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Survivors of hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can negatively affect quality of life. Given limited studies, we aimed to describe the neurocognitive outcomes in a cohort of long-term adult HCT survivors. Eligible survivors (age ≥21 years at HCT and alive ≥2 years following HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL) and the Childhood Cancer Survivor Study Neurocognitive Questionnaire (NCQ). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Survivors (n = 1861, 47.7% female, 65.6% allogeneic HCT) were surveyed at a median age of 64.2 years (interquartile range [IQR], 56.8-70.5) and a median 12.0 years (IQR, 6.0-21.0) from HCT. Survivors reported average Neuro-QoL scores (50.0 allogeneic; 49.2 autologous survivors) compared with an expected mean of 50 in the general population. On the NCQ, 17.4% to 31.2% of survivors reported impairments (Z-score >1.28) in task efficiency, memory, emotional regulation, or organization, compared with an expected 10% in the general population (all P < .01). In multivariable regression analyses, impaired Neuro-QoL (T-score

Supplemental Table 1. Multivariate analysis of late relapse, transplant-related mortality, overall survival after HCT for each disease (AML, ALL, CML, MDS)

Purpose: Malignancy relapse remains a major obstacle for successful allogeneic hematopoietic cell transplantation (HCT). Chronic graft-versus-host disease (cGVHD) is associated with fewer relapses. However, when studying effects of cGVHD on relapse, it is difficult to separate from acute GVHD effects as most cases of cGVHD occur within the first year after transplant at the time when acute GVHD is still active.Experimental Design: This study based on CIBMTR registry data investigated cGVHD and its association with the incidence of late relapse and survival in 7,489 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndromes (MDS), who were leukemia free at 12 months after myeloablative allogeneic HCT.Results: Forty-seven percent of the study population was diagnosed with cGVHD at 12 months after transplant. The protective effect of cGVHD on late relapse was present only in patients with CML [RR, 0.47; 95% confidence interval (CI), 0.37–0.59; P < 0.0001). cGVHD was significantly associated with higher risk of treatment-related mortality (TRM; RR, 2.43; 95% CI, 2.09–2.82; P < 0.0001) and inferior overall survival (RR, 1.56; 95% CI, 1.41–1.73; P < 0.0001) for all diseases. In patients with CML, all organ sites and presentation types of cGVHD were equally associated with lower risk of late relapse.Conclusions: These results indicate that clinically relevant antileukemia effects of cGVHD on late relapses are present only in CML but not in AML, ALL, or MDS. Chronic GVHD in patients who are 1-year survivors after myeloablative allogeneic HCT is primarily associated with higher TRM and inferior survival. Clin Cancer Res; 21(9); 2020–8. ©2014 AACR.See related commentary by Gill, p. 1981

Supplemental Table 4. Multivariate analysis showing impact of cGVHD characteristics on treatment related mortality, disease free survival, overall survival in patients with AML, ALL, MDS who developed cGVHD

Supplemental Table 2. Multivariate analysis showing impact of cGVHD characteristics in CML patients on relapse

Supplemental Table 3. Multivariate analysis showing impact of cGVHD characteristics on treatment related mortality, disease free survival and overall survival in patients with CML who developed cGVHD

Supplemental Figure 1. Cumulative incidence of cGVHD, relapse and death in patients with AML, ALL, CML, MDS

The kinetics of early and late CMV reactivation after hematopoietic cell transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are poorly defined. We retrospectively compared CMV reactivation and disease among 780 seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and calcineurin-inhibitor plus post-transplantation cyclophosphamide (PTCy; n=44), mycophenolate mofetil (MMF; n=414) or methotrexate (MTX; n=322). Transplantation occurred between 2007-2018; CMV-monitoring/management followed uniform standard practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves were fit over average daily viral load, and areas under the curve (AUC) within one-year were calculated. PTCy and MMF were associated with an increased risk of early (day 100) CMV reactivation ≥250 IU/mL after multivariable adjustment (PTCy vs. MTX: HR=1.64; 95% CI: 1.03-2.61; p=0.039; MMF vs. MTX: HR=1.50; 95% CI: 0.97-2.32; p=0.067). The viral load AUC at one-year was highest with MMF (mean difference 0.125 units vs. MTX; 95% CI 0.061-0.189; p.001) and similar between PTCy vs. MTX (mean difference 0.016 units vs. MTX group; 95% CI, -0.126-0.158, p=0.827). CMV disease risk was similar across groups. There was no interaction between GVHD prophylaxis and CMV reactivation on chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast, MMF was associated with higher overall CMV viral burden in the 1-year posttransplant. While different mechanisms of immunosuppressive agents may impact CMV reactivation risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate infection risk over time.

ImportancePrior studies have demonstrated an association between cutaneous chronic graft-vs-host disease (cGVHD) and mortality. Assessment of the prognostic value of different measures of disease severity would assist in risk stratification.ObjectiveTo compare the prognostic value of body surface area (BSA) and National Institutes of Health (NIH) Skin Score on survival outcomes stratified by erythema and sclerosis subtypes of cGVHD.Design, Setting, and ParticipantsMulticenter prospective cohort study from the Chronic Graft-vs-Host Disease Consortium including 9 medical centers in the US, enrolled from 2007 through 2012 and followed until 2018. Participants were adults and children with a diagnosis of cGVHD requiring systemic immunosuppression and with skin involvement during the study period, who had longitudinal follow-up. Data analysis was performed from April 2019 to April 2022.ExposuresPatients underwent continuous BSA estimation and categorical NIH Skin Score grading of cutaneous cGVHD at enrollment and every 3 to 6 months thereafter.Main Outcomes and MeasuresNonrelapse mortality (NRM) and overall survival (OS), compared between BSA and NIH Skin Score longitudinal prognostic models, adjusted for age, race, conditioning intensity, patient sex, and donor sex.ResultsOf 469 patients with cGVHD, 267 (57%) (105 female [39%]; mean [SD] age, 51 [12] years) had cutaneous cGVHD at enrollment, and 89 (19%) developed skin involvement subsequently. Erythema-type disease had earlier onset and was more responsive to treatment compared with sclerosis-type disease. Most cases (77 of 112 [69%]) of sclerotic disease occurred without prior erythema. Erythema-type cGVHD at first follow-up visit was associated with NRM (hazard ratio, 1.33 per 10% BSA increase; 95% CI, 1.19-1.48; P P 2, 5.9; P = .05). Conversely, NIH Skin Score collected at the same intervals lost significant prognostic information (likelihood ratio test χ2, 14.7; P Conclusions and RelevanceIn this prospective cohort study, erythema-type cutaneous cGVHD was associated with increased risk of mortality. Erythema BSA collected at baseline and follow-up predicted survival more accurately than the NIH Skin Score in patients requiring immunosuppression. Accurate assessment of erythema BSA may assist in identifying patients with cutaneous cGVHD at high risk for mortality.

With improved survival after hematopoietic cell transplant (HCT), the number of individuals at risk for persistent or late effects is increasing. The importance of optimizing HCT survivor health and wellbeing is mounting. Fatigue is a common post-transplant symptom that impairs quality of life, yet it remains poorly understood and inadequately addressed. Multiple challenges to addressing fatigue exist, including its multidimensional presentation, multiple (often concomitant) causes, patient-clinician communication barriers, and few highly effective, evidence-based interventions that are readily implemented. To address these challenges, we sought to better describe its impact and potential causes in the post-transplant setting, fatigue-related communication with clinicians, and most effective patient-identified mitigation strategies (PIMS) for it.1703 adult HCT recipients from a single center completed a survey including the SF-36, PROMIS Fatigue, and other fatigue-related items between July 2017-June 2018. The survey was offered to recipients at their post-transplant anniversary occurring during this interval. Two independent raters categorized free-text responses about fatigue PIMS. PROMIS Fatigue scores were dichotomized into low (≤55) or high (55). Associations between high fatigue and participant characteristics and health outcomes were evaluated using Fisher's Exact Test (categorical variables) and Student's Two-Sample T-Test (continuous variables).Among1660 respondents with evaluable fatigue scores, 67% underwent allogeneic HCT. The majority (n=1588, 96%) had malignancy; hematologic malignancy was the most common diagnostic category (n=1555, 94%). Median (IQR) time post-transplant was 11 (4-20) years. PROMIS item responses indicate 44% were at least somewhat fatigued and 37% at least somewhat bothered by it. Mean (SD) fatigue score was 50.2 (11); 591 (36%) had high fatigue, which was associated with worse SF-36 scores across all domains (General Health, Physical Functioning, Emotional Well-being/Mental Health, Social Functioning, Role Limitation due to Physical Health, Role Limitation due to Emotional Health, Vitality (e.g., energy), and Bodily Pain). It was also associated with self-reported chronic GVHD, anxiety, depression and sleep problems. Diagnosis of plasma cell disorder and receipt of an autologous transplant were associated with high fatigue (p=0.001). Among the 553 individuals who received an autologous transplant, 226 (41%) had multiple myeloma. When compared to the autologous non-myeloma group, those with multiple myeloma were significantly more likely to have high fatigue (109/226, 48%) compared to the non-myeloma group (118/325, [36%], p0.01). 20% with high fatigue did not discuss it with their care team. Of the 89 reasons provided for not discussing it, the most common reason was "thought they already knew the answer" (n=21), The 370 survivors with high fatigue who identified at least one most effective PIMS generated a total of 639 PIMS. While PIMS for fatigue spanned an array of strategies, most PIMS were related to sleep/rest (n=192, 30%) or exercise (n=139, 22%).While associated with worse HCT survivor-reported outcomes, fatigue is only sometimes discussed with care teams. Survivors identify specific strategies that are most effective. Given its prevalence and impact, clinicians should promote communication about fatigue, treat underlying causes, and recommend sleep/rest and exercise, recognizing individualized approaches may also be beneficial.

PURPOSE Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

Although autologous and allogeneic hematopoietic cell transplantation are used to treat hematologic diseases, they are associated with high morbidity and mortality. The goal of this cross-sectional study was to describe the incidence, characteristics, severity and clinical correlates of neuropathy and muscle cramps, as self-reported by hematopoietic cell transplantation survivors. We included all respondents to a survey conducted July 1, 2020, to June 30, 2021. Surveys were completed online or on-paper according to participants' preferences; they received one reminder if no survey was received 1 month after distribution. Statistics are primarily descriptive comparing subgroups of patients. Of 4641 potentially eligible patients, 1745 responded and are included in the analysis. Participants (615 [35%] autologous, 1130 [65%] allogeneic) were a median age of 64.1 years (interquartile range [IQR] 55.2-70.8) and surveyed at a median of 11 years (IQR 4-21) after their most recent transplantation. Neuropathy symptoms were reported by 65% of autologous recipients, 66% of allogeneic transplant recipients with current chronic graft versus host disease (GVHD), and 45% of allogeneic recipients who never developed chronic GVHD. Muscle cramps were reported by 56% of autologous recipients, and 52% of allogeneic recipients and were rated as "very painful" by nearly half of patients who experienced them. These results suggest that neuropathy symptoms and muscle cramps are much more prevalent among survivors after hematopoietic cell transplantation than previously recognized. Better approaches for prevention and treatment of these bothersome complications are needed.

We determined the incidence of disability related to chronic graft-versus-host disease (bronchiolitis obliterans, grade ≥2 keratoconjunctivitis sicca, sclerotic features or esophageal stricture) for three categories of alternative donor: cord blood, haplorelated marrow or peripheral blood with post-transplant cyclophosphamide, and unrelated single HLA-allele mismatched peripheral blood. Among 396 consecutive hematopoietic cell transplant recipients, 129 developed chronic graft-versus-host disease with 3-year cumulative incidences of 8% for cord blood, 24% for haplorelated grafts, and 55% for unrelated single HLA-allele mismatched peripheral blood. Disability rates were significantly lower for cord blood [hazard ratio (HR) 0.13; 95% confidence interval (CI): 0.1-0.4] and for the haplorelated group (HR 0.31; 95% CI: 0.1-0.7) compared to the rate in the group transplanted with unrelated single HLA-allele mismatched peripheral blood. Cord blood recipients were also >2-fold more likely to return to work/school within 3 years from the onset of chronic graft-versus-host disease (HR 2.54; 95% CI: 1.1-5.7, P=0.02), and the haplorelated group trended similarly (HR 2.38; 95% CI: 1.0-5.9, P=0.06). Cord blood recipients were more likely to discontinue immunosuppression than were recipients of unrelated single HLA-allele mismatched peripheral blood (HR 3.96; 95% CI: 1.9-8.4, P=0.0003), similarly to the haplorelated group (HR 4.93; 95% CI: 2.2-11.1, P=0.0001). Progression-free survival and non-relapse mortality did not differ between groups grafted from different types of donors. Our observations that, compared to recipients of unrelated single HLA-allele mismatched peripheral blood, recipients of cord blood and haplorelated grafts less often developed disability related to chronic graft-versus-host disease, and were more likely to resume work/school, should help better counseling of pre-hematopoietic cell transplant candidates.

Non-myeloablative allogeneic hematopoietic cell transplantation (NMA-HCT) can provide prolonged remissions in patients with advanced B-cell lymphoma (B-NHL) via the graft versus lymphoma (GVL) effect, though inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy (RIT) can safely induce responses in B-NHL with minimal non-hematologic toxicity. Initial results of (90)Y-ibritumomab tiuxetan-based allografting demonstrated early safety and disease control in non-remission patients but with short follow up (Blood, 2011). Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions. Eleven of 40 patients are alive at a median follow up of 9 years (range 5.3–10.2). There were 14 (35%) deaths due to disease progression, and 14 (35%) deaths attributed to complications from HCT. One patient died of a Merkel cell carcinoma. The 5-year OS and PFS for patients with indolent B-NHL was 40% and 27.5% respectively. None of the patients with diffuse large B-cell lymphoma (DLBCL) were long-term disease-free survivors regardless of early remission status. (90)Y-ibritumomab tiuxetan-based allografting represents a viable option in patients with indolent histologies. Improved strategies are needed for aggressive B-NHL. The original trial was registered at www.clinicaltrials.gov as NCT00119392.

Patient-reported outcomes for hematopoietic cell transplantation (HCT) survivors are well characterized with established measures; however, there is little experience with the new, freely available Patient-Reported Outcomes Measurement Information System (PROMIS) measures in this population. The aim of this study was to compare the performance of the PROMIS measures in the HCT setting with the performance of the commonly used 36-Item Short Form Health Survey (SF-36).Adult HCT survivors from the Fred Hutchinson Cancer Research Center (n = 4446) were mailed a survey that included the following as part of an annual follow-up survey: the Patient-Reported Outcomes Measurement Information System-Global Health (PROMIS-GH; 10 questions), the 29-Item Patient-Reported Outcomes Measurement Information System Profile (PROMIS-29), and the SF-36.Both the SF-36 and PROMIS measures were available for 1634 HCT recipients (503 autologous recipients and 1131 allogeneic recipients). The overall response rate was 46%. The median time after transplantation for allogeneic and autologous recipients was 12.0 years (range, 0.4-44.1 years) and 6.1 years (range, 0.4-30.1 years), respectively. With the SF-36 or PROMIS-GH, overall physical functioning was somewhat lower in comparison with the general population, but mental functioning was similar. Component and domain scores with similar contents were strongly correlated by Pearson correlation coefficients: the Global Health-Physical and SF-36 Physical Component Summary scores for autologous (r = 0.82) and allogeneic recipients (r = 0.83) and the PROMIS-29 and SF-36 physical function, pain, and vitality/fatigue scores for allogeneic (0.87, -0.82, and -0.82, respectively) and autologous recipients (0.84, -0.82, and -0.81, respectively). The correlation between the Global Health-Mental and SF-36 Mental Component Summary scores was lower (0.70 for autologous recipients and 0.72 for allogeneic recipients).Physical and mental symptoms and function in autologous and allogeneic HCT survivors can be adequately assessed with PROMIS-29 and PROMIS-GH. Cancer 2018;124:841-9. © 2017 American Cancer Society.

Patients treated with hematopoietic cell transplantation (HCT) often experience depression and fatigue but analyses to determine risk factors have typically lacked statistical power. The current study examined sociodemographic and clinical risk factors for depression and fatigue in a large cohort of survivors of HCT.Measures of depression and fatigue were included in an annual survey of HCT recipients that also included self-reported sociodemographic and health information. Patient clinical characteristics were obtained from the clinical database.The sample consisted of 1869 recipients (with a mean age of 56 years; 53% male) who were a mean of 13 years (allogeneic recipients) and 6 years (autologous recipients) from HCT. Moderate to severe depression was reported by 13% of participants; moderate to severe fatigue was reported by 42%. Among allogeneic recipients, female sex, younger age, current presence of chronic pain, and current patient-reported severity of chronic graft-versus-host disease were found to be independently associated with greater depression whereas female sex, current presence of chronic pain, and current severity of chronic graft-versus-host disease were independently associated with greater fatigue (P values.01). Among autologous recipients, younger age and current presence of chronic pain were found to be independently associated with both greater depression and greater fatigue (P values.01).Rates of depression and fatigue in this group of survivors suggest a high symptom burden. Better screening, referral, and interventions are needed.

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.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.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).Patient-reported resilience is independently associated with health and psychosocial outcomes. Future studies must determine whether interventions can bolster resilience and improve survivorship outcomes.

Background: Sclerotic graft-versus-host disease (GVHD) is a distinctive phenotype of chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), characterized by fibrosis of the skin or fascia, and often associated with severe disability and morbidity. Sclerotic GVHD has clinical and histopathological similarities with systemic sclerosis, an autoimmune disease whose risk is influenced by genetic polymorphisms. Patients and methods: We identified 15 candidate single-nucleotide polymorphisms (SNPs) that have well-documented association with susceptibility to systemic sclerosis. We hypothesized that these SNPs would also have associations with risk of sclerotic GVHD if the two diseases have similar pathogenic mechanisms. We evaluated the candidate SNPs for association with the sclerotic phenotype in a cohort of 891 patients who were diagnosed with chronic GVHD and had recipient or donor samples available for genotyping. The candidate SNPs were located in BANK1, BLK, CD247, HLA-DRA, HLA-DQB1, HLA-DPA1, IL12RB2, IRF8, PTPN22, STAT4, TNFSF4, TNIP1 and TNPO3-IRF5. Genotyping assays used the Affymetrix 5.0 Human GeneChip and Illumina 1M Quad and Illumina 2.5M BeadArrays. Candidate SNPs not genotyped on the array were imputed using the 1000 Genomes Project Phase 1 SNPs as a reference panel. Cox regression models were used to examine associations of donor and recipient SNPs with risk of sclerotic GVHD. Each SNP was assessed for allelic (additive) and genotypic (dominant and recessive) models. A two-sided P-value of Results: Three of the candidate SNPs were associated with risk of sclerotic GVHD (Table): rs10516487 (BANK1: B-cell scaffold protein with ankyrin repeats 1), rs2056626 (CD247: T-cell receptor zeta subunit) and rs987870 (HLA-DPA1). Despite adequate power to detect associations, candidate SNPs in HLA-DRA and HLA-DQB1 did not show statistically significant associations with risk of sclerotic GVHD. Results for r987870 motivated further exploration of the association between HLA-DP and the risk of sclerotic GVHD. HLA-DP molecules have a P1 peptide-presentation pocket defined by M (methionine) or Q (glutamine) at position 31 of the DP alpha chain and by EAV (glutamic acid-alanine-valine) or GPM (glycine-proline-methionine) motifs at positions 85-87 of the DP beta chain. The risk of sclerotic GVHD was decreased in patients who had HLA-DP molecules with a Q~GPM pocket (HR 0.55, 95% CI 0.38-0.80, P=0.002). Conclusion: These results suggest similarities in the mechanisms that cause sclerotic GVHD and systemic sclerosis, and indicate a critical role of the adaptive immune system, including B cells, T cells, and HLA-DP-mediated antigen presentation in the pathogenic mechanisms of both sclerotic GVHD and systemic sclerosis. Genetic variation can modify the immune pathology and significantly alter the disease phenotype of chronic GVHD after HCT. Abstract 665. Table 1 SNPs showing statistically significant associations with risk of the sclerotic phenotype among patients with chronic GVHD Genome Gene SNP Alleles* MAF N Model HR (95% CI) P Donor BANK1 rs10516487 T/C 0.30 857 Allelic 0.87 (0.69-1.08) .21 Dominant 0.96 (0.73-1.27) .80 Recessive 0.43 (0.21-0.88) .02 Recipient CD247 rs2056626 G/T 0.40 839 Allelic 1.21 (1.00-1.48) .05 Dominant 1.49 (1.09-2.03) .01 Recessive 1.09 (0.75-1.57) .65 Donor CD247 rs2056626 G/T 0.41 858 Allelic 1.21 (1.00-1.48) .05 Dominant 1.58 (1.15-2.18) .005 Recessive 0.99 (0.68-1.44) .97 Recipient HLA-DPA1 rs987870 C/T 0.16 829 Allelic 0.80 (0.59-1.09) .15 Dominant 0.68 (0.48-0.96) .03 Recessive 2.04 (1.01-4.14) .05 Donor HLA-DPA1 rs987870 C/T 0.15 843 Allelic 0.87 (0.65-1.17) .35 Dominant 0.75 (0.54-1.04) .09 Recessive 2.28 (1.12-4.63) .02 *minor/major Disclosures No relevant conflicts of interest to declare.

Although graft-vs-host disease (GVHD) remains a significant problem following allo HCT, tolerance eventually occurs in many patients. To better understand the mechanism(s), RNA from purified CD4 T cells from 22 tolerant patients (T) and 20 normal controls (NC) was hybridized on Illumina Ref-8 expression arrays. Transcriptional profiles of tolerant patients were very different from NC. A cluster analysis of genes showing differential expression revealed 2 distinct subgroups based on the time of study post-HCT: "early" (mean 1.0, 1.0-2.6) years (TE, n=10), and "late" (mean 4.0, 2.5-7.4) years (TL, n=12). 1073 genes were differentially expressed between TE and NC, 810 genes were differentially expressed between TL and NC, and there were 203 genes overlapping TE and TL. Analysis of TE revealed increased gene expression of the IFNG, TCR and IL2 signaling pathways, with increased expression of CTLA4. Analysis of TL revealed down regulation of genes involved in glycolysis, nucleotides biosynthesis and cell cycle, and down regulation of the IL2 and TCR signaling pathways compared to NC and TE. These data suggest that 1) tolerance is an active and dynamic process, and 2) that this adaptive response evolves over time. The changes observed suggest elements of both immune regulation and immune exhaustion. Functional studies will be necessary to further interpret these transcriptional changes and define mechanisms.