Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI.

Graft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.

A randomized phase 2 trial of pomalidomide in subjects failing prior therapy for chronic graft-versus-host disease.

Steroid-refractory chronic graft-versus-host disease (cGVHD) is a therapeutic challenge. Sclerotic skin manifestations are especially difficult to treat. We conducted a randomized phase 2 clinical trial (#NCT01688466) to determine the safety, efficacy, and preferred dose of pomalidomide in persons with moderate to severe cGVHD unresponsive to corticosteroids and/or subsequent lines of therapy. Thirty-four subjects were randomized to receive pomalidomide 0.5 mg per day orally (n = 17; low-dose cohort) or 2 mg per day at a starting dose of 0.5 mg per day increasing to 2 mg per day over 6 weeks (n = 17; high-dose cohort). The primary endpoint was overall response rate (ORR) at 6 months according to the 2005 National Institutes of Health cGVHD Response Criteria. Thirty-two patients had severe sclerotic skin and received a median of 5 (range, 2-10) previous systemic therapies. ORR was 47% (95% confidence interval, 30-65) in the intention-to-treat analyses. All were partial responses, with no difference in ORR between the cohorts. ORR was 67% (45%-84%) in the 24 evaluable subjects at 6 months. Nine had improvement in National Institutes of Health joint/fascia scores (P = .018). Median change from the baseline in body surface area involvement of skin cGVHD was -7.5% (-10% to 35%; P = .002). The most frequent adverse events were lymphopenia, infection, and fatigue. Eight subjects in the high-dose cohort had dose decreases because of adverse events. There was 1 death in the low-dose cohort from bacterial pneumonia. Our data indicate antifibrotic effects of pomalidomide and possible association with increases in concentrations of blood regulatory T-cell and interleukin-2. Pomalidomide 0.5 mg per day is a safe and effective therapy for advanced corticosteroid-refractory cGVHD.

The clinical landscape of chronic graft-versus-host disease management in 2021.

Chronic graft-versus-host disease (cGVHD) is an important systemic complication of allogeneic haematopoietic stem cell transplantation with heterogeneous, multi-organ involvement that can lead to increased morbidity and mortality. Despite significant advances in understanding the complex pathophysiology driving the disease, curative treatment options remain suboptimal. The past decade, however, has seen much growth in collaborative research efforts and standardization of criteria for clinical trials that have led to discovery of several new second-line therapies in cGVHD. The key to successful cGVHD control and management includes a comprehensive and sustained multidisciplinary effort with emphasis on ancillary and supportive care for these patients. The focus of this review is to summarize the new developments in systemic, organ-specific, and topical treatments in the management of cGVHD that emerged since the 2014 NIH consensus conference.

Collection of peripheral blood mononucleated cells for chronic graft-versus-host disease immunology research: safety and effectiveness of leukapheresis in 132 patients.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is a major cause of late morbidity and non-relapse mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Its biology, however, remains poorly understood, making the studies of its biology and immunomodulatory therapies a difficult task. Such research is often hampered by lymphopenia which is common in these patients and precludes studies of critical cellular subsets across the spectrum of severity of disease. This study explores the potential of leukapheresis to safely acquire and efficiently store immune cells for immunology research in chronic GVHD. METHODS: This is a cross-sectional study in which 132 consecutively accrued patients undergo optional research leukapheresis and a one-week comprehensive outpatient evaluation. Baseline clinical and laboratory data and efficiency of the procedure were reported. RESULTS: Ninety-four of 132 patients (71%) achieved the goal collection of 2 × 10^9 PBMNCs with a mean volume processed of 4.6 L. Only mild decreases in hemoglobin, platelet, lymphocyte and monocytes were observed. All adverse events were mild (grade 1) and had resolved by the time of discharge from the apheresis unit. CONCLUSION: This study demonstrates feasibility, safety, and efficiency of research leukapheresis in a frail patient population. Results presented promote leukapheresis as a standard research practice option in studies of chronic GVHD in humans which may expedite advances in our understanding of this complex multisystem disease.

Long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus.

OBJECTIVE: Autologous haematopoietic cell transplantation (AHSCT) improves immunologic dysfunction in patients with SLE. However, the curative potential of this therapy remains uncertain. This study reports outcomes in SLE patients receiving a lymphodepleting, reduced intensity regimen for AHSCT in SLE. METHODS: Eight patients with SLE refractory to treatment, including i.v. cyclophosphamide (CYC), were enrolled. Five had LN and three CNS involvement as primary indications for transplant. Haematopoietic cell mobilization with CYC, G-CSF and rituximab was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of concurrent administration of CYC, fludarabine and rituximab. All immunosuppressive medications were discontinued at the start of mobilization and CS were rapidly tapered after the transplant. RESULTS: Five of eight patients achieved a complete response, including a decline in the SLEDAI to zero, which was sustained in four patients for a median of 165 months (range 138-191). One patient achieved a partial response, which was followed by relapse at month 18. Two patients with nephritis and underlying comorbidities in most organs had early deaths from infection and multiorgan failure. AHSCT resulted in profound lymphodepletion, followed by expansion of Treg cells and repopulation of naive T and B cells. Patients with a complete response showed a sustained suppression of the SLE-associated IFN-induced gene signature, marked depletion of memory and plasmablast B cells and resultant sustained elimination of anti-dsDNA antibody. CONCLUSION: Durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory SLE following lymphodepleting AHSCT. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00076752.

Rehabilitation Interventions in the Multidisciplinary Management of Patients With Sclerotic Graft-Versus-Host Disease of the Skin and Fascia.

Graft-versus-host disease (GVHD) is a multisystemic disorder that affects 30%-80% of patients who undergo allogeneic hematopoietic stem cell transplantation 10%-15% of GVHD patients develop sclerotic features affecting the skin or deeper tissues, leading to functional limitations and poor quality of life. There is limited literature regarding the indications and efficacy of specific rehabilitative interventions in sclerotic GVHD (sclGVHD). In this article, we summarize the current evidence supporting rehabilitation intervention in sclGVHD and offer our approach to the multidisciplinary management of this disease. In addition, we review techniques that have been employed in other sclerotic skin diseases (eg, iontophoresis, extracorporeal shock waves, botulinum toxin A, adipose derived stromal vascular fraction), but that require further validation in the sclGVHD setting. Ultimately, optimal care for this complex disease requires a multidisciplinary approach that includes a rehabilitation and adaptive program tailored to each patient's needs.

B regulatory cells and monocyte subpopulations in patients with chronic graft-vs-host disease.

AIM: To assess the correlations of B regulatory cells (Bregs) and monocyte subsets in peripheral blood with the National Institutes of Health (NIH)-consensus-defined clinical manifestations of chronic graft-vs-host disease (cGvHD), in an attempt to establish their role as cellular biomarkers. METHODS: This multidisciplinary prospective study enrolled adult cGVHD patients treated in the University Hospital Center Zagreb and University of Zagreb School of Medicine. Immunophenotypic subpopulations of CD24highCD38high Bregs (CD27-, CD27+, and total) and monocyte (classical, intermediate, and non-classical) counts were correlated with demographic, transplant, and cGVHD-related data. Bivariate correlation analysis was performed to evaluate the correlations between Bregs and monocytes subsets and cGVHD organ involvement, as well as cGVHD severity and immunosuppression intensity. RESULTS: Twenty-two adult patients (54.5% female) with cGVHD were enrolled. The median (range) age was 44.5 years (24-65). All patients were transplanted for hematologic malignancies and 40.9% had severe NIH cGVHD global score. The median time from cGVHD diagnosis to the analysis was 16.6 months (0-176). The organ most frequently affected with cGVHD were the eyes (68.2%), skin (45.5%), lungs (45.5%), and liver (40.9%). Lower total and CD27-Bregs counts were correlated with worse cGVHD severity, higher immunosuppression intensity, and lung cGVHD, in terms of cell count, but also with skin cGVHD, in terms of percentages. Patients with liver and joint/fascia cGVHD had a lower percentage of non-classical monocytes and patients with more severe global NIH score had a higher classical monocytes count. CONCLUSION: Different organs affected by cGVHD are differently associated with different subpopulations of Bregs and monocytes.

Introduction to a review series on emerging immunotherapies for hematologic diseases.

Immune therapies are fast becoming paradigm-changing treatment options for patients with hematologic cancers. The field has grown exponentially as it expands to nonmalignant blood diseases. This Perspective article introduces the review series describing some of the latest advances in this field and highlighting some of the current obstacles and new opportunities for the future. Specifically, the series provides in-depth discussion on a selection of emerging immunotherapies now available to patients for hematologic diseases, including cancer vaccines, chimeric antigen receptor T cells, and immunotherapies to regulate inflammation in nonmalignant blood disorders.

Clinical characteristics and cytokine biomarkers in patients with chronic graft-vs-host disease persisting seven or more years after diagnosis.

Chronic graft-versus-host disease (cGVHD) is the leading late complication after allogeneic hematopoietic stem cell transplantation (HSCT). Many patients receive multiple lines of systemic therapy until cGVHD resolves, but about 15% remain on systemic treatment for more than 7 years after cGVHD diagnosis. This study describes the clinical and biological factors of patients who present with cGVHD persisting for ≥7 years (persistent cGVHD). Patients with persistent cGVHD (n = 38) and those with cGVHD for <1 year (early cGVHD) (n = 83) were enrolled in a prospective cross-sectional natural history study. Patients in the persistent cGVHD group were a median of 10.2 years from cGVHD diagnosis (range 7-27 years). Fifty-eight percent of persistent cGVHD patients (22/38) were receiving systemic immunosuppression, compared to 88% (73/83) in the early cGVHD group. In multivariable analysis, bone marrow (BM) stem cell source, presence of ENA autoantibodies, higher NIH lung score, higher platelet counts, and higher IgA levels were significantly associated with persistent cGVHD. A high sensitivity panel of serum biomarkers including seven cytokines diagnostic for cGVHD was analyzed and showed significantly lower levels of BAFF and CXCL10 in patients with persistent cGVHD. In conclusion, standardly accepted clinical measures of disease severity may not accurately reflect disease activity in patients with persistent cGVHD. However, many patients with persistent cGVHD are still receiving systemic immunosuppression despite lacking evidence of disease activity. Development of reliable clinical biomarkers of cGVHD activity may help guide future systemic treatments.

Motor ability, function, and health-related quality of life as correlates of symptom burden in patients with sclerotic chronic graft-versus-host disease receiving imatinib mesylate.

PURPOSE: To explore improvement in motor ability, function, health-related quality of life (HRQOL), and symptom severity in patients with sclerotic chronic graft-versus-host disease (ScGVHD) in response to treatment as well as the relationship among changes on such measures. METHODS: This study was a secondary analysis of data from 13 individuals with severe ScGVHD enrolled in a clinical trial evaluating the efficacy of imatinib mesylate (clinicaltrials.gov identifier: NCT00702689). Self-reported, clinician-reported, and performance-based indicators of motor ability, function, HRQOL, and symptom severity were assessed at baseline and 6 months following the administration of imatinib mesylate. RESULTS: Participants did not show statistically significant improvement on any measures over time. Approximately one-third of patients displayed clinically significant improvement on measures of motor ability (palmar pinch strength, dominant hand, 30.8%), functioning (Manual Ability Measure-36, 41.7%), HRQOL (Short Form 36 [SF-36] Mental Component Summary, 33.3%), and symptom severity (Lee Symptom Scale, 38.5%). Improvement in cGVHD symptom burden was correlated with improvement in function (Assessment of Motor and Process Skills [AMPS] and Disabilities of the Arm, Shoulder, and Hand [DASH] scores) and HRQOL (SF-36 Physical Component Summary scores). CONCLUSIONS: Findings suggest the potential utility of administering patient-reported and performance-based functional measures, such as the DASH and the AMPS, to patients with cGVHD. By understanding the functional consequences of ScGVHD, interdisciplinary teams of health care providers, including rehabilitation professionals, can work to improve long-term outcomes.

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution.

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Axicabtagene ciloleucel (YESCARTA; Kite Pharma, a Gilead Company, Los Angeles CA) and tisagenlecleucel (KYMRIAH; Novartis Pharmaceuticals Corp., Basel, Switzerland) are two CD19-directed chimeric antigen receptor (CAR) T cell products currently approved by the US Food and Drug Administration; the European Medicines Agency; Health Canada; Ministry of Health, Labor and Welfare (Japan); and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL). Although this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate use of this novel therapy and of short- and long-term toxicities. To address these issues, representatives of the American Society of Transplantation and Cellular Therapy convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts. The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the use of CD19 CAR T cell products for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas.

Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Blood and Marrow Transplantation.

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8, each critical to B-cell differentiation and fate. All-trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4-to-IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5, but not BLIMP1 (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.

Steroid Refractory Chronic Graft-Versus-Host Disease: Cost-Effectiveness Analysis.

Given the increasing incidence of chronic graft-versus-host disease (cGVHD) and its rapidly escalating costs due to many lines of drug treatments, we aimed to perform a meta-analysis to assess the comparative effectiveness of various treatment options. Using these results, we then conducted a cost-effectiveness analysis for the frequently utilized agents in steroid-refractory cGVHD. We searched for studies examining tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, extracorporeal photopheresis, pomalidomide, and methotrexate. Studies with a median follow-up period shorter than 6 months and enrolling fewer than 5 patients were excluded. Meta-analysis for overall and organ system-specific GVHD response (overall response [ORR], complete response [CR], and partial response [PR]) was conducted for each intervention. Cost per CR and cost per CR + PR were calculated as the quotient of the 6-month direct treatment cost by CR and CR + PR. Forty-one studies involving 1047 patients were included. CR rates ranged from 7% to 30% with rituximab and methotrexate, respectively, and ORR ranged from 30% to 85% with tacrolimus and ruxolitinib, respectively. Cost per CR ranged from US$1,187,657 with ruxolitinib to US$680 with methotrexate. Cost per ORR ranged from US$453 for methotrexate to US$242,236 for ibrutinib. The most cost-effective strategy was methotrexate for all of the organ systems. Pomalidomide was found to be the least cost-effective treatment for eye, gastrointestinal, fascia/joint, skin, and oral GVHD, and imatinib was found to be the least cost-effective treatment for liver and extracorporeal photopheresis for lung GVHD. We observed huge cost-effectiveness differences among available agents. Attention to economic issues when treating cGVHD is important to recommend how treatments should be sequenced, knowing that many patients will cycle through available agents.

Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-versus-Host Disease.

Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score ≤-2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of ≤-2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF.

Predictors of survival, nonrelapse mortality, and failure-free survival in patients treated for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is a pleotropic syndrome that lacks validated methods of measuring response in clinical trials, although several end points have been proposed. To investigate the prognostic significance of these proposed end points, such as the 2005 National Institutes of Health (NIH) response measures, 2014 NIH response measures, clinician-reported response, and patient-reported response, we tested their ability to predict subsequent overall survival (OS), nonrelapse mortality (NRM), and failure-free survival (FFS). Patients (n = 575) were enrolled on a prospective chronic GVHD observational trial. At 6 months, clinician-reported response (P = .004) and 2014 NIH-calculated response (P = .001) correlated with subsequent FFS, and clinician-reported response predicted OS (P = .007). Multivariate models were used to identify changes in organ involvement, laboratory values, and patient-reported outcomes that were associated with long-term outcomes. At 6 months, a change in the 2005 NIH 0 to 3 clinician-reported skin score and 0 to 10 patient-reported itching score predicted subsequent FFS. Change in the Lee skin symptom score and Functional Assessment of Cancer Therapy-Bone Marrow Transplant score predicted subsequent OS. Change in the Lee skin symptom score predicted subsequent NRM. This study provides evidence that clinician-reported response and patient-reported outcomes are predictive of long-term survival. The trial was registered at www.clinicaltrials.gov as #NCT00637689.