Altered serum metabolome as an indicator of paraneoplasia or concomitant cancer in patients with rheumatic disease.

OBJECTIVES: A timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both cancer and RMD, we analysed if a metabolic signature can indicate paraneoplasia (PN) or reveal concomitant cancer in patients with RMD. METHODS: Metabolic alterations in the sera of rheumatoid arthritis (RA) patients with (n=56) or without (n=52) a history of invasive cancer were quantified by nuclear magnetic resonance analysis. Metabolites indicative of cancer were determined by multivariable regression analyses. Two independent RA and spondyloarthritis (SpA) cohorts with or without a history of invasive cancer were used for blinded validation. Samples from patients with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, non-invasive (NI) precancerous lesions and non-melanoma skin cancer and systemic lupus erythematosus and samples prior to the development of malignancy were used to test the model performance. RESULTS: Based on the concentrations of acetate, creatine, glycine, formate and the lipid ratio L1/L6, a diagnostic model yielded a high sensitivity and specificity for cancer diagnosis with AUC=0.995 in the model cohort, AUC=0.940 in the blinded RA validation cohort and AUC=0.928 in the mixed RA/SpA cohort. It was equally capable of identifying cancer in patients with PN. The model was insensitive to common demographic or clinical confounders or the presence of NI malignancy like non-melanoma skin cancer. CONCLUSIONS: This new set of metabolic markers reliably predicts the presence of cancer in arthritis or PN patients with high sensitivity and specificity and has the potential to facilitate a rapid and correct diagnosis of malignancy.

Post-transplant cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil compared to anti-thymocyte globulin, calcineurin inhibitor, and methotrexate combinations as graft-versus-host disease prophylaxis post allogeneic stem cell transplantation from sibling and unrelated donors in patients with acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Post-transplant cyclophosphamide plus calcineurin inhibitor (CNI)(tacrolimus or cyclosporine A) plus mycophenolate mofetil (PTCy/TAC or CSA/MMF) and anti-thymocyte globulin plus CNI (tacrolimus or cyclosporine A) plus methotrexate (ATG/TAC or CSA/MTX) are common graft-versus-host disease (GVHD) prophylaxis regimens. We compared the two regimens in patients with acute myeloid leukemia (AML) undergoing allogeneic transplantation from matched siblings or unrelated donors. 402 received PTCy/TAC or CSA/MMF and 5648 received ATG/TAC or CSA/MTX. Patients in the PTCy-based group were younger (48.7 vs. 51.5 years, p = 0.024) and there was a higher frequency of patient cytomegalovirus seropositivity and female donor to male patient combination in this group (77.8% vs. 71.8%, p = 0.009 and 18.4% vs. 14.4%, p = 0.029, respectively). More patients in the PTCy-based group received reduced-intensity conditioning (51.5% vs. 41%, p < 0.0001). No differences were observed in the incidence of acute GVHD grade II-IV and III-IV (21.2% vs. 20.4%, p = 0.92 and 8.1% vs. 6%, p = 0.1) or 2-year total and extensive chronic GVHD (33.7% vs. 30%, p = 0.09 and 10.7% vs. 11.2%, p = 0.81) between the groups. In the multivariate analysis, all transplant outcomes did not differ between the groups. PTCy/CNI/MMF and ATG/CNI/MTX are alternative regimens for GVHD prophylaxis in AML patients.

Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study.

BACKGROUND: We previously reported that the "Endothelial Activation and Stress Index" (EASIX; ((creatinine×lactate dehydrogenase)÷thrombocytes)) measured before start of conditioning predicts mortality after allogeneic hematopoietic stem cell transplantation (alloSCT) when used as continuous score. For broad clinical implementation, a prospectively validated EASIX-pre cut-off is needed that defines a high-risk cohort and is easy to use. METHOD: In the current study, we first performed a retrospective cohort analysis in n=2022 alloSCT recipients and identified an optimal cut-off for predicting non-relapse mortality (NRM) as EASIX-pre=3. For cut-off validation, we conducted a multicenter prospective study with inclusion of n=317 first alloSCTs from peripheral blood stem cell in adult patients with acute leukemia, lymphoma or myelodysplastic syndrome/myeloproliferative neoplasms in the European Society for Blood and Marrow Transplantation network. RESULTS: Twenty-three % (n=74) of alloSCT recipients had EASIX-pre ≥3 taken before conditioning. NRM at 2 years was 31.1% in the high EASIX group versus 11.5% in the low EASIX group (p<0.001). Patients with high EASIX-pre also had worse 2 years overall survival (51.6% vs 70.9%; p=0.002). We were able to validate the cut-off and found that EASIX ≥3 was associated with more than twofold increased risk for NRM in multivariate analysis (HR=2.18, 95% CI 1.2 to 3.94; p=0.01). No statistically significant difference could be observed for the incidence of relapse. CONCLUSIONS: The results of this study provide a prospectively validated standard laboratory biomarker index to estimate the transplant-related mortality risk after alloSCT. EASIX ≥3 taken before conditioning identifies a population of alloSCT recipients who have a more than twofold increased risk of treatment-related mortality.

The remission status of AML patients after allo-HCT is associated with a distinct single-cell bone marrow T-cell signature.

ABSTRACT: Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient graft-versus-leukemia (GVL) effect and relapse. Here, we performed single-cell RNA-sequencing (scRNA-seq) on bone marrow (BM) T lymphocytes and CD34+ cells of 6 patients with AML 100 days after allo-HCT to identify T-cell signatures associated with either imminent relapse (REL) or durable complete remission (CR). We observed a higher frequency of cytotoxic CD8+ effector and gamma delta (γδ) T cells in CR vs REL samples. Pseudotime and gene regulatory network analyses revealed that CR CD8+ T cells were more advanced in maturation and had a stronger cytotoxicity signature, whereas REL samples were characterized by inflammatory tumor necrosis factor/NF-κB signaling and an immunosuppressive milieu. We identified ADGRG1/GPR56 as a surface marker enriched in CR CD8+ T cells and confirmed in a CD33-directed chimeric antigen receptor T cell/AML coculture model that GPR56 becomes upregulated on T cells upon antigen encounter and elimination of AML cells. We show that GPR56 continuously increases at the protein level on CD8+ T cells after allo-HCT and confirm faster interferon gamma (IFN-γ) secretion upon re-exposure to matched, but not unmatched, recipient AML cells in the GPR56+ vs GPR56- CD8+ T-cell fraction. Together, our data provide a single-cell reference map of BM-derived T cells after allo-HCT and propose GPR56 expression dynamics as a surrogate for antigen encounter after allo-HCT.

Prehabilitative high-intensity interval training and resistance exercise in patients prior allogeneic stem cell transplantation.

Physical capacity prior allogeneic stem cell transplantation (allo-HCT) has been shown as a relevant prognostic factor for survival after transplant. Therefore, we evaluated feasibility and preliminary efficacy of a high-intensity interval training (HIIT) and moderate to high-intensity resistance exercise (RE) to increase physical capacity in patient's prior allo-HCT. In this multicentre single arm pilot study, a supervised exercise program was performed twice weekly for 4-12 weeks prior allo-HCT, depending on the individual time remaining. Outcomes were feasibility (recruitment, adherence, safety), physical capacity (cardiorespiratory fitness [VO2peak], muscle strength) and patient reported outcomes (physical functioning, fatigue). Thirty patients were intended, 16 could be included, and 14 completed post intervention assessment (75% male, 55 ± 11 years). The study was stopped early due to a low recruitment rate. Nine patients (64%) reached the initial minimum planned number of eight exercise sessions. Individual adherence was high with 92% for HIIT and 85% for RE. 87% of all performed exercise sessions were completed without complaints and VO2peak increased significantly from 20.4 to 23.4 ml/kg/min. The low recruitment rate suggests that initiation of the intervention concept immediately before allo-HCT is feasible only in a small number of patients. In particular, the timeframe directly prior allo-HCT seems too short for exercise interventions, although the exercise program was designed to improve outcomes in a very short time frame. HIIT and RE were feasible, effective and well accepted by the included patients.

Data-driven grading of acute graft-versus-host disease.

Despite advances in allogeneic hematopoietic cell transplantation, acute graft-versus-host disease (aGVHD) remains its leading complication, yet with heterogeneous outcomes. Here, we analyzed aGVHD phenotypes and clinical classifications in depth in large, multicenter cohorts involving 3019 patients and addressed prevailing gaps by developing data-driven models. We compared, tested and verified these along with all conventional classifications in independent cohorts and found that data-driven grading outperformed conventional grading in Akaike information criterion and concordance index metrics. Data-driven classifications refined aGVHD assessment with up to 12 severity grades, which were associated with distinct nonrelapse mortality (NRM) and confirmed the key role of intestinal aGVHD. We developed an online calculator for physicians to implement principal component-derived grading (PC1). These results provide substantial insight into the evaluation of aGVHD phenotypes and multiorgan involvement, which relegates the exclusive reporting of overall aGVHD severity grades in transplant registries and clinical trials. Data-driven aGVHD grading provides an expandable platform to refine classification and transplant risk assessment.

EASIX-1year and late mortality after allogeneic stem cell transplantation.

Patients with hematological malignancies who survive the first year after allogeneic stem cell transplantation (allo-SCT) without relapse have a substantial risk of nonrelapse mortality (NRM) and missing predictive markers. The Endothelial Activation and Stress Index (EASIX) predicts endothelial complications and NRM early after allo-SCT. We hypothesized that EASIX assessed 1 year after allo-SCT in survivors who were disease free may predict late NRM. Survivors who were relapse-free at 1 year after allo-SCT were retrospectively studied in 2 independent cohorts (training cohort, n = 610; merged validation cohort, n = 852). EASIX determined 1 year after allo-SCT correlated with the overall survival (OS), NRM, and relapse. Serum endothelial and inflammatory markers were measured in the training cohort and correlated with EASIX-1year, which predicted OS and NRM but not relapse risk in both the training and validation cohorts in univariable and multivariable Cox regression analyses. Brier score and c-index analyses validated the univariable EASIX effects. There was no significant interaction between EASIX-1year and incidence of chronic graft-versus-host disease (GVHD) on OS. EASIX-1year predicted the outcome irrespective of preexisting comorbidities. Principal causes of NRM in both training and validation cohorts were infections with and without GVHD as well as cardiovascular complications. EASIX-1year correlated with sCD141 and interleukin-18 but not with C-reactive protein, suppressor of tumorigenicity-2, angiopoietin-2, CXCL9, or CXCL8. To our knowledge, EASIX-1year is the first validated predictor of late overall and NRM. Patients who are high risk as defined by EASIX-1year might be considered for intensified surveillance and prophylactic measures.

IFNγ Causes Keratinocyte Necroptosis in Acute Graft-Versus-Host Disease.

Epidermal keratinocytes form the first-line cellular barrier of the skin for protection against external injuries and maintenance of local tissue homeostasis. Expression of ZBP1 was shown to cause necroptotic keratinocyte cell death and skin inflammation in mice. We sought to characterize the relevance of ZBP1 and necroptosis in human keratinocytes and type 1-driven cutaneous acute graft-versus-host disease. in this study, we identify ZBP1 expression, necroptosis, and interface dermatitis as being the hallmarks of acute graft-versus-host disease. ZBP1 expression was dependent on leukocyte-derived IFNγ, and interference with IFNγ signaling by Jak inhibition prevented cell death. In predominantly IL-17-driven psoriasis, both ZBP1 expression and necroptosis could not be detected. Of note, in contrast to the signaling in mice, ZBP1 signaling in human keratinocytes was not affected by RIPK1's presence. These findings show that ZBP1 drives inflammation in IFNγ-dominant type 1 immune responses in human skin and may further point to a general role of ZBP1-mediated necroptosis.

Statin-based endothelial prophylaxis and outcome after allogeneic stem cell transplantation.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (alloSCT) often remains the only curative therapy for hematologic malignancies. Although the management of transplant-associated adverse events considerably improved over the last decades, nonrelapse mortality (NRM) remains a challenge, and endothelial dysfunction was identified as a major contributor to NRM. METHODS: Statin-based endothelial prophylaxis (SEP) has been implemented in the standard of care in our transplant centre to reduce NRM caused by endothelial injury. Here, we retrospectively analysed the impact of SEP on clinical outcome in a cohort of 347 alloSCT patients. RESULTS: SEP (n = 209) was associated with significantly reduced NRM (hazard ratio 0.61, 95% CI 0.38-0.96) and better overall survival (OS) after acute graft-versus-host disease (HR 0.59, 95% CI 0.37-0.93). Subgroup analyses showed that the NRM benefit was mainly found in patients with an intermediate endothelial activation and stress index (EASIX), while relapse risk was not affected. On day 100 post-alloSCT, patients receiving SEP had significantly higher levels of the rate-limiting enzyme of tryptophan metabolism, indoleamine 2,3-dioxygenase (IDO), higher kynurenine to tryptophan ratios as a proxy of IDO activity and tended to have lower levels of the endothelial injury marker ST2 (p = .055). No significant differences in interferon-gamma or IL18 levels were observed. These biomarker signatures suggest that the beneficial effects of SEP might be mediated by both endothelial protection and immunomodulation. CONCLUSIONS: Together, these data suggest that SEP improves NRM and OS post-alloSCT in particular in patients with intermediate endothelial risk and provide first mechanistic clues about its potential mode of action.

Comparison of outcomes for HLA-matched sibling and haplo-identical donors in Myelodysplastic syndromes: report from the chronic malignancies working party of EBMT.

Myelodysplastic syndromes (MDS) are the second common indication for an Allo-HCT. We compared the outcomes of 1414 matched sibling (MSD) with 415 haplo-identical donors (HD) transplanted with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis between 2014 and 2017. The median age at transplant with MSD was 58 and 61 years for HD. The median time to neutrophil engraftment was longer for HD being 20 vs 16 days for MSD (p < 0.001). Two-year overall survival (OS) and PFS (progression free survival) with MSD were significantly better at 58% compared with 50%, p ≤ 0.001, and 51% vs 47%, p = 0.029, with a HD. Relapse at 2 years was lower with a HD 23% than with MSD 29% (p = 0.016). Non relapse mortality (NRM) was higher with HD in the first 6 months post-transplant [HR 2.59 (1.5-4.48) p < 0.001] and was also higher at 2 years being 30% for HD and 20% for MSD, p ≤ 0.001. The incidence of acute GVHD grade II-IV and III-IV at 100 days was comparable for MSD and HD, however, chronic GVHD at 2 years was significantly higher with MSD being 44% vs 32% for HD (p < 0.001). After multivariable analysis, OS and primary graft failure were significantly worse for HD particularly before 6 months [HR 1.93(1.24-3.0)], and HR [3.5(1.5-8.1)]. The median age of HD 37 (IQR 30-47) years was significantly lower than sibling donors 56 (IQR 49-62 years) p < 0.001. However, there was no effect on NRM, relapse or PFS. This data set suggests that a MSD donor remains the preferred choice in MDS over a haplo donor. Transplants with haploidentical donors result in satisfactory long-term outcome, justifying it's use when no better donor is available.

EASIX and Severe Endothelial Complications After CD19-Directed CAR-T Cell Therapy-A Cohort Study.

Background: Endothelial dysfunction is associated with two main complications of chimeric antigen receptor T (CAR-T) cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This study evaluates the Endothelial Activation and Stress Index (EASIX) as a prognostic marker for high-grade CRS and ICANS in patients treated with CD19-directed CAR-T cells. Methods: In this retrospective study, a training cohort of 93 patients from the ZUMA-1 trial and a validation cohort of 121 patients from two independent centers (University Hospital Heidelberg, Charité University Medicine Berlin) were investigated. The primary objective was to assess the predictive capacity of EASIX measured immediately before the start of lymphodepletion (EASIX-pre) for the occurrence of grade ≥3 CRS and/or ICANS. To explore a possible endothelial link, serum levels of endothelial stress markers (angiopoietin-2, suppressor of tumorigenicity-2, soluble thrombomodulin, and interleukin-8) were determined before lymphodepletion and on day 7 after CART infusion in the validation cohort (n = 47). Results: The prognostic effect of EASIX-pre on grade ≥3 CRS and/or ICANS was significant in the training cohort [OR 2-fold increase 1.72 (1.26-2.46)] and validated in the independent cohort. An EASIX-pre cutoff >4.67 derived from the training cohort associated with a 4.3-fold increased odds ratio of severe CRS/ICANS in the independent cohort. Serum endothelial distress markers measured on day+7 correlated with EASIX-pre and associated with severe complications. Conclusions: EASIX-pre is a powerful predictor of severe CRS/ICANS after CD19-directed CART therapy and might be used as a basis for risk-adapted prevention strategies.

Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD (IRENE-G study) - design and rational of a randomized controlled trial.

BACKGROUND: Graft-versus-host disease (GvHD) remains a major complication and limitation to successful allogeneic hematopoietic stem cell transplantation. Treatment of GvHD is challenging due to its heterogeneous nature of presentation, with steroids remaining the established first-line treatment. Long-term doses of systemic corticosteroids have many well-known side-effects including muscle atrophy. Despite the fact that reports in non-cancer clinical populations treated with glucocorticoids demonstrated that resistance training can reverse atrophy and weakness, no RCT has evaluated the potential of resistance training on preventing the disease- and treatment-induced loss of skeletal muscle mass and function in GvHD patients yet. In this context, ensuring adequate nutrition is important as protein deprivation may accelerate the wasting process. As GvHD patients are commonly found to be malnourished, nutritional medical care should be considered when investigating the effect of exercise in GvHD patients. Therefore, the aim of the present "Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD" - Study (IRENE-G) is to evaluate the effects of resistance exercise in combination with nutritional endorsement on physical, nutritional and patient-reported outcomes in GvHD patients. METHODS: IRENE-G is a 24-week prospective interventional RCT. One hundred twelve participants will be randomly allocated (1:1) to one of two arms: resistance exercise and nutritional optimization (experimental) vs. nutritional optimization only (control). Participants in the experimental group will engage in a supervised, progressive moderate-to-high intensity resistance training that is consistent with exercise guidelines for cancer patients, while additionally receiving nutritional support/therapy. Subjects of the control group solely receive nutritional support/therapy based on individual needs. Participants will be assessed at baseline, at 8, 16, 24 weeks for physical performance and various physiological, nutritional and patient-reported outcomes. Follow-up will be 6 months after intervention completion. DISCUSSION: To our knowledge, this will be the first RCT to assess and compare the effects of a resistance intervention supplemented by nutritional support/therapy against nutritional support only on various health-related outcomes in GvHD patients. The study will contribute to our understanding of the value of exercise and nutritional endorsement in counteracting the negative consequences of GvHD and its treatment. TRIAL REGISTRATION: ClinicalTrials.gov : NCT05111834 . Registered 8 November 2021 - Retrospectively registered.

Pre-Transplant Serum Leptin Levels and Relapse of Acute Myeloid Leukemia after Allogeneic Transplantation.

Weight loss and metabolic activity influence outcome after allogeneic stem cell transplantation (alloSCT). This study evaluates pre-conditioning Leptin, a peptide hormone involved in metabolism and immune homeostasis, as a prognostic factor for survival, relapse and non-relapse mortality (NRM) following alloSCT. Leptin serum levels prior to conditioning were determined in a cohort of patients transplanted for various hematologic malignancies (n = 524) and correlated retrospectively with clinical outcome. Findings related to patients with acute leukemia (AL) from this sample were validated in an independent cohort. Low pre-conditioning serum Leptin was an independent prognostic marker for increased risk of relapse (but not of NRM and overall mortality) following alloSCT for AL of intermediate and advanced stage (beyond first complete remission). Multivariate analysis revealed a hazard ratio (HR) for relapse of 0.75 per log2 increase (0.59-0.96, p = 0.020). This effect was similar in an independent validation cohort. Pre-conditioning serum Leptin was validated as a prognostic marker for early relapse by fitting the multivariate Cox model to the validation data. Pre-conditioning serum Leptin levels may serve as an independent prognostic marker for relapse following alloSCT in intermediate and advanced stage AL patients. Prospective studies are required to prove whether serum Leptin could be used for guiding nutritional intervention in patients with AL undergoing alloSCT.

Humoral Responses and Chronic GVHD Exacerbation after COVID-19 Vaccination Post Allogeneic Stem Cell Transplantation.

The COVID-19 pandemic threatens patients with a compromised immune and endothelial system, including patients who underwent allogeneic stem cell transplantation (alloSCT). Thus, there is an unmet need for optimizing vaccination management in this high-risk cohort. Here, we monitored antibodies against SARS-CoV-2 spike protein (anti-S1) in 167 vaccinated alloSCT patients. Humoral immune responses were detectable in 81% of patients after two vaccinations with either mRNA-, vector-based, or heterologous regimens. Age, B-cell counts, time interval from vaccination, and the type of vaccine determined antibody titres in patients without systemic immunosuppression (sIS). Similar to a healthy control cohort, mRNA vaccine-based regimens induced higher titres than vector-based vaccines. Patients on two or more immunosuppressants rarely developed immunity. In contrast, 62% and 45% of patients without or on only one immunosuppressant, respectively, showed a strong humoral vaccination response (titre > 100). Exacerbation of cGVHD upon vaccination was observed in 6% of all patients and in 22% of patients receiving immunosuppression for cGVHD. cGVHD exacerbation and low antibody titres were both associated with higher angiopoietin-2 (ANG2) serum levels. In conclusion, mRNA-based vaccines elicit strong humoral responses in alloSCT patients in the absence of double sIS. Biomarkers such as ANG2 might help with weighing cGVHD risk versus beneficial responses.

Response to extracorporeal photopheresis therapy of patients with steroid-refractory/-resistant GvHD is associated with up-regulation of Th22 cells and Tfh cells.

Extracorporeal photopheresis (ECP), a personalized cellular immunotherapy, constitutes a promising treatment for steroid-refractory/-resistant graft-versus-host disease (SR-GvHD), with encouraging clinical response rates. To further investigate its mechanism of action, ECP's effects on T helper (Th) cells as well as on expression of immune checkpoint (PD-1 and Tim-3) and apoptotic (Fas receptor [FasR]) molecules were investigated in 27 patients with SR-GvHD. Our data show that GvHD patients had significantly higher levels of Th2, Th17, Th22 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-positive Th (ThG) cells and clearly lower levels of T follicular helper (Tfh) cells, including Th1- and Th2-like cells, compared with healthy donors. ECP therapy for GvHD was effective through the modulation of different Th subsets: increases of Th22 (1.52-fold) and Tfh cells (1.48-fold) in acute GvHD (aGvHD) and increases of Th2-like Tfh cells (1.74-fold) in chronic GvHD (cGvHD) patients were associated with clinical response. Expression of FasR was further upregulated in CD4+CD8+ T cells. Additionally, Tim-3-expressing effector T cells associated with the severity of GvHD were reduced. Taken together, these data show that ECP therapy exerts immunomodulatory effects by promoting a balanced immune reconstitution and inducing immune tolerance. Therefore it represents an attractive option for the treatment of GvHD.

Kynurenine pathway activation and deviation to anthranilic and kynurenic acid in fibrosing chronic graft-versus-host disease.

Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogeneic stem cell transplantation (alloSCT). A driver of fibrosis is the kynurenine (Kyn) pathway, and Kyn metabolism patterns and cytokines may influence cGVHD severity and manifestation (fibrosing versus gastrointestinal [GI] cGVHD). Using a liquid chromatography-tandem mass spectrometry approach on sera obtained from 425 patients with allografts, we identified high CXCL9, high indoleamine-2,3-dioxygenase (IDO) activity, and an activated Kyn pathway as common characteristics in all cGVHD subtypes. Specific Kyn metabolism patterns could be identified for non-severe cGVHD, severe GI cGVHD, and fibrosing cGVHD, respectively. Specifically, fibrosing cGVHD was associated with a distinct pathway shift toward anthranilic and kynurenic acid, correlating with reduced activity of the vitamin-B2-dependent kynurenine monooxygenase, low vitamin B6, and increased interleukin-18. The Kyn metabolite signature is a candidate biomarker for severe fibrosing cGVHD and provides a rationale for translational trials on prophylactic vitamin B2/B6 supplementation for cGVHD prevention.

Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT.

Allogeneic haematopoietic-cell transplantation (allo-HCT) is a potentially curative therapy for high-risk myelodysplastic syndrome (MDS). Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM), higher relapse rate and similar overall-survival (OS) as myeloablative-conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced-toxicity regimen with intense anti-leukaemia activity and a favourable toxicity profile. We investigated post-transplant outcomes in 1722 MDS patients following allo-HCT with FT (n = 367), RIC (n = 687) or MAC (n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0·001) but other disease characteristics were similar. The median follow-up was 64 months (1-171). Five-year relapse rates were 25% (21-30), 38% (34-42) and 25% (22-29), after FT, RIC and MAC, respectively, (P < 0·001). NRM was 30% (25-35), 27% (23-30) and 34% (31-38, P = 0·008), respectively. Five-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), respectively (P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P < 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo-HCT in MDS.