Onset Of Chronic Graft-versus-host Disease Research Articles

Higher risk for chronic graft-versus-host disease (GvHD) in HLA-G mismatched transplants following allogeneic hematopoietic stem cell transplantation: A retrospective study.

Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is highly influenced by the degree of HLA matching between recipient and donor. The HLA-class Ib molecule HLA-G has been shown to promote tolerogenicity through its interaction with inhibitory receptors found on several immunocompetent cells. We hypothesized that in an allo-HSCT setting, HLA-G mismatches may negatively impact the HLA-G-mediated tolerogenicity either due to inefficient interaction with the inhibitory receptors of the transplanted immune cells or due to direct allorecognition of mismatched HLA-G on host cells by the immune cells of the donor. In order to explore this hypothesis, we investigated the impact of HLA-G mismatching in 2.083 10/10 matched high resolution HLA-typed allo-HSCT transplants. We found that the risk of chronic GvHD was significantly higher in HLA-G-mismatched transplant cases as compared with the HLA-G-matched control group (HR: 1.46, 95%CI=1.11-1.91, p= 0.006). Sub-analysis of the mismatch vector revealed that this effect was only detectable in the GvH (HR: 1.89, 95%CI 1.39-2.57, p < 0.001) but not the HvG direction (HR: 1.01, 95%CI=0.63-1.63, p= 0.967). In addition, the negative impact of HLA-G mismatching on chronic GvHD was only significant in younger patients (<30y HR: 3.02, 95%CI=1.25-7.28, p=0.014; >29y HR: 1.28, 95%CI=0.94-1.72, p= 0.113). Our results indicate that HLA-G mismatches may contribute to the onset of chronic GvHD, especially in younger patients and should therefore be avoided when possible.

Durable discontinuation of systemic therapy in patients affected by chronic graft-versus-host disease.

Successful treatment of chronic graft-versus-host disease (GvHD) often requires long-term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GvHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from two prospectively followed cohorts from the Chronic GvHD Consortium (n=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half of the patients received non-myeloablative conditioning. The median time from transplantation to chronic GvHD diagnosis was 7.7 months (range, 1.0-141.3) and the median time from chronic GvHD onset to enrollment into the cohorts was 0.9 months (range, 0.0-12.0). The cumulative incidence estimate of durable ST discontinuation was 32% (95% confidence interval: 28%-37%) at 10 years after enrollment into the cohort. Among patients who discontinued ST, the median time from chronic GvHD diagnosis to durable ST discontinuation was 3.6 years (range, 1.2-10.5). In multivariate analysis, patients who received myeloablative conditioning, had chronic GvHD manifested as moderate/severe lower gastrointestinal involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower gastrointestinal involvement and cord blood (vs. peripheral blood) as the graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue ST permanently, most patients require prolonged ST. Viewing chronic GvHD in this way has implications for management approaches.

Autoimmune thyroid disease following hematopoietic stem cell transplantation in childhood cancer survivors.

.Thyroid dysfunction has been observed in childhood cancer survivors (CCSs) who have undergone hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the thyroid function of 54 CCSs who underwent HSCT and were referred to our endocrinology department at Chiba Children’s Hospital between January 1, 2008, and December 31, 2019. Three patients developed autoimmune thyroid disease (AITD) after HSCT. Two of these patients had Graves’ disease (GD), and the third had autoimmune thyroiditis. The association between HSCT and AITD remains unclear. All three patients had chronic graft versus host disease (GVHD). AITD was reported to be induced by the transmission of abnormal T or B lymphocyte clones from the donor to the recipient. One patient with GD was treated with a high dose of anti-thymocyte globulin (ATG). Some studies have reported that ATG is associated with a risk of severe T cell depletion and GD onset. In conclusion, CCSs who received HSCT rarely developed AITD. We suggest that CCSs treated with ATG and/or experiencing an onset of chronic GVHD should be carefully monitored for thyroid function because it might reveal AITD.

Alterations in NKG2A and NKG2C Subsets of Natural Killer Cells Following Epstein–Barr Virus Reactivation in CTLA4Ig-based Haploidentical Transplantation Is Associated With Increased Chronic Graft-Versus-Host Disease

The impact of newer approaches to haploidentical transplantation on Epstein-Barr virus (EBV) is largely unknown. We prospectively evaluated the incidence of EBV reactivation and its impact on transplantation outcomes in 71 patients undergoing haploidentical transplantation with posttransplantation cyclophosphamide in combination with CTLA4Ig-based T-costimulation blockade. Eight patients developed EBV reactivation at a median of 96 days with no incidence of lymphoproliferative disorder. There was no impact of EBV reactivation on acute graft-versus-host disease (GVHD), nonrelapse mortality, progression-free, or overall survival. Despite an overall incidence of 19%, there was a significant increase in chronic GVHD following EBV reactivation (62.5% versus 8%; P = 0.01). NKG2A subset of CD56 natural killer cells increased substantially and persisted following EBV reactivation and chronic GVHD, with a reciprocal decrease in NKG2C subset, whereas the reverse was witnessed in those without chronic GVHD (P < 0.01). Increase in NKG2C subset and a decrease in the NKG2A subset were witnessed within 3 months of subsidence of chronic GVHD. Thus, CTLA4Ig-based haploidentical transplantation was associated with a low incidence of EBV reactivation without EBV-lymphoproliferative disorder. However, EBV reactivation was associated with a sustained alteration in NKG2A and NKG2C subsets of CD56 natural killer cells which might have a pathogenic role in chronic GVHD.

Characterization of Late Acute and Chronic Graft-Versus-Host Disease according to the 2014 National Institutes of Health Consensus Criteria in Japanese Patients

To characterize the incidences and outcomes of late acute (LA) and chronic graft-versus-host disease (GVHD) in East Asians according to the 2014 National Institutes of Health criteria, we retrospectively analyzed 506 consecutive Japanese patients who had a first allogeneic hematopoietic cell transplantation (HCT) at our center between 2006 and 2013. According to manifestations at onset 91 patients (60%) had LA GVHD and 60 (40%) had chronic GVHD. The cumulative incidences of LA and chronic GVHD were 20% and 17%, respectively, at 48 months after HCT. The involved sites at the onset of LA GVHD included the skin (71%), gut (13%), and liver (8%). The cumulative incidences of relapse, nonrelapse mortality (NRM), transition to chronic GVHD, and discontinued systemic treatment were 11%, 6%, 22%, and 46%, respectively, at 48 months after onset of LA GVHD. Cox models showed that prior acute GVHD was associated with NRM, and HCT from a female donor to a male patient, myeloablative conditioning, and low Karnofsky performance status were associated with a longer duration of systemic treatment after LA GVHD. The most frequently involved sites at the onset of chronic GVHD included the mouth (83%), liver (75%), skin (69%), and eyes (62%). Cox models showed that use of antithymocyte globulin in conditioning regimens was associated with a higher risk of discontinued systemic treatment after the onset of chronic GVHD. The cumulative incidences of relapse, NRM, and discontinued systemic treatment were 16%, 11%, and 41%, respectively, at 48 months after the onset of chronic GVHD. Our results suggested several potential differences between Japanese patients and those of other ethnicities. A direct comparison is needed to formally investigate ethnic differences.

Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD.Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043).Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. DisclosuresKim:ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Upregulation of Interferon-Inducible and Damage Response Receptors in Chronic Graft-Versus-Host Disease

Chronic Graft Versus Host Disease (CGVHD) remains the main source of non-relapse mortality and morbidity among recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although our lab and others have identified infiltrates of Th1/Tc1 and Th17 effectors in skin and oral mucosa, CGVHD targets multiple organs and no common factor or pathway has been demonstrated to reflect the broad range of CGVHD inflammatory and fibrotic manifestations. To identify the systemic cytokine pathways supporting the development and persistence of CGVHD, we chose to profile gene expression in circulating monocytes; monocytes up-regulate distinct patterns of gene expression in response to different cytokines, acting as in situ reporters.The NIH Natural History Study of CGVHD (NCT00092235) has primarily enrolled moderate to severely affected patients. Microarray analysis was performed on sorted monocytes from 10 normal controls (ND) and 26 patients selected from this cohort based on severe cutaneous involvement. Two interrelated pathways, each containing multiple genes, were consistently up-regulated across a cutaneous CGHVD spectrum ranging from lichenoid infiltrates to extensive sclerosis: (1) Interferon (IFN)-inducible genes including those involved in signaling, lymphocyte homeostasis and trafficking, apoptosis and antigen uptake and presentation (STAT1, CXCL10, TNFSF13B, TNFSF10, TAP1), and (2) innate immune receptors for pathogens and cellular damage that can trigger IFN production and inflammasome assembly (TLR2, TLR4, TLR7, AIM2, DDX58, CLEC4E). Using multiplex RNA gene expression assays (Nanostring) to verify these pathways, we found significant up-regulation of IFN-inducible and damage-response genes in 69 CGVHD patients with a broad range of organ involvement, as compared with 14 allo-HSCT patients never developing CGVHD, or with 19 normal controls (Figure 1A, B). These pathways were further substantiated in plasma ELISA assays showing elevated levels of IFN-induced chemokines (CXCL9, CXCL10) in both lichenoid and severe sclerotic patients. Immunohistochemistry substantiated expression of Type I IFN-induced factors (MxA) in inflammatory infiltrates in CGVHD-targeted organs: lichenoid and sclerotic skin, oral mucosa and salivary gland. Consistent with induction of Type I IFN by activation of TLR and RIG-I receptors, levels of expression of DDX58 and TLR7 correlated with up-regulation of Type I IFN inducible genes (OAS1, IFIT1, XAF1). Finally, multiplex RNA assessments on monocytes collected from 18 patients over serial time courses following NCI allo-HSCT protocols (NCT00520130 and NCT00074490) substantiated a pattern of parallel up-regulation of multiple IFN-inducible and damage responsive genes at CGVHD onset, and of decline upon therapy and resolution (Figure 1C). A key point is that comparable up-regulation of these pathways was found in patients with extensive lichenoid or sclerotic CGVHD, both in the established CGVHD patients in the initial microarray and in the serial time courses of CGVHD development. These results support a model that IFN and inflammasome activation induced by the innate immune systemÕs response to damage initiates an inflammatory process in CGVHD; IFN then can induce damage receptors, chemokines, cytokines and enhanced antigen presentation that sustain CGVHD. These interlocking analyses of gene expression patterns, plasma analytes and tissue are the first to support a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase II Study Of Proteasome-Inhibition For Initial Therapy Of Chronic Graft-Versus-Host Disease

Chronic graft-versus-host disease (GVHD) is a major transplantation toxicity that impacts quality-of-life and long-term survival. Corticosteroids are standard-of-care for initial therapy of chronic GVHD despite limited efficacy and significant long-term toxicity. Proteasome-inhibition has immunomodulatory effects potentially beneficial in GVHD. We previously reported on peri-transplantation bortezomib (day +1, +3, +7) for GVHD prophylaxis. We now report on bortezomib plus corticosteroids for initial therapy of chronic GVHD.We undertook a single-arm prospective phase II trial for participants 18 years or older and 100 days or more after allogeneic transplantation from HLA-matched related, unrelated or mismatched donors (MRD, MUD, MMUD) with no active malignant relapse, and limited or extensive chronic GVHD requiring initiation of systemic therapy. IV bortezomib was dosed at 1.3 mg/m2 on days 1, 8, 15 and 22 of each 35 day cycle for 3 cycles (15 weeks). Concurrent prednisone dose was initially 0.5 mg/kg/d, but the study was later amended to allow up to 1 mg/kg/d. The suggested steroid taper after cycle 1 was 10-25% every 1-2 weeks. No addition or subtraction of other immunosuppressive medications was permitted. Topical GVHD therapies (e.g. eye, mouth) were allowed. The primary endpoint was week 15 overall response rate (ORR) per NIH chronic GVHD criteria, excluding ocular/oral sites where topical treatment was permitted. Secondary endpoints included the proportion of participants tolerating 50% or greater prednisone dose reduction at 15 weeks, prednisone dose requirement at 1 year, and long-term overall and progression-free survival (OS, PFS).Between March 2009 and November 2011, 22 participants with a median age of 51 years (range, 25-69) comprising 5, 13, and 4 recipients of 8/8 MRD, MUD, and 7/8 MMUD PBSC grafts, respectively, were enrolled. 45% were male. 18% had prior acute GVHD (1 gr. 1; 2 gr. 2; 1 gr. 3). The median time from transplantation to chronic GVHD onset was 215 days (range, 133-666), and to initiation of chronic GVHD therapy was 257 days (range, 186-2070). Participants had a median of 3 (range, 1-6) sites of chronic GVHD, with liver (73%), oral (68%), skin (64%), ocular (46%) and joint/muscle/fascia (J/M/F) (27%) the most common. The median follow up duration in survivors was 25 months (range, 19.3-48.5).Bortezomib plus prednisone as initial chronic GVHD therapy was well tolerated, with 1 grade 3 CTCAE (sensory neuropathy) possibly related to bortezomib. One participant died of relapsed AML after 2 cycles of treatment and was not evaluable for toxicity or response. Another died of fungal infection during cycle 1 and was not evaluable for response. 18 of 22 participants (82%) completed the 3 cycles of therapy. For the 20 participants evaluable for response, the week 15 ORR (per NIH chronic GVHD global score) was 80% (CR: 2 [10%], PR: 14 [70%]). Additionally, 1 participant (5%) had a mixed response, with CR at sentinel sites (liver, skin) but interval progression of pulmonary GVHD; 1 participant (5%) had stable disease; and 2 participants (10%) with prednisone starting dose of 0.5 mg/kg/d had progressive GVHD. The change of median NIH chronic GVHD global score from baseline to week 15 was 5.5 (range, 1-7) → 3 (range, 0-6), respectively. Sites of response included skin (n = 11; CR = 8 [73%], PR = 1, SD = 2); liver (n = 15; CR = 8 [53%], PR = 5, PD = 2); and J/M/F (n = 6; CR = 2 [33%], PR = 1, SD = 3). The change of median NIH chronic GVHD organ score from baseline to week 15 was: liver 3 (range, 1-3) → 0 (range, 0-2); skin 2 (range, 1-3) → 0 (range, 0-2); J/M/F 1 (range, 1-2) → 1 (range, 0-2). 14 participants (70%) tolerated a 50% or greater steroid dose reduction by week 15. The median steroid dose taper from baseline to week 15 was 50 mg (range, 30-100) → 20 mg (range, 5-40) (p<0.001). The ability to taper steroids persisted beyond the 3 treatment cycles (Figure). The cohort 2-year OS and PFS was 73% each, with non-relapse mortality and relapse incidence of 14% each.Bortezomib plus prednisone for initial therapy of chronic GVHD was feasible and well tolerated, with an 80% ORR alongside substantial steroid dose taper. Proteasome-inhibition may offer steroid-sparing efficacy in chronic GVHD therapy, particularly for visceral and skin involvement. Of note, the need for weekly clinic visits for parenteral bortezomib was a barrier to accrual. Oral proteasome-inhibitors may be especially suitable for future trials in chronic GVHD. [Display omitted] Disclosures:Off Label Use: Bortezomib is a proteasome inhibitor with a number of immunomodulatory effects that are potentially beneficial in GVHD. We studied bortezomib plus prednisone as initial therapy for chronic GVHD.

Evaluation of NIH-Defined Chronic Graft-Versus-Host-Disease in a Rapamycin-Based Haploidentical Stem Cell Transplantation: Analysis of 113 Consecutive Patients with High Risk Haematological Malignancies

Abstract 4198 Background and Methods.Chronic Graft-versus-Host-Disease (GvHD) remains a serious complication after allogeneic stem cell transplantation. In 2005 the National Institutes of Health (NIH) established new criteria for chronic GvHD based on retrospective data and expert recommendations.Here we are reporting the prospectively evaluation of the incidence of NIH-defined chronic GvHD and its prognostic impact in 113 consecutive patients who underwent unmanipulated peripheral blood graft from an HLA-haploidentical relative after a treosulfan based conditioning at our Institution.The peculiarity of this setting relies on the exploitation of a rapamycin-based, calcineurin-inhibitor-free regimen for prophylaxis of GvHD to induce in-vivo expansion of T-regulatory cells (Tregs). Results.Chronic GvHD was evaluable in 81 patients: 41 patients were diagnosed with chronic GvHD according to the revised Seattle criteria, 28 were classified as having extensive chronic GvHD and 13 were classified as having limited. The 1-year cumulative incidence was 43 +/− 9%.According to the NIH Consensus Criteria, 1 patient was reclassified as having late-acute GvHD, 20 patients as having overlap syndrome and 20 patients as having classic chronic GvHD. The late-acute consisted of late onset subtype.The 40 patients with classic chronic GvHD and overlap syndrome were graded as moderate (26 patients) and severe (14 patients) by NIH consensus criteria. The onset was classified as progressive in 4 cases, de novo in 27 cases, quiescent in 9 cases.The median number of organs involved was 3 (range 1–7), the majority of patients presented with skin and oral involvement, but also eyes, liver, joint, genitalia and gastro-intestinal damages were present – maximum severity of chronic GvHD according to organ manifestation is presented in figure 1.Twenty-seven out of 40 patients started a specific immunosuppressive treatment for chronic GvHD, noteworthy 21 patients restarted rapamycin (in combination with prednisone, or alone) with clinical benefit.In univariable analysis patients with overlap GvHD tended to present a lower overall survival (OS) compared to those with classic chronic GvHD (36% versus 63%, p 0.07). Patients with severe chronic GvHD at onset had a significantly lower OS compared to those with moderate chronic GvHD (19% versus 69%, p0.017). OS was significantly worse for patients with platelets counts below 100 g/l at onset of chronic GvHD (29% vs 67%, p0.003)– figure 2. Conclusion.This analysis confirms in haploidentical setting thrombocytopenia, overlap category and severe presentation as prognostic items for overall survival after allogeneic stem cell transplantation. Further investigations on implementation of immunosuppressive treatment strategy for high-risk GvHD patients (namely patients with overlap GvHD diagnosis and concomitant thrombocytopenia and/or progressive onset) are actually ongoing to enhance response and improve outcome. [Display omitted] [Display omitted] Disclosures:Bordignon:MolMed SpA: Employment. Bonini:MolMed S.p.A.: Consultancy.

Gastrointestinal and Hepatic Involvement in Chronic Gvhd: An Analysis From the Chronic Gvhd Consortium

AbstractAbstract 1940 Background:Chronic graft-versus-host disease (GVHD) is a significant source of morbidity, mortality, impaired patient-reported quality of life (QOL), greater symptom burden, and prolonged duration of immune suppressive therapy following allogeneic hematopoietic cell transplantation (HCT). While available data support the adverse prognosis of overlap subtype of chronic GVHD, the relative importance of site of gastrointestinal (GI) and type of hepatic involvement is not known. Methods:We analyzed prospectively acquired observational cohort data to examine whether the site of GI involvement (esophageal, upper GI, lower GI) and type of hepatic laboratory test abnormality (bilirubin, alkaline phosphatase (AP), alanine aminotransferase (ALT) elevation over the upper limit of normal based on study site-specific laboratory reference ranges) among chronic GVHD-affected patients are associated with overall survival (OS) and non-relapse mortality (NRM), symptoms (Lee Symptom Scale), and quality of life (QOL) per SF-36 and FACT-BMT instruments. Results:This analysis included 567 individual subjects with baseline and 1548 follow up visits. The majority were incident cases (59%), adults (98%), and predominantly White/Non-Hispanic. Median time from HCT to cohort enrollment was 11.9 months (range 3–294 months). Overall NIH chronic GVHD severity was mild in 10%, moderate in 52%, and severe in 38% at enrollment. Prior acute GVHD was noted in 66%, KPS < 80% in 17%, and platelet count at chronic GVHD onset of < 100 K/uL in 23%. At enrollment, GI involvement was seen in 40% (upper GI 20%, esophagus 16%, lower GI 13%), and liver involvement was seen in 52% (AP 38%, ALT 38%, bilirubin 10%). Time from transplant to cGVHD onset was not different for patients with or without GI involvement or hepatic involvement. In multivariate analysis utilizing data from enrollment visits only and adjusting for patient and transplant variables, lower GI involvement (HR 1.7, p=0.03) and elevated bilirubin (HR 2.36, p=0.001) were associated with OS; both were also associated with NRM. In multivariable analysis using all visits (time-dependent covariates), GI score greater than zero (HR 1.7, p=0.01) and elevated bilirubin (HR 3.7, p<0.001) were associated with OS; results were similar for NRM. Separate models were constructed to examine the relationship of severity of GI and hepatic involvement (0–3 severity score per NIH consensus) and mortality: Increasing lower GI severity at enrollment was significantly associated with non-relapse mortality, with progressively increasing HR for greater severity levels (lower GI score 2/3 vs. 0: HR 5.5, 95% CI 2.3–13.1, p = 0.0001). Increasing bilirubin was also associated with NRM (bilirubin score 2/3 vs. 0: HR 3.3, 95% CI 1.3–8.4, p=0.01). A similar association was observed for bilirubin elevation and NRM in the time-dependent model (bilirubin 2/3 vs. 0: HR 8.9, 95% CI 3.3–24, p < 0.0001). When analyzing all visits, any esophageal involvement and GI score greater than zero were associated with both symptoms and QOL while elevated bilirubin was associated with QOL. We found no consistent evidence that upper GI involvement, AP, ALT, or NIH liver score add prognostic value for survival, overall symptom burden, or quality of life. Conclusion:These data support important differences in patient-reported outcomes according to GI and hepatic involvement among chronic GVHD affected patients, and identify those with elevated bilirubin or higher GI score at any time, or lower GI involvement at cohort enrollment, as patients at greater risk for mortality under current treatment approaches. Disclosures:No relevant conflicts of interest to declare.

Significantly worse survival of patients with NIH-defined chronic graft-versus-host disease and thrombocytopenia or progressive onset type: results of a prospective study

Chronic graft-versus-host disease (GVHD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HCT). In 2005 the National Institutes of Health (NIH) established new criteria for chronic GVHD based on retrospective data and expert recommendations. We prospectively evaluated the incidence of NIH-defined chronic GVHD and its prognostic impact in 178 consecutive patients. The cumulative incidence of chronic GVHD at 3 years was 64, 48 and 16% for chronic classic GVHD and overlap syndrome. Prior acute GVHD and myeloablative conditioning were significantly associated with increased risk of chronic GVHD. Three-year survival (overall survival (OS)) for late-acute GVHD, chronic classic and overlap chronic GVHD when assigned on day 100 were 69, 83 and 73%. OS was significantly worse for patients with platelet counts below 100 g/l at onset of chronic GVHD (35% versus 86%, P<0.0001) and progressive as compared with de novo and quiescent onset of chronic GVHD (54.5% versus 89.5% versus 84%, P = 0.022 and 0.001). Peak severity of chronic GVHD had no impact on non-relapse mortality (NRM) and OS. Recurrent acute GVHD, platelet counts below 100 g/l at diagnosis of chronic GVHD, progressive onset of chronic GVHD and advanced disease stage prior to HCT were significantly associated with increased NRM. This prospective analysis provides for the first-time data on the incidence rates of NIH-defined chronic GVHD categories and identified risk factors for the occurrence of chronic GVHD. A prognostic value of thrombocytopenia and progressive onset type of chronic GVHD for survival after HCT was observed in NIH-defined chronic GVHD.

Evaluation of NIH Consensus Criteria for Classification of Late Acute and Chronic Gvhd in Reduce Intensity Conditioning (RIC) Stem Cell Transplantation (SCT).

Abstract 1139Poster Board I-161 BackgroundChronic graft-versus-host disease (GVHD) occurs frequently after allogeneic stem cell transplantation (SCT) and has an impact on morbidity and survival. The National Institutes of Heath (NIH) consensus criteria for the diagnosis of GVHD, emphasized clinical manifestations of GVHD rather than the classical time of onset (day 100). Incidence and impact in term of relapse and no-relapse mortality (NRM) of this new classification is not well known after RIC. MethodsWe retrospectively reviewed 116 consecutive patients (pts) in Saint Louis' Hospital undergoing an SCT for hematologic malignancy and surviving at least day + 100 after RIC between August 2005 and December 2008. We evaluated non-relapse mortality (NRM) and recurrent malignancy. Cumulative incidence was computed using death as a competing event. Incidence of relapse and NRM was counted from 100 days post-transplant for patients without chronic GVHD or from chronic GVHD onset. Patients with relapse/progression before chronic GVHD onset were considered as not having chronic GVHD in these analyses. The association of occurrence of chronic GVHD with the risk of relapse and non-relapse death was analyzed using time-dependent covariates in cause-specific proportional hazards models. ResultsAmong 116 pts ( M/F: 71/45), with a median age of 53 years old (19-68 years) 28 pts (24%) were transplanted for acute leukemia in, 11 pts (9%) for chronic leukemia, 27 pts (23%) for lymphoma, 30 pts (26%) for MPD/MDS and 20 pts (17%) for plasma cell disorder. Sixty-three pts (54%) received HLA-identical sibling transplantation, 53 pts (46%) received transplantation from unrelated donors. Source of stem cells was mobilized peripheral blood stem cell for 108 pts (93%), bone marrow for 4 pts (3%) and 4 cord blood (3%).After a median follow-up of 18 months (range 5-45 months), a total of 67 pts (58%) developed chronic GVHD according to the Seattle day 100 landmark criteria and when using NIH consensus criteria, 55 pts (47%) developed chronic GVHD, including 43 pts (53%) with classic chronic GVHD and 8 pts (10%) overlap syndrome. Patients reclassified included; 3 pts with late onset acute GvHD, 19 pts had recurrent and 8 had persistent acute GVHD (numbers do not to previous sentence because some of these patients latter developed chronic GvHD). The cumulative incidence of chronic GVHD at 36 months was 64% (95%CI; 53%-73%) when using Seattle criteria compared to 56% (95%CI; 45%-67%) with NIH chronic GVHD criteria.Two-year Cumulative incidences of relapse and NRM using both classifications are summarized in Table.Relapse / progressionNRMSeattle criteriaChronic GVHD5%33%No chronic GVHD14%8%NIH criteriaclassic chronic / overlap syndrome12%26%No chronic GVHD13%14%In Cox model with GvHD as a time dependent covariate, the NRM was significantly higher in patients with late onset, persistent and recurrent acute GVHD compared to no GVHD (hazard ratio (HR) 31, 47 and 30; p = 0.005, p <0.0001, p <0.0001, respectively), whereas the NRM was statistically increased in case of chronic GVHD using Seattle day 100 criteria (HR: 2.8; P=0.034). ConclusionThe cumulative incidence of chronic GVHD “decrease” about 10% when using NIH consensus criteria compared to Seattle criteria in our cohort of RIC. Most of the NRM occurred beyond 100 days after SCT was due to the increased risk of NRM in patients with late onset, recurrent or persistent acute GVHD. DisclosuresNo relevant conflicts of interest to declare.

Duration of immunosuppressive treatment for chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) requires long-term immunosuppressive therapy after hematopoietic cell transplantation. We retrospectively analyzed a cohort of 751 patients with chronic GVHD to identify characteristics associated with the duration of immunosuppressive treatment. Among the 274 patients who discontinued immunosuppressive therapy after resolution of chronic GVHD before recurrent malignancy or death, the median duration of treatment was 23 months. Results of a multivariable model showed that treatment was prolonged in patients who received peripheral blood cells, in male patients with female donors, in those with graft-versus-host HLA mismatching, and in those with hyperbilirubinemia or multiple sites affected by chronic GHVD at the onset of the disease. Nonrelapse mortality was increased among patients with HLA mismatching or hyperbilirubinemia but not among those with other risk factors associated with prolonged treatment for chronic GVHD. Nonrelapse mortality was also increased in older patients and those with older donors, in patients with platelet counts less than 100 000/microL or progressive onset of chronic GVHD from acute GVHD, and in those receiving higher doses of prednisone immediately before the diagnosis of chronic GVHD. After the dose of prednisone was taken into account, progressive onset was not associated with an increased risk of nonrelapse mortality.

Graft-versus-host disease (GVHD)-specific survival and duration of systemic immunosuppressive treatment in patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation.

We investigated graft-versus-host disease (GVHD)-specific survival (GSS) and the duration of systemic immunosuppressive treatment (IST) in 82 patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation (HCT). These two major study endpoints were calculated using the Kaplan-Meier method. Deaths solely due to the relapse of underlying disease or accidental deaths were censored at the time of occurrence for the analysis of GSS. The probability of GSS at 5 years was 74.2%. The median duration of systemic IST for chronic GVHD was 272 d (range: 7-1450), and the probability of withdrawal of systemic IST at 1, 2 and 3 years was 67.3%, 82.4% and 89.0% respectively. Analysis based on a multivariate model showed that a diagnosis other than leukaemia or myelodysplastic syndrome (P = 0.049), prior occurrence of grade III-IV acute GVHD (P = 0.021), onset of chronic GVHD before d 120 (P = 0.013), serum alkaline phosphatase over 120 IU/l (P = 0.034), and serum bilirubin over 34.2 micromol/l (P = 0.015) were independent adverse prognostic factors for GSS. Prior occurrence of grade III-IV acute GVHD significantly influenced the duration of systemic IST (P = 0.048). In conclusion, analyses of GSS and the duration of systemic IST will allow patients with different outcomes to be stratified for appropriate treatment application and will provide important parameters in prospective trials for the treatment of chronic GVHD.

Chronic graft-versus-host disease: a prospective cohort study.

Chronic graft-versus-host disease (CGVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). We studied 159 patients with CGVHD longitudinally to characterize the natural history of CGVHD and identify reliable predictors of response and long-term mortality. Rates of response to treatment were 61%, 53%, and 50% at 6 months, 1 year, and 2 years, respectively. A high incidence of infections (7 of 1,000 patient-days at 0 to 6 months, 2.5 of 1,000 patient-days at 6 months to 1 year, and 0.6 of 1,000 patient-days at 1 to 2 years) was observed. After a median follow-up of 8.4 years, an overall survival rate of 40% was observed. The overall survival rate was 63% (95% confidence interval [CI], 56%-71%) at 1 year, 51% (95% CI, 43%-59%) at 2 years, and 39% (95% CI, 31%-47%) at 10 years. In multivariate analysis, age older than 20 years (RR = 1.5; 95% CI, 0.9%-2.5%; P =.09), progressive onset of CGVHD (RR = 1.6; 95% CI, 1.0%-2.4%; P =.04), platelet count of <100,000/ microL (RR = 2.1; 95% CI, 1.3%-3.4%; P =.001), and GI involvement (RR = 1.5; 95% CI, 1.0%-2.4%; P =.05) were associated with increased mortality. Among patients surviving more than 6 months, no response (RR = 4.5; 95% CI, 1.9%-10.5%; P =.0006) and partial response (RR = 2.5; 95% CI, 1.1%-6.1%; P =.04) to treatment at 6 months also were significant predictors of mortality. The prevalence of active CGVHD was 33% at 2 years. However, the cumulative incidence of successful discontinuation of therapy was only 13% at 2 years. Among patients with clinical resolution of CGVHD, only 18% were off immunosuppressive therapy by 2 years, and 89% by 4 years. Despite high initial response rates, a large majority of patients had active disease requiring prolonged immunosuppression. This requires improved infection prevention for a longer time. Recognition of a high-risk group should facilitate assignment of more intensified regimens. Better treatment regimens need to be identified to improve survival and limit toxicity of prolonged immunosuppression.

Response to thalidomide therapy in refractory chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) refractory to standard immunosuppressive therapy remains a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). Thalidomide may be effective in some patients with high-risk or refractory chronic GVHD. We report a single-institution study of thalidomide in 37 BMT patients with extensive chronic GVHD refractory to standard immunosuppressive therapy. Acute GVHD occurred in 34 (91%) of patients and evolved progressively into chronic GVHD in 23 (62%) patients. Thalidomide was added to standard immunosuppressive therapy a median of 11 months (range 0-105 months) after the diagnosis of chronic GVHD. Fourteen of 37 (38%) patients responded after introduction of thalidomide (one complete, 13 partial). Ten of 21 (46%) children and four of 16 (25%) adults responded. Responses were seen in eight of 17 (47%) recipients of related donor marrow and six of 20 (30%) recipients of unrelated donor marrow. Eight of 23 (34%) patients with progressive onset of chronic GVHD showed a response. There were no deaths among the responders. The remaining 23 patients (62%) did not respond and of these only two survive, one with progressive scleroderma, and the other with bronchiolitis obliterans. Chronic GVHD with associated infection (most commonly disseminated fungal infection) was a major contributor to mortality in all cases. Overall, after initiation of thalidomide, the 2-year Kaplan-Meier survival was 41% (95% C.I. 24%-59%). We conclude that thalidomide is a useful and well-tolerated therapy for patients with previously treated refractory chronic GVHD, including those with progressive onset of chronic GVHD, recipients of unrelated donor marrow, and children. Earlier introduction of thalidomide as an adjunct to standard immunosuppressive therapy may lead to more frequent responses and possible better survival.

Clinical Relevance of Serum Soluble Interleukin-2 Receptor Levels in Acute and Chronic Graft-versus-Host Disease

Soluble interleukin-2 receptor (sIL-2R) levels were analyzed in the sera from 27 patients who underwent allogeneic bone marrow transplantation (BMT) in order to to examine whether there was any correlation between sIL-2R levels and graft-versus-host disease (GVHD). The sIL-2R levels markedly increased at the engraftment period, mainly due to cytokine administration shortly after BMT. Although the sIL-2R levels increased at the onset of acute GVHD, the subsequent development of GVHD could not be predicted by the sIL-2R levels documented before acute GVHD. As acute GVHD improved, the sIL-2R levels decreased, thus showing that the sIL-2R levels correlated with the disease status. In patients without acute GVHD, the sIL-2R levels gradually decreased with time and returned to the pretransplant levels after about 12 weeks post BMT. The sIL-2R levels were higher in unrelated allogeneic BMT patients with acute GVHD when compared with related allogeneic BMT patients. There was a significant increase in the sIL-2R levels at the engraftment period and at the onset of acute GVHD. At the onset of chronic GVHD, the sIL-2R levels once again increased and then decreased as chronic GVHD improved. Prolonged increase in sIL-2R levels was followed by subsequent development of chronic GVHD. Patients with a poor prognosis had higher sIL-2R levels than those with a good prognosis. Therefore, it seems that sIL-2R is a useful marker for monitoring the disease status of acute and chronic GVHD.

The management of chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) is a major cause of late morbidity and mortality following allogeneic marrow transplantation. The pathogenesis and clinical features of chronic GVHD resemble those of several autoimmune diseases including progressive systemic sclerosis, systemic lupus erythematous, lichen planus, Sjögren's syndrome, rheumatoid arthritis, and primary biliary cirrhosis. Chronic GVHD retards the tempo of immune reconstitution following allogeneic transplantation and is a major risk factor for late infections. Although in vivo immunosuppression and in vitro depletion of T-cells can reduce the incidence of acute GVHD, improved long-term survival free of chronic GVHD has not been observed. Early treatment of multiorgan extensive chronic GVHD with an alternating-day regimen of cyclosporine and prednisone has led to improved disability-free survival. Functional performance of the long-term survivors receiving combination immunosuppressive therapy remained near normal and the incidence of disabling scleroderma has decreased from over 50% to 6%. However, infections remain a frequent cause of morbidity especially in high-risk patients with advanced age, HLA-nonidentical marrow grafts, progressive onset of chronic GVHD and continued thrombocytopenia.