Diagnosis Of cGVHD Research Articles

Epidemiology and Real-World Treatment of Chronic Graft-Versus-Host Disease Post Allogeneic Hematopoietic Cell Transplantation: A US Claims Analysis

Background Chronic Graft-Versus-Host Disease (cGVHD) is a complication of hematopoietic cell transplantation (HCT). While the clinical outcomes of cGVHD are well documented, few studies have assessed its treatment practices in the real-world. The objectives of this study are to quantify the prevalence of cGVHD, to examine provider prescribing patterns, and to evaluate the healthcare cost and resource utilization (HCRU) in a real-world US cGVHD population. Methods This study analyzed de-identified claims from the Medicare FFS 5% sample for beneficiaries enrolled from 2013-2016 and Pharmetrics commercial 2013-2018 databases to identify cGVHD in allogenic HCT patients. cGVHD was identified based on ICD-9/10 diagnosis codes for cGVHD or unspecified GVHD with a first diagnosis >180 days post HCT, or subsequent unspecified GVHD diagnosis >12 months post index diagnosis. Chronic GVHD prevalence was estimated by calculating age-adjusted prevalence rates within the Medicare and Pharmetrics sample populations and applying rates to the total US patient subpopulations as determined by CMS and Census data. Prevalence estimates were based on the last complete year of both Medicare FFS and Pharmetrics data (2016). Longitudinal and Line of Therapy (LOT) analyses were based on data from 2013-2018. A new LOT was defined as starting with the addition of systemic therapy to a patient's cGVHD regimen, regardless of prior lines of therapy or prior treatment. Treatments that stopped and restarted within 60 days were considered continuous treatment. Healthcare costs were calculated by adding the inpatient, outpatient, and pharmacy insurer and beneficiary paid amounts for the commercially insured population. Total HCRU was assessed using the number of inpatient and outpatient visits following the initial cGVHD diagnosis. Results In 2016, the projected prevalence of cGVHD in the US based on the Medicare FFS and Pharmetrics commercial databases was 14,017 individual patients. Within 3 years post allogeneic HCT, 42% of patients developed cGVHD; 66% of cGVHD patients had a prior diagnosis of acute GVHD. The majority of cGVHD patients received at least one systemic therapy; 71% and 47% of cGVHD patients progressed to a second and third LOT, respectively (Table 1). Of patients that received a second and third LOT, the average time from diagnosis to the second and third LOT was approximately 7 months and 10 months, respectively. Over 80% of cGVHD patients received systemic corticosteroid therapy for the treatment of cGVHD within 12 months post diagnosis, and 41% of cGVHD patients were receiving a corticosteroid within the 30 days prior to diagnosis. Within the 12 months post cGVHD diagnosis, most patients received a corticosteroid or a corticosteroid combination as a first LOT (57%), which decreased slightly as patients progressed to second and third line of therapy (49% and 48%, respectively). A total of 25 unique therapeutic agents and over 150 combinations were used in second and third LOT. While newer agents, such as ibrutinib and ruxolitinib, are continuing to increase in utilization among cGVHD patients, these therapies are only used among 1% (ibrutinib) and 1-3% (ruxolitinib) of patients through their first three lines of therapy in the patients captured in Pharmetrics commercial database through June 2018. In the 12 months post diagnosis, cGVHD patients had an average of 21.0 GVHD-related inpatient and outpatient visits (2.8 inpatient and 18.2 outpatient visits). In 2016 the average total annual cost per commercially insured cGVHD patient was $291,357. Conclusion A significant proportion of allogenic HCT patients continue to develop cGVHD, and despite advances in the understanding of cGVHD, corticosteroids remain the mainstay of therapy. However, most cGVHD patients are not adequately managed with first line corticosteroids, and many patients are cycling through several therapies, likely in part due to lack of efficacy and toxicity associated with currently available treatments. Real-world utilization of systemic therapies is highly variable, particularly for patients who progress beyond the first LOT, which highlights the need for evidence-based treatment approaches. cGVHD is a highly burdensome complication of allogenic HCT, and safer, more effective treatments are needed as many patients are not currently well managed on available therapies. Disclosures Bachier: Viracyte: Consultancy; Kadmon Corporation, LLC: Consultancy; Sanofi: Speakers Bureau. Aggarwal:Kadmon Corporation, LLC: Employment, Equity Ownership. Hennegan:Kadmon Corporation, LLC: Consultancy. Milgroom:Kadmon Corporation, LLC: Consultancy. Francis:Kadmon Corporation, LLC: Consultancy. Rotta:Jazz: Speakers Bureau; Kadmon Corporation, LLC: Consultancy.

Osteogenic/Adipogenic Imbalance in Bone Marrow Nestin+ mesenchymal Stem Cells in Patients with Chronic Graft-Versus-Host Disease

Background: Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The roles of bone marrow niche in cGVHD pathogenesis have gained increasing attention in recent years. Nestin+ mesenchymal stem cells (MSCs) is an important component of bone marrow niche. However, the potential implication of Nestin+ MSCs in the pathophysiology of cGVHD has not been completely clarified. Methods: A total of 68 patients with hematologic malignancies who underwent allo-HSCT at Nanfang Hospital between April 2016 and October 2018 were enrolled in this experimental study. We analyzed expanded Nestin+ MSCs from patients with cGVHD and compared them with patients without cGVHD. The diagnosis and grade of cGVHD was made at the time of sample collection according to National Institutes of Health criteria (Howard M.S. et. al. BBMT 2015). The results were compared using one-way ANOVA and unpaired two-tailed Student t-test. Statistical significance was defined as P value of <.05. Result: The Nestin+ MSCs from both groups showed similar morphology, immunophenotype, proliferation, and apoptosis. However, the adipogenic differentiation capacity of Nestin+ MSCs in patients with cGVHD was significantly reduced compared with patients without cGVHD (relative expression of PPARγ 2.22±0.27, and 6.82±0.87, respectively, P<0.05). The osteogenic differentiation capacity was significantly increased in patients with cGVHD (relative expression of RUNX2 3.84±0.38, and 1.95±0.52, respectively, P<0.05)(Figure 1A,B). These abnormal differentiations were more significant in patients with moderate/severe cGVHD. Furthermore, β-catenin phosphorylation decreased and nuclear β-catenin increased in the Nestin+ MSCs of cGVHD patients(Figure 1 C). Conclusion: These results demonstrate that Nestin+ MSCs from cGVHD patients had abnormal differentiation characterized by decreased adipogenic differentiation capacity and enhanced osteogenic capacity. The reduction of phosphorylation of β-catenin play an important role in these abnormal differentiations. Disclosures No relevant conflicts of interest to declare.

Ibrutinib for Chronic Pulmonary Graft-Versus-Host-Disease after Progression on Prior Therapy

Introduction: Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Pulmonary cGVHD consists of both obstructive and restrictive pulmonary changes, and as such, represents a broad spectrum of disease. While corticosteroids are a mainstay of treatment, there is no established standard-of-care for second line therapy. The Bruton's tyrosine kinase inhibitor ibrutinib was recently approved for treatment of cGVHD after failure of 1 or more lines of systemic therapy. However, the role of ibrutinib in patients with pulmonary cGVHD is not well understood. Here we report an institutional experience of ibrutinib as non-first-line therapy for pulmonary cGVHD. Methods: We performed a retrospective study of adult patients with steroid-dependent or steroid-refractory pulmonary cGVHD treated with ibrutinib as non-first line therapy between 2014 and 2018. Patients were diagnosed with pulmonary cGVHD if they met the 2014 National Institutes of Health cGVHD Consensus Panel criteria or were diagnosed based on expert opinion. All patients received appropriate GVHD prophylaxis at the time of transplant. The severity of pulmonary cGVHD was assessed by pulmonary function testing (PFT) done prior to and 180 days after initiation of ibrutinib therapy. The primary clinical outcome was absolute change in the percentage of predicted forced expiratory volume in 1 second (%FEV1) over 180 days. Patients were identified as having a complete response (normalization of %FEV1), partial response (≥10% increase in %FEV1), stable disease (<10% change in %FEV1), or progression (≥10% decrease in %FEV1). Results: A total of 17 patients received ibrutinib for pulmonary cGVHD (mean age 46 ± 11 years, 59% male), with a mean duration of 34 ± 17 weeks from transplant to diagnosis of cGVHD (31% de novo, 31% progressive, 38% interrupted). On average, patients had 5 involved organs, received 4 treatments for cGVHD prior to ibrutinib, and 14/17 (82%) were on at least 0.25 mg/kg/day of prednisone (or an equivalent dose of corticosteroid) at the time of ibrutinib initiation. The median %FEV1 at time of ibrutinib initiation was 50 ± 24%. At 180 days after initiation, 14/17 patients (82%) continued receiving ibrutinib (1 patient each discontinued therapy for lack of symptomatic improvement, oral ulcers, and enrollment in a clinical trial). Among the 14 patients who completed 180 days of therapy, only 3 had disease progression (Figure 1). Conclusions: Ibrutinib was generally well tolerated as a non-first line therapy for pulmonary cGVHD. In this cohort of patients with steroid-dependent or steroid-refractory disease who had progression on multiple lines of therapy, most had stable or improved pulmonary function by %FEV1 while on ibrutinib. Given the heterogeneity of pulmonary cGVHD, further studies can help clarify which patients are most likely to demonstrate response. Disclosures Miklos: Becton Dickinson: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Celgene-Juno: Consultancy; AlloGene: Consultancy; Janssen: Consultancy; Precision Bioscience: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Miltenyi: Consultancy, Research Funding; Novartis: Consultancy.

KD025 for Patients with Chronic Graft-Versus-Host Disease (cGVHD) - Long-Term Follow-up of a Phase 2a Study (KD025-208)

KD025 for Patients with Chronic Graft-Versus-Host Disease (cGVHD) - Long-Term Follow-up of a Phase 2a Study (KD025-208)

Clinical Outcomes of Ruxolitinib in the Salvage Treatment of Chronic Graft-Versus-Host Disease

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for malignant and non-malignant hematological diseases. Chronic Graft-versus-Host Disease (cGVHD) is a major contributor to late morbidity and mortality, significantly affects patients' quality of life.The first-line systemic therapy is corticosteroid,but 40%-60% patients need second-line or additional treatments. Available second-line therapies such as cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus and sirolimus are less than ideal. Ruxolitinib is is an orally selective JAK1 and JAK2 inhibitor that has been approved by the FDA for the treatment of myelofibrosis. Prospective phase II and III trials using Ruxolitinib have demonstrated that it's effective and safe in the treatment of cGVHD. In this report, we share the clinical outcomes of using Ruxolitinib as salvage treatment of cGVHD. Method s This is a retrospective study of 39 patients with cGVHD who received Ruxolitinib as salvage treatment after failure of first-line or second-line therapies given at least one week.All patients were informed of the off-label use of Ruxolitinib and provided informed consent. Patients were treated with Ruxolitinib orally as an add-on immunosuppressive therapy(5mg twice daily if body weight ≥ 25kg and 2.5mg twice daily if body weight <25kg).If their cGVHD improved,2.5 mg was reduced weekly until withdrawal.Patients were monitored weekly for blood test and cytomegalovirus (CMV) DNA. Results Among the 39 patients,19 were male (48.7%) and 20 were female(51.3%). According to the 2015 NIH cGVHD diagnosis and staging criteria, 10 patients had mild,14 patients had moderate and 15 patients had severe cGVHD.The median time of cGVHD was 112 days (range 38-2000 days),the median time of Ruxolitinib taken was 56 (7-154) days,the median follow-up time was 221 (33-312) days,and the median time of Ruxolitinib taking effect was 14 (7-28) days.All patients tolerated Ruxolitinib well.According to the 2015 NIH cGVHD therapeutic response criteria,the overall response rate was 84.6%, including complete remission (CR) in 24 (59% )and partial response (PR) in 10 (25.6%). However,four patients (10.3%) had no response (NR) and two patients (5.1%) had disease progression. The organ responses (CR+PR) were as follows: skin 19/21 (90.5%),gastrointestinal tract 5/6 (83.3%),liver 5/6 (83.3%),lung 8/11(72.7%),hematologic 1/1(100%),mouth 3/5(60%),eyes 4/8 (50%),genitourinary tract 0/2 (0%),and musculoskeletal 0/1(0%).Among the adverse effects,eight cases (20.5%) had CMV reactivation and was controlled with antiviral therapy,ten cases (25.6%)had cytopenia, six cases (15.4%)had cGVHD relapse after Ruxolitinib was discontinued,two cases (5.1%) developed relapse of primary disease, and three cases (8%) died of pulmonary infection. Conclusions Low-dose of Ruxolitinib was effective to refractory cGVHD with good drug tolerance and controllable adverse effects. Ruxolitinib is expected to be a first- or second-line treatment for cGVHD but requires a randomized controlled trial. OffLabel Disclosure: Ruxolitinib,an orally selective JAK1 and JAK2 inhibitor,has been approved by the FDA for the treatment of myelofibrosis.We applied Ruxolitinib as a salvage treatment of chronic Graft-Versus-Host Disease after failure of the first or second-line therapies.

Clinical Characterization and Cytokine Profile of Fatigue in Patients with Chronic Gvhd

Introduction Chronic graft-versus-host disease (cGVHD) is an autoimmune-like condition caused by allogeneic hematopoietic stem cell transplantation. It is the major cause of non-relapse mortality and morbidity after transplant. The majority of patients with cGVHD experience longstanding fatigue that is associated with decreased quality of life and impaired physical functioning. The pathophysiology and clinical characteristics of fatigue in cGVHD remain poorly understood and no effective treatments exist. Methods This cross-sectional study aimed to describe characteristics of fatigue experienced by patients with cGVHD using SF-36 self-report vitality scale as the primary outcome. 109 patients with fatigue and 72 patients without fatigue were prospectively enrolled and compared using a set of clinical, demographic and behavioral data along with 7 potential cytokine biomarkers of active cGVHD (IFN- γ, IL-6, CXCL-10, MCP-1, CXCL-9, BAFF, ST2). IFN- γ, IL-6, IP-10, and MCP-1 were assayed using V-PLEX by from Meso-ScaleDiscovery (MSD). The BAFF, CXCL9, and ST2 high sensitive assays were developed and customized for clinical testing using MSD electrochemiluminescence immunoassay technology with antibody pairs obtained from R&D Systems. A patient was considered fatigued if SF-36 vitality score was >10 points below the mean of the general population (<40). Results The median Lee cGVHD symptom scale energy score was 6 (1-12) in fatigued individuals as compared to 3 (0-9) in non-fatigued individuals (P=0.0001) suggesting internal validity of the primary endpoint definition. SF-36 MCS and PCS scores were also significantly lower in the fatigued group by 10 points (P=0.0001 for both). Several measures including walk velocity, human activity profile, SF-36 physical and mental health self-report scales were potential predictors of fatigue in univariate analysis (Table 1). Patients with increasing levels of joint involvement were more likely to be fatigued (72% vs 60% with any involvement, p= 0.0067 for increasing involvement score). In addition, fatigued individuals had higher Lee cGVHD symptom burden in skin, breathing, muscles and joints and mental domains. None of the tested cytokines showed significant association with fatigue, even after stratification for time elapsed after cGVHD diagnosis to study enrollment. However, BAFF was shown to decrease in a consistent manner when more time elapsed from cGVHD diagnosis to study enrolment (p=0.015). BAFF levels were significantly associated with NIH joint score, NIH skin score, intensity of immunosuppression and Karnofsky performance status, thus confirming the usefulness of BAFF as a marker of cGVHD activity or severity, but not fatigue. Similarly, none of standard clinical laboratory serum markers of inflammation (e.g. ESR, CRP, C3, C4, albumin) showed significant association with fatigue. Multivariable analysis revealed that NIH joint score (P=0.03), Lee symptom scale sleep (P=0.0004) and depression (P=0.03) questions and PG-SGA nutrition score (P=0.0007) were predictors of fatigue after adjusting for confounders. Antidepressant use or sleep medication use did not differ significantly between the 2 groups (p=0.63 and 0.51, respectively), although patients reporting depression and sleep problems were more likely to be in the fatigued group, thus delineating a potential area for intervention and increasing quality of life. After adjusting for NIH lung score and performance status, known poor predictors of survival in this patient population, fatigue was associated with a slight trend toward lower probability of survival, median 130.6 months vs. median not reached (p=0.074) for fatigued and non-fatigued respectively (HR: 1.45, CI 0.88 to 2.40). Conclusions These results demonstrate that the pathophysiology of fatigue in cGVHD may involve mechanisms other than those reflected by cytokine markers of inflammation known to be associated with disease activity or severity. Musculoskeletal and lung involvement as well as decreased functional performance and capacity are significant features of fatigued patients with cGVHD. Sleep, nutrition and depression may be important therapeutic targets in these patients affected by clinically significant fatigue. Further studies involving longitudinal follow-up and deeper studies of biology are imperative to better understand or treat fatigue in cGVHD patients. Disclosures No relevant conflicts of interest to declare.

Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia.

Chronic graft-versus-host disease (cGVHD) is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia (n = 280). The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria. A total of 169 patients suffered from cGVHD. The patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD (total, 66.0% vs. 53.7%, P = 0.031; moderate to severe, 42.4% vs. 30.1%, P = 0.036) than the patients who had 1 to 2 loci mismatched. The patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD (49.2% vs. 32.9%, P = 0.024) compared with the patients who had other donors. The patients who had grades III to IV acute GVHD (aGVHD) had higher 8-year incidence of cGVHD (total, 88.0% vs. 50.4%, P < 0.001; moderate to severe, 68.0% vs. 27.0%, P < 0.001) compared with the patients without aGVHD. In multivariate analysis, grades III to IV aGVHD was the only independent risk factor for cGVHD. Thus, further interventions should be considered in patients with severe aGVHD to prevent cGVHD.

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria

AbstractChronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

Cellular Immune Function Assay (ImmuKnow) Values during Treatment of Chronic Gvhd Status with Combined Immunosuppressive Drug and Extracorporeal Photopheresis Therapy

Introduction Chronic graft-versus-host disease (cGVHD) is the leading cause of allogeneic hematopoietic stem cell transplantation (alloHSCT) related mortality and morbidity with limited understanding of its pathophysiology. The Cyclex ImmuKnow (IK) test, quantitatively measures the intracellular adenosine triphosphate levels in stimulated T cells. The IK test was FDA approved in 2002 as a functional measure of cell-mediated immunity (CMI) in the immunosuppressed population demonstrating predictive value in acute GVHD but its role in cGVHD is unclear. Methods We conducted a retrospective analysis of the role of IK in 8 alloHSCT. Four patients had a diagnosis of AML, two each had ALL and AA/MDS. All patients had IK drawn at initial diagnosis of cGVHD; five developed refractory cGVHD requiring photopheresis and had IK drawn during the period of ECP. The IK assay results were stratified as: low (0-225 ng/ml), normal (225-525 ng/ml) and high (>525 ng/ml). Results Of the 8 patients with cGVHD, at the time of diagnosis 6 had low IK, 1 was normal, and 1 was high. All of them were on two or more immune suppressive agents (IST) during the time of assay measurement. Post ECP levels did not vary significantly compared to pre-ECP levels except for one patient (Patient 3, Fig. 1) with high IK level (737 ng/ml) at diagnosis of cGVHD and subsequently had significant drop in her IK level after ECP (256 ng/ml at 60 days and 158 ng/ml at 140 days from the start of photopheresis). Discussion The IK values did not correlate with degree of chronic GVHD or its response to treatment with IST and ECP although it should be noted that cGVHD remained stable in all but one patient during the period of IK measurement. Nonetheless, in one patient with increased IK levels at the diagnosis of cGVHD IK decreased over time with slow improvement in her cGVHD, suggesting that levels might show some correlation with the treatment in responding patients. Longitudinal measurements over time may help to adjust IST, and further studies with standardized timing seem warranted.

Metabolic MRI for In Vivo Detection of Graft-Versus-Host Disease in a Pre-Clinical Model

Chronic graft-versus-host disease (cGVHD) remains a prominent barrier preventing successful allogeneic hematopoietic stem cell transplantation (AHSCT). Diagnosis of cGVHD is challenging since biopsies of the involved tissues are associated with bleeding and infection risks. In the absence of biopsy specimens, clinicians rely on subjective clinical scoring for cGVHD diagnosis and monitoring of therapeutic responses. Our previous studies in the pre-clinical cGVHD mouse model demonstrated that the primary cellular mediators of cGVHD, alloreactive donor-derived CD4+ T cells, are distributed to target rather than lymphoid organs. This is in direct contrast to syngeneic HSCT recipients (matched host and donor pairings) where T cells are primarily localized to lymphoid organs. Our prospective metabolic screening and ex vivo metabolic profiling of CD4+ T cell subsets indicated that effector memory T cells (Tem) preferentially utilize aerobic glycolysis. Thus, we hypothesized that visualization of tissues exhibiting high rates of glycolysis could allow in vivo detection of cGVHD in the affected organs since they are infiltrated by alloreactive glycolytic Tem cells. In order to test this, we initiated metabolic magnetic resonance imaging (MRI) in the minor antigen mismatched HSCT mouse model. Following administration of 13C-pyruvate, we measured the conversion of the glycolytic end product, pyruvate, into lactate as a means of evaluating glycolytic rates in target organs. Indeed, hyperpolarized 13C-pyruvate MRI of the liver and gut distinguished allogeneic versus syngeneic HSCT recipients, prior to the development of clinically evident cGVHD. This imaging approach is amenable to clinical translation to potentially allow for cGVHD diagnosis and disease monitoring in patients.

Differential Expression of Immunity Related Genes Can Predict Moderate-Severe Chronic GvHD Early after Myeloablative Hematopoietic Stem Cell Transplantation.

Introduction Chronic graft versus host disease is the major cause of poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Clinically significant moderate-severe chronic GvHD (cGvHD) rarely shows a sustained complete response to immunosuppressive drugs and non-responders either die or suffer long-term. Early and accurate prediction of ensuing cGvHD can help identify high risk patients to make preemptive treatment possible. In the present study, we retrospectively analyzed the transcriptome of immunity related genes at one month post-transplant with the aim to identify a potential early and accurate predictor of clinically significant cGvHD. Methods An adult retrospective cohort of 73 human leukocyte antigen (HLA) matched myeloablative allogeneic HCT recipients were included. All patients received 4.5 mg/kg antithymocyte globulin as GvHD prophylaxis. Diagnosis of cGvHD was based on National Institutes of Health consensus criteria with the median day of diagnosis being 126 days. Total RNA extracted from cryopreserved peripheral blood mononuclear cells at one month post-transplant was used to run a gene expression CodeSet profiling of 594 immunity related genes including 15 internal reference genes using Nanostring Technology. Benjamini Hochberg procedure was used to calculate the P value and the false discovery rate (FDR) of differentially expressed genes. Results A set of 12 differentially expressed genes with a Benjamini Hochberg P-value (BHP) of 7 in this panel of 12 genes was able identify patients with high risk of developing mod-severe cGVHD with a sensitivity of 79% and specificity of 88% (AUC = 0.88, P Conclusion The robust and rapid technique of Nanostring based transcriptome profiling identified a gene panel consisting of 12 genes for an early prediction of moderate-severe cGVHD (one month) with high sensitivity and specificity. A precision medicine approach of preemptive treatment of cGVHD can be possible using this study leading to improved outcomes of HCT.

Continuation of Secondary Systemic Treatment Among Patients with Chronic Graft Versus Host Disease in the United States Is Associated with Reduced Hospital Cost (2009-2016)

Introduction Chronic graft-versus-host disease (cGvHD) is a complication following allogeneic hematopoietic stem-cell transplants (HSCT) occurring when immune cells transplanted from a non-identical donor (i.e., the graft) recognize the transplant recipient (i.e., the host) as foreign. Systemic therapy for ≥1 year is required for patients who meet criteria for moderate-to-severe cGvHD using NIH consensus criteria. This study assessed continuation of secondary systemic treatments (SSTs) in cGvHD patients in the United States (US). Methods A retrospective analysis was conducted using the Truven Health MarketScan® claims databases (2009–2016). Adult cGvHD patients receiving SST with continuous enrollment (3 months before first cGvHD diagnosis [baseline] and 6 months after SST initiation) were eligible. SST was defined by Flowers et al (2015)1 and included extracorporeal photopheresis (ECP), rituximab, imatinib, pentostatin, or mTOR inhibitors, continuous SST use was defined as ≥180 days of therapy (yes vs. no) and treatment persistence was evaluated using a 45-day gap. Patient demographics, clinical characteristics, health care resource use, and costs were summarized by SST continuation status. A multivariate regression model assessed factors associated with SST continuation. Results The study included 464 patients with ≥2 SST claims (mean age 49.7 years; 61.0% male). The most frequently used SSTs (not mutually exclusive) were mTOR inhibitors 293 (63.1%), ECP 210 (45.3%) and imatinib 51 (11.0%). The mean (median) treatment duration was 12.9 (8.3), 11.1 (8.0), and 12.5 (7.5) months for mTOR inhibitors, ECP and imatinib, respectively. A total of 172 (37.1%) patients were SST continuers and 292 (62.9%) were discontinuers. Baseline demographic and clinical characteristics were similar between SST continuers and discontinuers. The mean time from cGvHD diagnosis to initiation of SST was shorter for discontinuers vs. continuers (5.0 vs 6.2 months, (P =.118). Compared with SST continuers, SST discontinuers had higher average monthly hospital costs post-SST initiation ($15,848 vs. $6,286, P =0.047). The proportion of SST continuers was the highest (52.9%) among ECP patients, followed by patients receiving imatinib (33.3%) and mTOR inhibitors (21.5%). Regression results revealed that ECP patients were >3 times more likely to be SST continuers (adjusted OR: 3.18, P Conclusions Approximately 2 in 5 cGvHD patients were SST continuers with median treatment duration of 15 months. SST continuers had lower monthly hospitalization costs than discontinuers during the follow-up period, indicating a potential cost benefit for treatment continuity. Multivariate regression analysis indicated that ECP treatment is significantly associated with SST continuation. These findings should be interpreted with caution as the reasons for discontinuation are unknown.

Healthcare Resource Utilization (HCRU) and Costs Among Patients with Steroid-Resistant (SR) Chronic Graft-Vs-Host Disease (cGVHD) in the United States: A Retrospective Claims Database Analysis

Introduction cGVHD remains the most serious nonrelapse complication affecting long-term survivors of allogeneic hematopoietic stem cell transplant (allo-HSCT). The therapeutic mainstay for cGVHD is steroids; however, the overall response rate is only approximately 50%. Objective To estimate HCRU and costs associated with SR cGVHD following allo-HSCT in the United States. Method Administrative claims from the Optum Research Database were used to identify allo-HSCT patients from 01/01/10 to 08/31/16. Patients with cGVHD had ≥2 outpatient or ≥1 inpatient claim with cGVHD diagnosis specified as (1) cGVHD (ICD-9 279.52 or ICD-10 d89.811) within study period or (2) unspecified GVHD (ICD-9 279.50 or ICD-10 D89.813) beyond 120 days after HSCT. Patients with SR cGVHD were those treated with additional therapy at least 7 days after initiation of systemic steroids based on outpatient treatment records. The no-GVHD group had no GVHD claim during the follow-up. Patients were included if ≥12 years old, enrolled in commercial or Medicare Advantage plan ≥6 months preceding and ≥360 days post-HSCT (≥720 days for 720-day analysis) while surviving. All-cause HCRU and costs (uninflated amount in US dollars) during 360 and 720 days post-HSCT were compared between patients with SR cGVHD and no GVHD using chi-square test for categorical variables and nonparametric test for costs. Result 296 (178) patients with SR cGVHD and 227 (158) patients with no GVHD were included in the 360-day (720-day) analysis. Mean age (50 vs 49 years) and female (40% vs 41%) were similar in patients with SR cGVHD and no GVHD (P>0.05). The primary diagnoses for HSCT were acute myeloid leukemia (42% vs 36% in patients with SR cGVHD and no GVHD), non-Hodgkin lymphoma (13% vs 15%), and acute lymphoblastic leukemia (12% vs 10%). Median time from cGVHD diagnosis to initiation of second-line therapy was 60 days (interquartile range [IQR]: 33–121). 75% of patients with SR cGVHD used ≥4 lines of therapy over the period of follow-up. SR cGVHD patients had significantly more office visits, outpatient consultations, emergency room visits, and inpatient admissions within both 360 and 720 days post-HSCT than patients with no GVHD (all P Conclusion Most patients with SR cGVHD received multiple lines of therapy and additionally used significantly more outpatient and inpatient resource through 2 years post-HSCT than those without GVHD. Improved prevention as well as early and effective treatment of cGVHD may substantially reduce their costs of care.

Best Practices for Medical Photography in Blood and Marrow Transplant (BMT) Long-Term Follow-up (LTFU) Telemedicine

Topic Significance & Study Purpose/Background/Rationale BMT survivors have complex follow-up needs including treatment of chronic Graft vs Host Disease (cGVHD). After the first 100 days, most care is provided in community settings. Our LTFU program supports greater than 6,000 survivors and their community providers via telemedicine, an on-site clinic and ongoing research. The use of photography in telemedicine allows LTFU to remotely assist patients who would otherwise need to travel a distance to the BMT center and prioritizes the most urgent cases for in-person evaluation. Photography is a useful tool for cGVHD affecting skin, oral, and joint/fascia, both for initial diagnosis and assessment of response to treatment. Education is essential to ensure patients and providers capture key diagnostic features in quality photos. Methods, Intervention, & Analysis LTFU clinic nurses take medical photos prior to BMT service discharge to establish a baseline, as well as with every LTFU visit. When patients or community providers contact LTFU to request consultation, they are asked to securely email photos to LTFU. Photos are saved in a private database filed by patient name and date. Photos are reviewed by the LTFU telemedicine team in rounds and compared to prior dates. Recently developed educational pamphlets and an instructional video are located on the LTFU website, providing detailed instructions for medical photography of skin, range of motion, and oral cavity. Photos of classic cGVHD signs are used in education materials for patients and providers. Findings & Interpretation A comprehensive photography program for LTFU patients should be based on best practices and be responsive to technology changes and process improvements. Standardized processes, consistent verbal and written communication, and concern for security of patient photos ensure the foundation for a successful photography program. Initial evaluations of process improvements to the photography program have been favorable. Discussion & Implications Continued access to LTFU experts is critical for community BMT survivors. The BMT center's photography program allows for improved diagnosis of cGVHD, reveals physical changes over time, and informs the triage process for scheduling patient visits on-site. Newer technologies may become available for digital file transfer to increase efficiency. Currently only still photographs are used, but looking ahead, LTFU is exploring videography or livestreamed physical assessments.

KD025-208: A Phase 2a Study of KD025 for Patients with Chronic Graft Versus Host Disease (cGVHD) - Pharmacodynamics (PD) and Updated Results

Introduction cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of IL-17 and IL-21. A reduction in the regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment. KD025 is an oral Rho kinase 2 (ROCK2) selective inhibitor. In vitro data demonstrate KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards Treg. Methods 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy were treated in 28-Day cycles until disease progression. The primary endpoint is overall response rate (ORR) (partial/complete response) per 2014 NIH criteria. Additional endpoints include duration of response (DOR), corticosteroid (CS) dose reductions, Lee Symptom Scale (LSS) score and PD. Blood samples were collected at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. Intracellular expression of IL-17A and FOXP3 was determined by flow cytometry. Results Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, time from cGVHD diagnosis to KD025 treatment of 19 months, and 3 prior regimens. Median duration of treatment was37 (C1) and 33 (C2) weeks. KD025 demonstrated ORR of 65% in C1 and 63% in C2. Responses were rapid (76% at first assessment at 8 weeks) and durable (≥20 weeks) in 82% (C1) and 50% (C2) of responders. Median CS dose was reduced 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score. Common AEs were increased LFTs 42%, URI 33%, anemia 27%, nausea 24%, diarrhea 24% and fatigue 21%. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 pts, none considered related to KD025. There was no apparent increased risk of infection. Exploratory PD analyses revealed an early increase in the percentage of CD4+ Treg cells by C2D1 with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C6D25. Conclusion KD025 achieved responses with little toxicity. Responses are clinically meaningful with durability, reductions in CS doses and improvement in LSS score. PD data indicate KD025 may restore the Th17/Treg balance.

Safety and efficacy of rituximab-based first line treatment of chronic GVHD.

Initial therapy of chronic GVHD (cGvHD) has not changed for over three decades, despite limited efficacy and long-term toxicity. We have previously shown in a small pilot study the feasibility of rituximab-based first-line therapy of cGVHD. To better assess safety and efficacy, we now evaluate 69 patients that received rituximab as part of their initial treatment. Median follow-up for surviving patients was 47 (11-81) months. Resolution of cGVHD occurred in 49 patients with median time to IST discontinuation of 349 (138-920) days. The cumulative incidence (CI) of cGHVD resolution was 41%, 69 and 77% at 1-, 2- and 3-years, respectively. No systemic corticosteroids were used in 27 patients, and 67% received ≤ 10 mg/kg cumulative exposure. Overall survival (OS) at 1-, 2- and 3-years following cGVHD diagnosis was 87, 79 and 77% respectively; corresponding rates of non-relapse mortality (NRM) were 10%, 16 and 19%. The probability of being alive and free of cGVHD at 1-, 2-, and 3-years was 36, 55, and 57% respectively. This study demonstrates the feasibility and efficacy of rituximab-based first-line cGVHD treatment. This approach demonstrates significant activity and avoids long courses of corticosteroids in most patients.

Early Prediction of Moderate-Severe Chronic GvHD By Immunity Related Transcriptome

Introduction:Graft versus host disease (GvHD) is the most common and debilitating complication of allogeneic hematopoietic cell transplantation (HCT). Among the two clinically significant forms, moderate-severe chronic GvHD (cGvHD) is more difficult to treat than grade 2-4 acute GvHD (aGvHD). Chronic GvHD rarely shows a sustained complete response to immunosuppressive drugs and non-responders either die or suffer long-term. However, if an early and accurate prediction of ensuing cGvHD is posiible, then the high risk patients can be identified and treated preemptively. In the present investigation, we retrospectively analyzed the transcriptome of immunity related genes at one month post-transplant with the aim to identify a potential early and accurate predictor of clinically significant cGvHD.Methods:A cohort of 73 HLA matched first allogeneic HCT recipients with moderate-severe cGvHD (n = 31) and no chronic GvHD (n = 42) were included in the study. All patients received similar myeloablative conditioning regimens along with 4.5 mg/kg antithymocyte globulin as GvHD prophylaxis. The diagnosis of cGvHD was based on National Institutes of Health consensus criteria and median day of diagnosis in our cohort was 126 days. Total RNA was extracted from cryopreserved peripheral blood mononuclear cells (PBMNCs) at one month post-transplant. Gene expression CodeSet profiling of 594 immunity related genes including 15 internal reference genes was performed using Nano string Technology Immunology panel. Differential gene expression and receiver operating characteristic (ROC) analyses was performed using R statistical packages and GraphPad PRISM software. Benjamini Hochberg procedure was used to calculate the P value and the false discovery rate (FDR). Differentially expressed genes with a Benjamini Hochberg P value (BHP) of <0.05 and FDR of <0.01 were considered significant. Cumulative incidence of moderate-severe chronic GvHD was calculated using Fine-Gray competing risk analysis.Results:A gene panel consisting of immunity related 12 genes was identified at one month post-transplant whose transcriptome profile was significantly different between patients that developed moderate-severe cGvHD compared to the patients who did not develop cGvHD. The identified gene panel included highly upregulated T cell activation and proliferation markers like CD3D (BHP=0.005), CD3E (BHP=0.01), CCR7 (BHP=0.005), CD5 (BHP=0.006); TNF receptor superfamily markers like B- and T-lymphocyte attenuator-BTLA (BHP=0.004), CD27 (BHP=0.004), CD40LG (BHP=0.005); and Costimulatory signaling molecules like Inducible T-cell Co-stimulator ICOS (BHP=0.001), CD28 (BHP=0.006) in patients with cGVHD. A gene score of >7 in this panel of 12 genes was able to differentiate patients with high risk of developing mod-severe cGvHD with a sensitivity of 79% and specificity of 88% (AUC = 0.88, P <0.0001) (Figure 1).Conclusions:The cGvHD gene panel consisting of 12 genes from multiple immune regulatory pathways identified in the present study provided an early prediction of moderate-severe cGvHD (one month) with high sensitivity and specificity. The robust and rapid technique of nanostring based transcriptome profiling has the potential to be implemented in the clinic. Differentiating patients at high risk of mod-severe cGvHD can help develop new strategies for preemptive therapy and pave the way towards precision medicine leading to improved outcomes of HCT. DisclosuresNo relevant conflicts of interest to declare.

Expansion of Peripheral Extra-Follicular Helper T Cells in Patients with Chronic Graft-Versus-Host Disease

Introduction:Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). In contrast to acute GVHD, cGVHD is an autoimmune-like syndrome. The clinical manifestations of cGVHD are highly variable, including skin pathology varying from lichen planus-like lesions to full sclerosis, oral lichen planus-like lesions, muscle or joint fasciitis, and bronchiolitis obliterans (BO) (Bruce Blazar et. al. Blood 2016). Recently, extrafollicular CD4+ T- and B- cell interactions are gaining more and more attentions in the pathogenesis of autoimmune diseases. It has been reported that mice with cGVHD had an expansion of extrafollicular CD4+ T cells (Ruishu D et. al. Nature communications 2017). It is still unclear whether extrafollicular CD4+ T helper cells play an important role in the development of human cGVHD or not.Methods:A total of 70 patients with hematologic malignancies who underwent allo-HSCT at Nanfang Hospital between June 2015 and June 2017 were enrolled in this experimental study. The diagnosis and grade of cGVHD was made at the time of sample collection according to National Institutes of Health criteria (Howard M.S. et. al. BBMT 2015). Comparison of three means was analyzed using a one-way ANOVA test. Comparison of two means was analyzed using an unpaired two-tailed Student t-test. Correlation studies were performed using the Pearson correlation coefficient test.Results:We found that the frequency and count of circulating T follicular helper cells (cTfh) markedly decreased in patients with active cGVHD compared with patients without cGVHD (median, 3.16% vs 1.19% of CD4+ T cells; P <0.0001 and median,11.26 x10^6 vs 1.77 x10^6; P <0.0001). These decreases are more significant in patients with moderate/severe cGVHD. We further found that the frequency of extrafollicular CD4+ T cells in patients with active cGVHD significantly increased (median, 3.93% vs 8.69% of CD4+ T cells; P <0.001). There was also an increased trend in the count of extrafollicular CD4+ T cells of patients with active cGVHD, although patients with active cGVHD have lymphopenia (median, 6.91 x10^6 vs 13.20 x10^6; P =0.19). Multivariable linear regression analysis confirmed that active cGVHD was a significant factor for high percentage of extrafollicular CD4+ T cells after adjusting for other transplant characteristics (P <0.001). Moreover, expansion of extrafollicular CD4+ T cells correlated with the clinical grade of cGVHD (P <0 .005), and the difference lasted until 1 year after allo-HCT. The expansion of extrafollicular CD4+ T cells was highly correlated with the generation of IgG1 antibodies (P <0 .05).Conclusions:These results demonstrate that expansion of extrafollicular CD4+ T cells plays a critical role in the pathogenesis of human cGVHD. Targeting extrafollicular CD4+ T-B-cell interactions may be an effective strategy in patients with cGVHD. DisclosuresYang:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding. Zhang:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding. Fan:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding. Huang:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding. Chai:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding. Xuan:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding. Chen:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.

KD025-208: A Phase 2a Study of KD025 for Patients with Chronic Graft Versus Host Disease (cGVHD) — Pharmacodynamics and Updated Results

Introduction: cGVHD remains a leading cause of post-transplant morbidity / mortality, exhibiting features of both autoimmune and fibrotic diseases across multiple organ systems.cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of inflammatory cytokines including IL-17 and IL-21. Moreover, a persistent reduction in the number of regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment.KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor. In vitro data have demonstrated that KD025 (1) attenuates IL-21 and IL-17 secretion in human CD4+ T cells via STAT3, IRF4 and RORγt regulation, and (2) leads to increased percentages of Foxp3+ CD4+ T cells via a STAT5-dependent mechanism and upregulates the suppressive function of human Tregs. These MOA suggest that KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards a Treg phenotype. No studies have examined KD025 effects in patients with dysregulation associated with high Th17 and low Tregs.Methods: KD025-208 enrolled 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy. Treatment is in 28-Day cycles until disease progression or unacceptable toxicity. The primary endpoint is the overall response rate (ORR) (% pts achieving partial response (PR) or complete response (CR)) as per 2014 NIH response criteria. Secondary endpoints include duration of response (DOR) and corticosteroid (CS) dose reductions. Exploratory endpoints include Lee Symptom Scale (LSS) score and pharmacodynamics (PD).Peripheral blood samples were collected from all pts at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. The intracellular expression of IL-17A and FOXP3 on viable CD3+ CD4+ cells was determined by using multicolor flow cytometry.Results: Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, median time from cGVHD diagnosis to KD025 treatment of 19 months, and a median of 3 prior treatment regimens. Median duration of treatment was 37 (C1) and 33 (C2) weeks (wks). KD025 demonstrated an ORR of 65% in C1 and 63% in C2. ORR in key subgroups is shown below. Responses were rapid (76% achieved at first assessment at 8 wks) and durable with 82% (C1) and 50% (C2) of responders sustaining response for ≥20 wks.Responses including CRs were observed across all affected organ systems except lung (mouth, eyes, joints/ fascia, skin, upper GI, lower GI, esophagus, liver). A previously reported lung PR was deemed on review to be IPF with no cGVHD involvement.During treatment with KD025, median CS dose was reduced by 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score, including both responders (67%) and non-responders (42%).KD025 has been well tolerated. AEs reported were generally consistent with those expected in pts with advanced cGVHD treated with CS. Common AEs were increased LFTs (42%), URI (33%), anemia (27%), nausea (24%), diarrhea (24%) and fatigue (21%). Increased LFTs did not lead to treatment discontinuation, commonly occurred prior to KD025 dosing and were often considered attributable to cGVHD. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 (33%) pts, none considered related to KD025 treatment. There was no apparent increased risk of infection.Exploratory PD analyses of PBMCs across C1 and C2 revealed an early increase in the percentage of CD4+ Treg cells by C2D1 of KD025 treatment with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C4D1 and C6D25.Conclusion: Treatment with KD025 has demonstrated encouraging clinical responses in cGVHD pts with little toxicity. Responses have been clinically meaningful as evidenced by durability, reductions in CS doses and improvement in LSS score. Exploratory PD data indicate treatment with KD025 may modulate immune homeostasis by restoring the Th17/Treg balance. DisclosuresJagasia:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Bachier:Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau. Weisdorf:Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy; SL Behring: Consultancy; FATE: Consultancy. Green:Kadmon Corporation, LLC: Employment. Schueller:Kadmon Corporation, LLC: Employment. Zanin-Zhorov:Kadmon Corporation, LLC: Employment. Weiss:Kadmon Corporation, LLC: Employment. Eiznhamer:Kadmon Corporation, LLC: Employment. Aggarwal:Kadmon Corporation, LLC: Employment. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Lee:Takeda: Research Funding; Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding.

PSY41 - OVERALL SURVIVAL AND NON-RELAPSE MORTALITY OF PATIENTS WITH CHRONIC GRAFT-VERSUS-HOST DISEASE: A SYSTEMATIC LITERATURE REVIEW

Chronic graft-versus-host disease (cGVHD) is the leading cause of mortality following allogeneic hematopoietic stem cell transplantation, also contributing to morbidity and worse quality of life. This study aimed to collect evidence on overall survival (OS) and non-relapse mortality (NRM) among cGVHD patients. A systematic review of English-language publications was conducted using PubMed. Search was limited to studies using the National Institute of Health Consensus Criteria for the diagnosis of cGVHD, published between 2007 and 2017, and studied human subjects with a cohort size of ≥100 patients. Thirty-eight studies were included. From the onset of cGVHD, the 1 and 2 year NRM rates ranged from 10% to 26%, and 10% to 32%, respectively. The 1 and 2 year OS rates from the onset of cGVHD ranged from 66% to 75%, and 59% to 81%, respectively. Patients with cGVHD had better OS (range of hazard ratio [RoHR]: 0.09 - 0.38), but increased NRM (RoHR: 2.4 - 4.8) compared to patients without cGVHD. Studies found that improved OS was primarily due to differences in relapse rate (RR). Higher cGVHD severity was reported to be associated with worse NRM (severe vs. mild/moderate, RoHR: 3.04 - 3.07). Four studies found a significant association between OS and cGVHD severity and 3 indicated better OS in case of lower cGVHD severity. Evidence suggests that the improved OS in cGVHD patients is due to lower risk of relapse, which can be explained with the presence of a potent graft-versus-tumor effect. However, NRM was found to be higher in patients with cGVHD and studies indicated an increased risk in the presence of more severe disease. A delicate balance is thought to exist between cGVHD severity as a source of NRM and a favorable effect on decreased RR in the presence of less severe cGVHD.