10 mg twice daily. Ruxolitinib was discontinued in 28% (n=3) of patients after 2-9 days and these patients were excluded from response analysis. Patients who received additional immune suppressive agents either 2 weeks prior to starting ruxolitnib (n=2) or after 2 weeks after initiation of ruxolitinib (n=1) were also excluded. Of the 7 evaluable aGVHD patients, 14% (n=1) had CR and 72% (n=5) had PR at a median of 20.5 days from initiation of ruxolitinib. NR was observed in 14 %( n=1) patients. Overall response rate of ruxolitinib was 86%. Durable responses were observed in 43% (n=3) of patients.cGVHD patients: Two patients with severe cGVHD involving skin, eye and GI (n=1), and skin, joints and liver (n=1) received ruxolitinib at 1486 and 2177 days after HSCT, respectively, at a maximum dose of 10 mg twice daily. One patient had PR in 2.5 weeks and one had NR.Adverse effects in all 15 patients included elevated liver enzymes (n=5; 30%), neutropenia (n=8; 53%) and thrombocytopenia (n=4; 26%) leading to discontinuation of ruxolitinib in 10/15 patients. Infectious complications in the 9 patients who were evaluated for responses included EBV viremia (n=2; 22%), adenovirus viremia (n=1; 11%), BK viremia (n=3; 33%), bacterial infections (n=5; 55%) and fungal infections (n=1; 11%). At a median follow up of 341 days (range 260-2331 days) after HSCT 55% (n=5) of patients were alive.Conclusion: Ruxolitinib may have a limited role in the durable salvage of acute and chronic SR-GVHD in pediatric HSCT patients and should be used cautiously in patients with pre-existing liver dysfunction or cytopenia. Future large scale studies may be needed to assess the effectiveness of ruxolitinib in pediatric HSCT patients with SR-GVHD. [Display omitted] DisclosuresDavies:Novartis: Honoraria.