Search

Minor histocompatibility antigens (mHAg) composed of peptides presented by HLA molecules can cause immune responses involved in graft-versus-host disease (GVHD) and graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (HCT). The current study was designed to identify individual graft-versus-host genomic mismatches associated with altered risks of acute or chronic GVHD or relapse after HCT between HLA-genotypically identical siblings. Our results demonstrate that in allogeneic HCT between a pair of HLA-identical siblings, a mHAg manifests as a set of peptides originating from annotated proteins and non-annotated open reading frames, which i) are encoded by a group of highly associated recipient genomic mismatches, ii) bind to HLA allotypes in the recipient, and iii) evoke a donor immune response. Attribution of the immune response and consequent clinical outcomes to individual peptide components within this set will likely differ from patient to patient according to their HLA types. [ABSTRACT FROM AUTHOR]

Efforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17−IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy. Pathogenesis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) remains unclear., Here the authors show in mouse models that dysbiosis caused by the expansion of Th/Tc22, as well as depletion of CX3CR1hi mononuclear phagocytes resulted from the reduction of Th/Tc1, contributes to SR-Gut-aGVHD onset. [ABSTRACT FROM AUTHOR]

Background: Allogeneic hematopoietic cell transplantation is indicated for refractory hematologic cancer and some nonmalignant disorders. Survival is limited by recurrent cancer and organ toxicity.Objective: To determine whether survival has improved over the past decade and note impediments to better outcomes.Design: The authors compared cohorts that had transplants during 2003 to 2007 versus 2013 to 2017. Survival outcome measures were analyzed, along with transplant-related complications.Setting: A center performing allogeneic transplant procedures.Participants: All recipients of a first allogeneic transplant during 2003 to 2007 and 2013 to 2017.Intervention: Patients received a conditioning regimen, infusion of donor hematopoietic cells, then immunosuppressive drugs and antimicrobial approaches to infection control.Measurements: Day-200 nonrelapse mortality (NRM), recurrence or progression of cancer, relapse-related mortality, and overall mortality, adjusted for comorbidity scores, source of donor cells, donor type, patient age, disease severity, conditioning regimen, patient and donor sex, and cytomegalovirus serostatus.Results: During the 2003-to-2007 and 2013-to-2017 periods, 1148 and 1131 patients, respectively, received their first transplant. Over the decade, decreases were seen in the adjusted hazards of day-200 NRM (hazard ratio [HR], 0.66 [95% CI, 0.48 to 0.89]), relapse of cancer (HR, 0.76 [CI, 0.61 to 0.94]), relapse-related mortality (HR, 0.69 [CI, 0.54 to 0.87]), and overall mortality (HR, 0.66 [CI, 0.56 to 0.78]). The degree of reduction in overall mortality was similar for patients who received myeloablative versus reduced-intensity conditioning, as well as for patients whose allograft came from a matched sibling versus an unrelated donor. Reductions were also seen in the frequency of jaundice, renal insufficiency, mechanical ventilation, high-level cytomegalovirus viremia, gram-negative bacteremia, invasive mold infection, acute and chronic graft-versus-host disease, and prednisone exposure.Limitation: Cohort studies cannot determine causality, and current disease severity criteria were not available for patients in the 2003-to-2007 cohort.Conclusion: Improvement in survival and reduction in complications were substantial after allogeneic transplant. Relapse of cancer remains the largest obstacle to better survival outcomes.Primary Funding Source: National Institutes of Health. [ABSTRACT FROM AUTHOR]

• Data came from 488 patients enrolled in prospective observational studies. • Some objective change measures were associated with overall response assessments. • The sensitivity and specificity parameters of this association need improvement. Assessments of overall improvement and worsening of chronic graft-versus-host disease (GVHD) manifestations by the algorithm recommended by National Institutes of Health (NIH) response criteria do not align closely with those reported by providers, particularly when patients have mixed responses with improvement in some manifestations but worsening in others. To elucidate the changes that influence provider assessment of response, we used logistic regression to generate an overall change index based on specific manifestations of chronic GVHD measured at baseline and 6 months later. We hypothesized that this overall change index would correlate strongly with overall improvement as determined by providers. The analysis included 488 patients from 2 prospective observational studies who were randomly assigned in a 3:2 ratio to discovery and replication cohorts. Changes in bilirubin and scores of the lower gastrointestinal tract, mouth, joint/fascia, lung, and skin were correlated with provider-assessed improvement, suggesting that the main NIH response measures capture relevant information. Conversely, changes in the eye, esophagus, and upper gastrointestinal tract did not correlate with provider-assessed response, suggesting that these scales could be modified or dropped from the NIH response assessment. The area under the receiver operator characteristic curve in the replication cohort was 0.72, indicating that the scoring algorithm for overall change based on NIH response measures is not well calibrated with provider-assessed response. [ABSTRACT FROM AUTHOR]

Severe intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3) in the duodenum or colon. We observed that 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3–4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with extensive mucosal injury. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (GVHD) is the leading cause of long-term morbidity and mortality after allogeneic hematopoietic cell transplantation. To identify prognostic plasma proteins associated with de novo– or quiescent-onset chronic GVHD (cGVHD), we performed a discovery and validation proteomic study. The total study cohort included 167 consecutive patients who had no clinical evidence of GVHD under minimum glucocorticoid administration and had available plasma samples obtained at 80 ± 14 days after transplantation. We first used high-throughput mass spectrometry to screen pooled plasma using 20 cases with subsequent cGVHD and 20 controls without it, and we identified 20 candidate proteins. We then measured 12 of the 20 candidate proteins by ELISA on the same individual samples and identified 4 proteins for further verification (LGALS3BP, CD5L, CD163, and TXN for de novo onset, and LGALS3BP and CD5L for quiescent onset). The verification cohort included 127 remaining patients. The cumulative incidence of de novo–onset cGVHD was higher in patients with higher plasma soluble CD163 concentrations at day 80 than those with lower concentrations (75% versus 40%, P  = .018). The cumulative incidence of de novo– or quiescent-onset cGVHD did not differ statistically according to concentrations of the 3 other proteins at day 80. CD163 is a macrophage scavenger receptor and is elevated in oxidative conditions. These results suggest that monocyte or macrophage activation or increased oxidative stress may contribute to the pathogenesis of cGVHD. [ABSTRACT FROM AUTHOR]

No gold standard has been established as a primary endpoint in trials of initial treatment of chronic graft-versus-host disease (GVHD), and evidence showing the association of any proposed primary endpoint with clinical benefit has not been conclusively demonstrated. To address this gap, we analyzed outcomes in a cohort of 328 patients enrolled in a prospective, multicenter, observational study within 3 months after diagnosis of chronic GVHD. Complete and partial response, stable disease, and progressive disease were defined according to the 2014 National Institutes of Health Consensus Development Conference on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease. Success was defined as complete or partial response with no secondary systemic treatment or recurrent malignancy at 1 year after enrollment. Success was observed in fewer than 20% of the patients. The burden of disease manifestations at 1 year was lower for patients in this category than for those with stable or progressive disease. Systemic treatment ended earlier, and subsequent mortality was lower among patients with complete or partial response than among those with stable or progressive disease and those who had received secondary systemic treatment. We conclude that survival with a complete or partial response and no previous secondary systemic treatment or recurrent malignancy at 1 year after initial systemic therapy is associated with clinical benefit, a critical characteristic for consideration as a primary endpoint in a pivotal clinical trial. This prospective observational study was registered at www.clinicaltrials.gov as #NCT00637689. [ABSTRACT FROM AUTHOR]

The risk of acute graft-versus-host disease (GVHD) is higher after allogeneic hematopoietic cell transplantation (HCT) from unrelated donors as compared with related donors. This difference has been explained by increased recipient mismatching for major histocompatibility antigens or minor histocompatibility antigens. In the current study, we used genome-wide arrays to enumerate single nucleotide polymorphisms (SNPs) that produce graft-versus-host (GVH) amino acid coding differences between recipients and donors. We then tested the hypothesis that higher degrees of genome-wide recipient GVH mismatching correlate with higher risks of GVHD after allogeneic HCT. In HLA-genotypically matched sibling recipients, the average recipient mismatching of coding SNPs was 9.35%. Each 1% increase in genome-wide recipient mismatching was associated with an estimated 20% increase in the hazard of grades III-IV GVHD (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.05-1.37; P = .007) and an estimated 22% increase in the hazard of stage 2-4 acute gut GVHD (HR, 1.22; 95% CI, 1.02-1.45; P = .03). In HLA-A, B, C, DRB1, DQA1, DQB1, DPA1, DPB1-phenotypically matched unrelated recipients, the average recipient mismatching of coding SNPs was 17.3%. The estimated risks of GVHD-related outcomes in HLA-phenotypically matched unrelated recipients were low, relative to the large difference in genome-wide mismatching between the 2 groups. In contrast, the risks of GVHD-related outcomes were higher in HLA-DP GVH-mismatched unrelated recipients than in HLA-matched sibling recipients. Taken together, these results suggest that the increased GVHD risk after unrelated HCT is predominantly an effect of HLA-mismatching. [ABSTRACT FROM AUTHOR]

Previous studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated, or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive, or allelic) reported in the original study. The 21 SNPs reported in this study represent 19 genes, and the analysis encompassed 22 SNP association tests. The hazard ratio (HR) point estimates and risk ratio point estimates corresponding to odds ratios in previous studies consistently fall outside the 95%confidence intervals ofHRestimates in the current study. Despite the large size of the cohorts available for the current study, the 95% confidence intervals for most HRs did not exclude 1.0. Three SNPs representing CTLA4, HPSE, and IL1R1 showed evidence of association with the risk of chronic GVHD in unrelated donor-recipient pairs from 1 cohort, but none of these associations was replicatedwhen tested in unrelated donor-recipient pairs from an independent cohort.TwoSNPs representingCCR6andFGFR1OP showed possible associations with the risk of chronic GVHD in related donor-recipient pairs but not in unrelated donor-recipient pairs. These results remain to be tested for replication in other cohorts of related donor-recipient pairs. [ABSTRACT FROM AUTHOR]

Sclerotic graft-versus-host disease (GVHD) is a distinctive phenotype of chronic GVHD after allogeneic hematopoietic cell transplantation, characterized by fibrosis of skin or fascia. Sclerotic GVHD has clinical and histopathological similarities with systemic sclerosis, an autoimmune disease whose risk is influenced by genetic polymorphisms. We examined 13 candidate single-nucleotide polymorphisms (SNPs) that have a well-documented association with systemic sclerosis to determine whether these SNPs are also associated with the risk of sclerotic GVHD. The study cohort included 847 consecutive patients who were diagnosed with chronic GVHD. Genotyping was performed using microarrays, followed by imputation of unobserved SNPs. The donor rs10516487 (BANK1:B-cell scaffold protein with ankyrin repeats 1) TT genotype was associated with lower risk of sclerotic GVHD (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.21-0.87; P = .02). Donor and recipient rs2056626 (CD247: T-cell receptor ζ subunit) GG or GT genotypes were associated with higher risk of sclerotic GVHD (HR, 1.57; 95% CI, 1.13-2.18; P = .007 and HR, 1.66; 95% CI, 1.19-2.32; P = .003, respectively). Donor and recipient rs987870 (5'-flanking region of HLA-DPA1) CC genotypes were associated with higher risk of sclerotic GVHD (HR, 2.50; 95% CI, 1.22-5.11; P = .01 and HR, 2.13; 95% CI, 1.00-4.54; P = .05, respectively). In further analyses, the recipient DPA1*01:03~DPB1*04:01 haplotype and certain amino acid substitutions in the recipient P1 peptide-binding pocket of the HLA-DP heterodimer were associated with risk of sclerotic GVHD. Genetic components associated with systemic sclerosis are also associated with sclerotic GVHD. HLA-DP-mediated antigen presentation, T-cell response, and B-cell activation have important roles in the pathogenic mechanisms of both diseases. [ABSTRACT FROM AUTHOR]

Background: Low patient-reported resilience is associated with an ongoing risk of poor health and psychosocial outcomes. Using a large cross-sectional sample of survivors of hematopoietic cell transplantation (HCT), this study explored associations between patient-reported resilience, psychological distress, posttraumatic growth, and health-related quality of life.Methods: Between July 1, 2013 and June 30, 2014, the annual Fred Hutchinson Cancer Research Center (FHCRC) posttransplant survivorship survey queried patient-reported health and functional status and included instruments assessing psychosocial outcomes: the 10-item Connor-Davidson Resilience Scale, the Posttraumatic Growth Inventory, the Cancer and Treatment Distress measure, and the 12-item Medical Outcomes Study Short Form quality-of-life scale. Multivariate linear and logistic regression models included demographic and health covariates extracted from the FHCRC research database.Results: Among 4643 adult survivors of HCT, 1823 (39%) responded after a single mailing and subsequent reminder letter. The participants' median age was 59 years (interquartile range [IQR], 50-66 years); 52.5% were male, and most were non-Hispanic white. The median time since HCT was 9 years (IQR, 3-18 years). Lower patient-reported resilience was associated with chronic graft-versus-host disease of higher severity, lower performance scores, missing work because of health, and permanent disability (all P < .0001). After adjustments for demographic and health characteristics, patients reporting low resilience scores had higher odds of having psychological distress (odds ratio [OR], 3.0; 95% confidence interval [CI], 2.1-4.3) and being in the lowest quartile for mental health-related quality of life (OR, 5.9; 95% CI, 4.4-8.0).Conclusions: Patient-reported resilience is independently associated with health and psychosocial outcomes. Future studies must determine whether interventions can bolster resilience and improve survivorship outcomes. [ABSTRACT FROM AUTHOR]

Treatment of chronic graft-versus-host disease is intended to produce a sustainable benefit by reducing symptom burden, controlling objective manifestations of disease activity, preventing damage and impairment, and improving overall survival without causing disproportionate harms related to the treatment itself. Successful management can control the disease until systemic treatment is no longer needed. The complexity of the disease, the extended duration of follow-up needed to observe disease resolution and withdrawal of immunosuppressive treatment, and the lack of fully developed shorter term endpoints impede progress in the field. Identification and characterization of primary endpoints demonstrating clinical benefit without requiring years of follow-up is urgently needed, with the understanding that clinical benefit encompasses not only the self-evident benefit of the primary endpoint but also any other associated benefits. This report discusses regulatory considerations, eligibility criteria, the value of controlled trial designs, the merits of proposed primary endpoints, and key considerations elaborated from experience and progress during the past decade. The report concludes by mapping an overall approach that could support and lead to maximally informative clinical trials, especially those that seek to demonstrate clinical benefit along a pathway to regulatory review and approval. [ABSTRACT FROM AUTHOR]

Objective To investigate the usefulness of various scales for evaluating joint and fascia manifestations in patients with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation, and to compare the scales in terms of simplicity of use and ability to yield reliable and clinically meaningful results. Methods In a prospective, multicenter, longitudinal, observational cohort of patients with chronic GVHD (n = 567), we evaluated 3 scales proposed for assessing joint status: the National Institutes of Health (NIH) joint/fascia scale, the Hopkins fascia scale, and the Photographic Range of Motion (P-ROM) scale. Ten other scales were also tested for assessment of symptoms, quality of life, and physical functions. Results Joint and fascia manifestations were present at study enrollment in 164 (29%) of the patients. Limited range of motion was most frequent at the wrists or fingers. Among the 3 joint assessment scales, changes in the NIH scale correlated with both clinician- and patient-perceived improvement of joint and fascia manifestations, with higher sensitivity than the Hopkins fascia scale. Changes in all 3 scales correlated with clinician- and patient-perceived worsening, but the P-ROM scale was the most sensitive in this regard. Onset of joint and fascia manifestations was not associated with subsequent mortality. Conclusion Joint and fascia manifestations are common in patients with chronic GVHD and should be assessed carefully in these patients. Our results support the use of the NIH joint/fascia scale and P-ROM scale to assess joint and fascia manifestations. The NIH scale better captures improvement, while the P-ROM scale better captures worsening. The utility of these scales could also be tested in the rheumatic diseases. [ABSTRACT FROM AUTHOR]

The author comments on the efficacy of the addition of sitagliptin to tacrolimus and sirolimus medication in acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HSCT) based on a study. Topics discussed include the role of sitagliptin in the inhibition of enzymatic degradation of growth factors needed in blood cell production after HSCT, the need for the study to undergo controlled trial, and the benefit of using parenteral formulation in the study.

To determine whether changes in objective response measures proposed by the National Institutes of Health correlate with clinical benefit, such as symptom burden, quality of life, and survival outcomes, we analyzed data from a multicenter prospective cohort of 283 patients with chronic graft-versus-host disease requiring systemic treatment. The median follow-up time of survivors was 25.1 months (range, 5.4-47.7 months) after enrollment. Symptom measures included the Lee symptom scale and 10-point patient-reported symptoms. Quality-of-life measures included the Short Form-36, Functional Assessment of Cancer Therapy–Bone Marrow Transplantation, and Human Activities Profile. Overall and organ-specific responses were calculated by comparing manifestations at the 6-month visit and those at the enrollment visit using a provisional algorithm. Complete or partial responses were considered “response,” and stable or progressive disease was considered “no response.” Overall response rate at 6 months was 32%. Organ-specific response rates were 45% for skin, 23% for eyes, 32% for mouth, and 51% for gastrointestinal tract. Response at 6 months, as calculated according to the provisional response algorithm, was correlated with changes in symptom burden in patients with newly diagnosed chronic graft-versus-host disease, but not with changes in quality of life or survival outcomes. Modification of the algorithm or validation of other more meaningful clinical endpoints is warranted for future clinical trials of treatment for chronic graft-versus-host disease. [Copyright &y& Elsevier]

Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of aGVHD, practices differ among centers with respect to the initial glucocorticoid dose, the use of additional immunosuppressive agents, and the approach to withdrawal of treatment after initial improvement. Despite many studies, practices vary considerably with respect to the selection of agents for treatment of glucocorticoid-resistant or refractory GVHD. Investigators and clinicians have recognized the lack of progress and lamented the absence of an accepted standard of care for secondary treatment of aGVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of aGVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Because the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous results and the design of future studies. [ABSTRACT FROM AUTHOR]

Management of steroid-resistant or steroid-refractory acute graft-versus-host disease (aGVHD) poses one of the most vexing and difficult problems faced by transplantation physicians. In the current study, we used 10 criteria to evaluate 67 reports describing secondary treatment of patients with aGVHD. The goal of this exercise was not only to provide a critical summary of the literature but also to offer suggestions that could improve future studies. Areas especially in need of improvement include the use of a consistent treatment regimen, the assessment of response at a consistent prespecified time point, consideration of concomitant treatment in assessing response, documentation that selection bias was minimized, and the use of methods that test a formal statistical hypothesis based on a contemporaneous or historical benchmark. Our results suggest that previous published reports collectively offer little guidance in discerning the most effective treatments for patients with steroid-resistant or steroid-refractory aGVHD. Adherence to the proposed criteria in future reports would enable meaningful comparisons across studies and thereby accelerate progress in evaluating new treatments for patients with aGVHD. [ABSTRACT FROM AUTHOR]

Allogeneic marrow transplantation offers curative therapy for children with severe aplastic anaemia ( SAA). We report the outcomes of 148 children with SAA who received human leucocyte antigen ( HLA)-matched related marrow grafts between 1971 and 2010. Patients were divided into three groups, reflecting changes in conditioning and graft- versus-host disease ( GVHD) prophylaxis regimens that occurred over time. Patients in Group 1 were conditioned with cyclophosphamide ( CY; 200 mg/kg) followed by 'long' (102 d) methotrexate ( MTX). Patients in Groups 2 and 3 received CY alone (Group 2) or combined with anti-thymocyte globulin (Group 3) followed by 'short' (days 1, 3, 6, and 11) MTX and ciclosporin (until day 180). With a median follow-up of 25 years, the 5-year survivals were 66%, 95%, and 100% for Groups 1, 2, and 3, respectively (overall P < 0·0001). The 3-year estimates of graft rejection were 22%, 32%, and 7%, respectively. The probabilities of grades III- IV acute and 2-year chronic GVHD were 15%, 0%, and 3%, and 21%, 21%, and 10%, respectively. Advances in preparative and GVHD prophylaxis regimens, and supportive care during the past 40 years have led to improved outcomes for children with SAA. These results confirm the use of allogeneic marrow transplantation for children with SAA who have HLA-matched related donors. [ABSTRACT FROM AUTHOR]

Results from two randomized trials have shown that oral beclomethasone dipropionate (BDP) is effective for treatment of acute gastrointestinal graft-versus-host disease. Here, we report results of a double-blind, randomized placebo-controlled phase II study designed to test the hypothesis that acute graft-versus-host disease could be prevented by administration of oral BDP, beginning before hematopoietic cell transplantation and continuing until day 75 after hematopoietic cell transplantation after myeloablative conditioning. Study drug (BDP or placebo) was administered as 1-mg immediate-release formulation plus 1-mg delayed-release formulation orally four times daily. According to the primary endpoint, systemic glucocorticoid treatment for graft-versus-host disease was given to 60 of the 92 participants (65%) in the BDP arm, versus 31 of 46 participants (67%) in the placebo arm. The secondary efficacy endpoints showed no statistically significant differences between the two arms. The proportion of participants who took at least 90% of the prescribed study drug during the first 4 weeks after hematopoietic cell transplantation was 54% overall. Lower severity of mucositis strongly correlated with higher adherence to the schedule of study drug administration. Inconsistent adherence related to mucositis during recovery after myeloablative conditioning may have obscured a beneficial therapeutic effect in the current study. [ABSTRACT FROM AUTHOR]

Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other's genome. One such disease, graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an individual whose genome is homozygous for a gene deletion could recognize epitopes encoded by that gene as alloantigens. Analyzing common gene deletions in three HSCT cohorts (1,345 HLA-identical sibling donor-recipient pairs), we found that risk of acute GVHD was greater (odds ratio (OR) = 2.5; 95% confidence interval (CI) 1.4–4.6) when donor and recipient were mismatched for homozygous deletion of UGT2B17, a gene expressed in GVHD-affected tissues and giving rise to multiple histocompatibility antigens. Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity. [ABSTRACT FROM AUTHOR]

Currently, no agents are approved by the United States Food and Drug Administration (FDA) for either prevention or treatment of acute graft-versus-host disease (aGVHD). Formal precedents establishing a comparative basis for assessing the efficacy and safety of new investigational agents are still lacking. As a step toward addressing this problem, a panel of experts met on 2 occasions to reach consensus on recommendations for terminology describing a clinically meaningful primary endpoint in studies assessing treatment for aGVHD. The panel recommended terminology for “very good partial response” (VGPR) that includes both diagnostic and functional criteria. The central hypothesis leading to this proposal is that the potential harm of giving more treatment than needed to produce or maintain complete response exceeds the harm of slight undertreatment that may be associated with less than complete response. VGPR clearly cannot be used as the sole outcome measure in GVHD treatment trials, and must be considered in the context of survival and safety. The proposed use of VGPR as the primary endpoint in GVHD treatment trials will remain provisional until its use has been validated through experience. [Copyright &y& Elsevier]

The design of clinical trials for prevention or treatment of acute or chronic graft-versus-host disease poses many challenges. These challenges include the selection of primary and secondary endpoints that demonstrate clinical benefit, and the identification of measures indicating success both for individual patients and groups. Assessment of response in treatment trials should ideally encompass the prior trajectory of change before treatment. The criteria, timing and duration of response should be specified, and the potential effects of concomitant treatment and complications other than GVHD should be taken into account in assessing outcomes. A crucial element in clinical trial design is the pre-specification of the hypothesis to be tested in quantitative terms. Potential barriers to enrollment should be carefully considered in order to ensure timely completion of the trial. [Copyright &y& Elsevier]

Abstract: The complexity of chronic graft-versus-host disease (GVHD) and the lack of established research methods have made it difficult to design, conduct, and analyze clinical trials involving subjects with this disease, even when promising treatment options are available. This consensus document was developed to offer an approach for overcoming these obstacles. Clinical trials in chronic GVHD should adhere to principles of good trial design and practice. Inclusion and exclusion criteria should allow as many subjects to participate as possible without compromising the interpretation of results. Pre-enrollment assessment of chronic GVHD characteristics should be standardized. The protocol should provide clear guidance about administration of study medication and other interventions. Methods of assessing response should be defined and validated in advance. Efficacy endpoints should be selected to reflect clinical benefit. Expert biostatistical support is needed to ensure the validity and reliability of trial results. The use of consistent standards in clinical trial designs to evaluate agents that have activity in pathogenic pathways could facilitate advances in the treatment of chronic GVHD. [Copyright &y& Elsevier]

Background: Despite recent advances, mortality rates after allogeneic hematopoietic cell transplantation remain high and cannot be accurately predicted. Objective: To develop a reliable and valid predictor of all-cause mortality during the first 2 years after allogeneic hematopoietic cell transplantation. Design: Retrospective cohort. Setting: Tertiary hematopoietic cell transplantation center. Patients: Patients (n = 2802) who received a first hematopoietic cell transplant between 1990 and 2002 were assigned to a development group or a validation group. Measurements: Potential predictor variables were assessed with univariate and multivariable Cox proportional hazards methods to generate a prediction model. The c-statistic was calculated for 5 validation cohorts to assess model performance across early and late time periods and among patients with different diagnoses. Results: The authors constructed a 50-point Pretransplantation Assessment of Mortality (PAM) score that incorporated 8 pretransplantation clinical variables: patient age, donor type, disease risk, conditioning regimen, FEV1, carbon monoxide diffusion capacity, serum creatinine level, and serum alanine aminotransferase concentration. The risk for death within 2 years for patients with PAM scores in the highest category was significantly higher than for those with scores in the lowest category. C-statistic values ranged from 0.69 to 0.76 for all validation cohorts. Limitations: The predictor model was not validated in an external cohort and is only useful for predicting the risk for death within the first 2 years after hematopoietic cell transplantation. Conclusions: Integrating pretransplantation clinical variables into a single score reliably predicts survival within 2 years after allogeneic hematopoietic cell transplantation. Accurate estimates of the risk for death may be useful in clinical trials and in epidemiologic studies. Such information can also be used to help physicians counsel patients regarding the expected outcomes of this potentially curative procedure. [ABSTRACT FROM AUTHOR]

Abstract: This review addresses pitfalls of clinical trials to evaluate new approaches for prevention or treatment of graft-versus-host disease. Determination of end points poses a difficult challenge in the design of clinical trials, and examples from previous studies are used to illustrate some of the pitfalls. Also discussed is the need for a new conceptual approach for evaluation of graft-versus-host disease after nonmyeloablative conditioning regimens, because the donor antirecipient alloimmune reaction is the primary mechanism of benefit with this type of treatment. Finally, investigators should be aware of regulatory and socioeconomic pitfalls that apply to all clinical trials. [Copyright &y& Elsevier]

We retrospectively analysed outcomes among 395 patients with haematologic malignancies who underwent non-myeloablative haematopoietic cell transplantation (HCT) from human leucocyte antigen (HLA)-matched related (n = 297) or unrelated donors (n = 98) in order to identify a possible correlation between the time of onset of graft-versus-host disease (GVHD) and survival. The non-myeloablative regimen consisted of 2 Gy total body irradiation with or without fludarabine, followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. The cumulative incidences of grades II–IV acute GVHD and extensive chronic GVHD were 45% and 47%, respectively, with related donors, and 68% and 68%, respectively, with unrelated donors. High-dose corticosteroid treatment for acute or chronic GVHD was started at a median of 79 (range, 8–799) days and 30 (range, 5–333) days after transplantation from related and unrelated donors respectively. With related donors, the cumulative incidence of non-relapse mortality among patients with GVHD was 55% at 4 years when prednisone was started before day 50 (n = 72), compared with 29% when treatment was started after day 50 (n = 115) (P < 0·001). With unrelated donors, time to onset of treatment for GVHD was not associated with survival. Patients with early-onset GVHD after non-myeloablative HCT from HLA-identical related donors might benefit from intensified primary immunosuppressive treatment. [ABSTRACT FROM AUTHOR]

Donor T cells activated by recipient alloantigens cause graft-versus-host disease (GVHD) after hematopoietic cell transplantation. Activated T cells express CD25, among other components of the interleukin-2 receptor. We conducted a phase I/II study to determine whether administration of CD25-specific antibody conjugated to ricin toxin A could reduce the risk of grade III or IV GVHD after marrow transplantation from HLA-matched unrelated donors. All patients received methotrexate and cyclosporine after the transplantation. The immunotoxin was given to 36 patients for 4 consecutive days beginning approximately 36 hours after the marrow infusion was completed. Fourteen (40%) of the 35 patients who could be evaluated developed grade III or IV GVHD. In a contemporaneous population of 121 patients who received marrow from HLA-matched unrelated donors and were given methotrexate and cyclosporine without the immunotoxin, the incidence of grades III and IV GVHD was 24%. Cyclosporine blocked the induction of CD25 expression on alloactivated T cells in vitro but had no detectable effect on CD25 expression by T-regulatory cells. Taken together, these results are consistent with the hypothesis that cyclosporine protected alloactivated donor T cells from the effects of the immunotoxin, whereas the CD25+ T-regulatory cells remained susceptible, causing an unexpected exacerbation of acute GVHD. [Copyright &y& Elsevier]

The reported incidence of grades II to IV acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation with HLA-identical sibling donors has increased considerably during the past 15 to 20 years at our center. The purpose of this study was to evaluate the potential reasons for this change. We reviewed organ stages and overall grades of GVHD for 2220 patients who received a first marrow or peripheral blood cell transplant from an HLA-identical sibling or an HLA-allele-matched unrelated donor with the use of a posttransplantation immunosuppressive regimen that included both methotrexate and cyclosporine between 1985 and 2001. The most striking change was an increased incidence of stage 1 gut involvement from 10% to 20% before 1992 to 50% to 60% since 1992, both with related and unrelated donors. This change increased the incidence of grade II GVHD with sibling donors, such that the overall incidence of grade II to IV GVHD is now 60% to 70%. Among patients with chronic myeloid leukemia in chronic phase, the increasingly frequent diagnosis of acute GVHD since 1992 has not been associated with decreased survival. A high diagnostic sensitivity and increased awareness that gut GVHD can occur without skin involvement account for the increased incidence of acute GVHD at our center. [Copyright &y& Elsevier]

Chronic graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent reports suggest that chronic GVHD is more frequent after G-CSF - mobilized peripheral blood mononuclear cell (G-PBMC) transplantation compared to marrow transplantation from human leukocyte antigen (HLA)-matched siblings. Furthermore, higher numbers of CD34 positive cells in G-PBMC grafts were associated with an increased risk of chronic GVHD, whereas a correlation between CD34 cell numbers and chronic GVHD has not been reported after bone marrow transplantation. Potential mechanisms that might explain the association between G-PBMC CD34 numbers and chronic GVHD include enhanced antigen presentation to donor T cells by large numbers of transplanted CD34 cells or their dendritic cell progeny, which may enhance GVHD induction. However, these mechanisms remain highly speculative and are not supported by experimental data. This review discusses implications of CD34 cell dose adjustments in HLA-identical sibling G-PBMC transplantation and weighs the benefits and risks with respect to chronic GVHD, hematopoietic recovery, immune reconstitution and relapse. [ABSTRACT FROM AUTHOR]

We recently identified a new minor histocompatibility antigen, termed HA-8, which is presented by human leucocyte antigen (HLA)-A*0201 or HLA-A*0202 and expressed ubiquitously among tissues. A retrospective analysis of 577 Caucasian patients with HLA-A*0201 or A*0202 who had received a haematopoietic stem cell transplant from a human leucocyte antigen (HLA)-identical sibling was conducted to determine whether HA-8 disparity correlated with clinical outcome. HA-8 disparity was detected in 72 recipients, and grades II–IV graft- versus-host disease (GVHD) occurred in 46 (64%), compared with 251 (50%) of the 503 patients without HA-8 disparity. After adjusting for known risk factors for acute GVHD, this difference was statistically significant (odds ratio, 1·8; 95% confidence interval, 1·0–3·1; P = 0·04). However, the hazards of clinical extensive chronic GVHD, overall mortality and recurrent malignancy were not statistically significantly different between the two groups. These data suggest that the increased risk of acute GVHD associated with recipient HA-8 disparity was not sufficient to change other clinical outcomes. [ABSTRACT FROM AUTHOR]

During the past 5 years, better understanding of immunomodulatory and anti-angiogenesis properties of thalidomide has increased interest in the use of this agent for a wider variety of clinical applications. This article reviews the clinical evaluation of thalidomide for treatment or prevention of chronic graft-versus-host-disease. [ABSTRACT FROM AUTHOR]

Two patients with acute leukemia were treated with chemoradiotherapy and allogeneic bone marrow transplantation. Despite the prophylactic use of methotrexate after grafting, both patients developed severe graft-versus-host disease that was refractory to treatment with methylprednisolone. The graft-versus-host disease was then treated with a monoclonal antibody, 64.1, that reacts with a p19 antigen on human T cells. The disease responded dramatically to this treatment, but both patients subsequently developed a fatal polyclonal lymphoproliferative disorder arising in donor-derived B cells. Hybridization studies showed Epstein-Barr virus in both tumors. The combined effect of severe end-stage graft-versus-host disease and potent immunosuppressive therapy probably resulted in a progressive immunodeficiency syndrome that abrogated the T-cell-mediated surveillance mechanism that normally modulates the proliferation of Epstein-Barr-virus-infected B lymphocytes. [ABSTRACT FROM AUTHOR]

In this issue of Blood, Hu¨ lsdu¨ nker et al show how recipient neutrophils contribute to the pathogenesis of acute graft-versus-host disease (GVHD), a complication of allogeneic hematopoietic cell transplantation (HCT) caused by donor T cells that recognize recipient alloantigens. [ABSTRACT FROM AUTHOR]

• Even among patients tolerating a chronic graft-versus-host disease treatment for 6 months, treatment failure (addition of a new systemic immunosuppressive agent, recurrent malignancy, death) occurs for more than half within the next 2 years. • Changes in the eye, joint/fascia, and mouth ulcer scores between enrollment and 6 months are associated with subsequent failure-free survival. In clinical trials of chronic graft-versus-host disease (cGVHD), the need to start a new systemic treatment is considered a treatment failure. A composite endpoint called "failure-free survival" (FFS), where events are initiation of a new systemic cGVHD treatment, recurrent malignancy, and death, has been suggested as a possible long-term indicator of success. The goal of the current study was to identify changes in cGVHD manifestations from baseline to 6 months that could accurately predict subsequent longer-term FFS, thereby making it possible to assess outcomes earlier than would otherwise be possible. We used data from 2 prospective, multicenter, observational studies to develop the cGVHD-FFS index. The cGVHD-FFS index was calculated at 6 months, a typical timepoint for assessment of the primary endpoint of phase II cGVHD trials. Subsequent FFS was only 45% within the next 2 years. We found that changes in the scores for the eyes, joint/fascia, and mouth ulcers from baseline to 6 months were associated with subsequent FFS, but the prognostic accuracy of these changes was not adequate for use in trials. Biomarker studies might help to identify criteria that improve prediction of long-term clinical outcomes in patients with cGVHD. [ABSTRACT FROM AUTHOR]

The author discusses the study "Allo-HLA reactive T-cells inducing graft versus host disease are single peptide specific," by A. L. Amir and colleagues. He mentions that the study shows that T cell receptors (TCRs) of a donor recognize major histocompatibility complex (MHC) alloantigens of a recipient in a patient with graft-versus-host disease (GVHD). He also notes the need of further study to provide more understanding of the rules governing alloreactive T cell ability to cause GVHD.

The article presents a comment on the study that indicates that intensive immunosuppressive treatment can overcome steroid-refractory acute graft-versus-host disease (GVHD). The researchers analyze the effects of increased immunosuppressive treatment on T-cell attack, epithelial injury, and serum samples on patients with GVHD. However, the result of the study indicates that intensive immunosuppressive treatment can increase the angiopoietin-2 (ANG2) in steroid-refractory GVHD.

The article focuses on the effect of granulocyte colony-stimulating factor (G-CSF) treatment on graft-versus-host disease (GVHD) in mice. It states that G-CSF could worsen the disease after cell transplantation and interfere blood cells production. It also notes that G-CSF increases the risk of the disease due to recipient antigen cells.

During hematopoietic stem cell transplantation, donor cell subsets mediate the delicate balance between graft rejection and the development of graft-versus-host disease. Is it possible to manipulate donor cell populations to facilitate engraftment of highly enriched hematopoietic stem cells in allogeneic recipients? [ABSTRACT FROM AUTHOR]

Administration of an agonistic anti-CD28 mAb paradoxically inhibits donor T cell expansion and prevents graft-versus-host disease (GVHD) in mice. Here we examined the mechanism of anti-CD28-mediated immunosuppression and found that anti-CD28 mAb activated, rather than blocked, CD28-mediated signaling in vivo. Anti-CD28 treatment prevented GVHD by selectively depleting alloantigen-activated donor T cells through apoptosis but spared the T cells that did not recognize recipient alloantigens. Overexpression of Bcl-x(L) did not protect T cells from depletion and did not affect GVHD prevention after anti-CD28 treatment. Depletion of activated T cells mediated through CD28 did not depend on the expression of death receptors Fas and TNF receptors type I and II, but both the depletion of activated T cells and the suppressive effect of anti-CD28 mAb on GVHD lethality required donor-derived IFN-gamma production. This study demonstrates that agonistic Ab's specific for the CD28 costimulatory molecule may be used as novel therapeutic agents to abrogate pathogenic T cell responses by selective depletion of activated T cells. [ABSTRACT FROM AUTHOR]

CD4+ T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular CD44hiCD62LloPSGL1loCD4+ T cells (PSGL1loCD4+ T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized MHC-/-HLA-A2+DR4+ murine models of cGVHD, we showed that murine and human PSGL1loCD4+ T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine PSGL1loCD4+ T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human PSGL1loCD4+ T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1loCD4+ T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD-L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted. [ABSTRACT FROM AUTHOR]

• Mesenchymal stem cells (MSC) versus placebo added to second-line therapy for treatment of steroid-refractory acute graft-versus-host disease (aGVHD) did not show benefit. • MSC infusions were well tolerated and did not result in excess adverse events compared with placebo. • Post hoc subgroup analyses suggested favorable odds of day 28 response in children and in patients with high-risk aGVHD or liver involvement. Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be effective against acute graft-versus-host disease (aGVHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid-refractory aGVHD (NCT00366145). In total, 260 patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009 and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGVHD symptoms for any period of at least 28 days after beginning treatment. Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% versus 30%; P = 0.42). In post hoc analyses, patients with liver involvement who received at least 1 infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% versus 5%; P =.047). Among high-risk patients (aGVHD grades C and D), remestemcel-L demonstrated significantly higher OR at day 28 than placebo (58% versus 37%; P = 0.03). Furthermore, pediatric patients had a higher OR with MSCs compared with placebo (64% versus 23%; P =.05). Similar rates of adverse events were observed between treatment groups. Remestemcel-L was safe and well tolerated. Results of this study did not demonstrate superior DCR compared with placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation. [ABSTRACT FROM AUTHOR]

• Disability as defined by progressive chronic graft-versus-host disease (GVHD) impairments are associated with decline in human activity profile scores and performance status at 18 months. • Worse oral scores and patient-reported eye and skin scores are significantly associated with progressive chronic GVHD impairment at 18 months. Chronic graft-versus-host disease (cGVHD) is a heterogenous syndrome whose symptoms and treatment are often associated with decreases in functional status and quality of life among survivors of transplantation. We explored definitions of cGVHD-related disability and factors associated with disability in cGVHD. We analyzed 371 patients with cGVHD requiring a new systemic therapy with enrollment and 18-month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any 1 of 5 impairments previously defined by Fatobene et al [1] (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability, defined as an ≥8-point decline in a human activity profile (HAP) score or a ≥20% decline in Karnofsky Performance Status (KPS) from enrollment to 18 months. At enrollment, 47% of patients had at least 1 of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 patients (53%) with no Flowers disability at enrollment, 50% progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with a decline in HAP/KPS as well as with increased National Institutes of Health severity scores at 18 months. Enrollment mouth scores and patient-reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent nonrelapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome. [ABSTRACT FROM AUTHOR]

• Antiepileptic medications other than phenytoin prevent seizures induced by busulfan. • Alternative antiepileptic medications (AEMs) do not affect relapse risk in adults. • Adults receiving i.v. busulfan and alternative AEMs are at decreased risk of renal failure. High-dose busulfan (BU) followed by high-dose cyclophosphamide (CY) before allogeneic hematopoietic cell transplantation (HCT) has long been used as treatment for hematologic malignancies. Administration of phenytoin or newer alternative antiepileptic medications (AEMs) prevents seizures caused by BU. Phenytoin induces enzymes that increase exposure to active CY metabolites in vivo, whereas alternative AEMs do not have this effect. Lower exposure to active CY metabolites with the use of alternative AEMs could decrease the risk of toxicity but might increase the risk of recurrent malignancy after HCT. Previous studies have not determined whether outcomes with alternative AEMs differ from those with phenytoin in patients treated with BU/CY before allogeneic HCT. We studied a cohort of 2155 patients, including 1460 treated with phenytoin and 695 treated with alternative AEMs, who received BU/CY before allogeneic HCT between 2004 and 2014. We found no differences suggesting decreased overall survival or relapse-free survival or increased risks of relapse, nonrelapse mortality, acute or chronic graft-versus-host disease, or regimen-related toxicity associated with the use of alternative AEMs compared with phenytoin. The risk of dialysis was lower in the alternative AEM group than in the phenytoin group. Alternative AEMs are safe for prevention of seizures after BU administration and can avoid the undesirable toxicities and drug interactions caused by phenytoin. [ABSTRACT FROM AUTHOR]

Highlights • The onset of chronic graft-versus-host disease (cGVHD) is associated with significantly higher CD19+CD10−CD27−CD21low B cell counts and lower T1 transitional CD27−CD10+ B cell counts. • These B cell populations remain significant regardless of steroid use at cGVHD diagnosis. • Soluble BAFF down-regulates B cell surface BAFF-R expression. ABSTRACT Previous studies have reported single B cell-related chronic graft-versus-host disease diagnostic (cGVHD) biomarkers, such as B cell-activating factor (BAFF), CD21low, and immature B cells, but research on the performance of biomarker combinations and the covariate effect of steroids is lacking. The primary objective of this study was to determine the most accurate combination of B cell populations using cell surface staining flow cytometry in an independent cohort of patients with cGVHD. Secondary objectives included assessing the effect of corticosteroid use at sample collection on the makeup and accuracy of the diagnostic panel and identifying the mechanism underlying low surface expression of BAFF receptor (BAFF-R) on B cells in cGVHD. Flow cytometry analysis was performed in an adult cohort of post-HCT patients with cGVHD onset (n = 44) and time-matched recipients without cGVHD (n = 63). We confirmed that the onset of cGVHD was associated with higher soluble BAFF (sBAFF) levels, elevated CD27−CD10−CD21low CD19+ B cell and classical switched memory B cell counts, and reduced transitional and naïve B cell counts. The highest single B cell population area under the receiver operating characteristic (ROC) curve (AUC) was.72 for transitional type 1 CD21low B cells. We also showed a significant inverse relationship between sBAFF and surface BAFF-R expression caused by sBAFF modulation of BAFF-R. Steroid use at sample collection influenced the significance of the sBAFF:B cell ratio, naïve and marginal zone-like B cells. The optimal combination of B cell subsets most significantly associated with cGVHD onset with or without concurrent corticosteroid use resulted in ROC AUCs of.87 and.84, respectively. Transitional and CD21low B cells were the only populations present in both panels; however, analyzing only these populations resulted in ROC AUCs of.79 and.78, respectively. This suggests that the inclusion of other populations and use of different panels depending on steroid use is necessary to achieve better accuracy. sBAFF was not a component of either panel. These novel B cell profiles could be tested prospectively in patients post-HSCT and could lead to focused mechanistic studies. [ABSTRACT FROM AUTHOR]

Moderate to severe chronic graft-versus-host disease (GVHD) is treated with potent immunosuppressive therapy (IST) to modulate the allo-immune response, control symptoms, and prevent further organ damage. We sought to understand the types of treatments used in clinical practice and the likelihood of successful treatment associated with each. A chart review was performed for 250 adult patients at Fred Hutchinson Cancer Research Center enrolled in a prospective observational study. After a median follow-up of 5.6 years for survivors, approximately one-third were still on IST (of whom half were on fourth or greater line of therapy), one-third were alive and off IST, and one-third had relapsed or died. Approximately half of survivors stopped all IST at least once, although half of these restarted IST after a median of 3.4 months (interquartile range, 2.3 to 8.0) off therapy. Successful discontinuation of IST for at least 9 months was associated with myeloablative conditioning ( P  = .04), more years since transplant ( P  = .009), and lack of oral ( P  < .001) and skin ( P  = .049) involvement compared with those who had to restart IST. We conclude that patients with chronic GVHD usually receive multiple lines and years of IST, with only a third off IST, alive, and free of malignancy at 5 years after chronic GVHD diagnosis. Patients stopping IST should be cautioned to self-monitor and continue close medical follow-up, especially for 3 to 6 months after stopping IST. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We examined the hypothesis that plasma biomarkers and concomitant clinical findings after initial glucocorticoid therapy can accurately predict failure of graft-versus-host-disease (GVHD) treatment and mortality. We analyzed plasma samples and clinical data in 165 patients after 14 days of glucocorticoid therapy and used logistic regression and areas under receiver-operating characteristic curves (AUC) to evaluate associations with treatment failure and nonrelapse mortality (NRM). Initial treatment of GVHD was unsuccessful in 49 patients (30%). For predicting GVHD treatment failure, the best clinical combination (total serum bilirubin and skin GVHD stage: AUC, .70) was competitive with the best biomarker combination (T cell immunoglobulin and mucin domain 3 [TIM3] and [interleukin 1 receptor family encoded by the IL1RL1 gene, ST2]: AUC, .73). The combination of clinical features and biomarker results offered only a slight improvement (AUC, .75). For predicting NRM at 1 year, the best clinical predictor (total serum bilirubin: AUC, .81) was competitive with the best biomarker combination (TIM3 and soluble tumor necrosis factor receptor-1 [sTNFR1]: AUC, .85). The combination offered no improvement (AUC, .85). Infection was the proximate cause of death in virtually all patients. We conclude that after 14 days of glucocorticoid therapy, clinical findings (serum bilirubin, skin GVHD) and plasma biomarkers (TIM3, ST2, sTNFR1) can predict failure of GVHD treatment and NRM. These biomarkers reflect counter-regulatory mechanisms and provide insight into the pathophysiology of GVHD reactions after glucocorticoid treatment. The best predictive models, however, exhibit inadequate positive predictive values for identifying high-risk GVHD cohorts for investigational trials, as only a minority of patients with high-risk GVHD would be identified and most patients would be falsely predicted to have adverse outcomes. [ABSTRACT FROM AUTHOR]

Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor CD4+ T cells increased serum IFN-γ but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor CD8+ T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment CD8+ T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1-mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptor expressed by CD8+ T cells, and the tissue environment in which the signaling occurs. [ABSTRACT FROM AUTHOR]

Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25 + FOXP3 + regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups ( P  = .68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.0 to 2.3; P  = .08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P  = .05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P  = .53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity. [ABSTRACT FROM AUTHOR]