The impact of pre-transplantation diabetes and obesity on acute graft-versus-host disease, relapse and death after allogeneic hematopoietic cell transplantation: a study from the EBMT Transplant Complications Working Party.

Obesity and diabetes can modulate immune responses, which may impact allogeneic HCT outcomes and GvHD. From the EBMT registry, we included 36,539 adult patients who underwent allogeneic HCT for a hematological malignancy between 2016 and 2020. Of these, 5228 (14%) had obesity (BMI ≥ 30 kg/m2), 1415 (4%) had diabetes (requiring treatment with insulin or oral hypoglycemics), and 688 (2%) had obesity + diabetes pre-transplantation. Compared with patients without diabetes or obesity, the hazard ratio (HR) of grade II-IV acute GvHD was 1.00 (95% confidence interval [CI] 0.94-1.06, p = 0.89) for patients with obesity, 0.95 (CI 0.85-1.07, p = 0.43) for patients with diabetes, and 0.96 (CI 0.82-1.13, p = 0.63) for patients with obesity + diabetes. Non-relapse mortality was higher in patients with obesity (HR 1.08, CI 1.00-1.17, p = 0.047), diabetes (HR 1.40, CI 1.24-1.57, p < 0.001), and obesity + diabetes (HR 1.38, CI 1.16-1.64, p < 0.001). Overall survival after grade II-IV acute GvHD was lower in patients with diabetes (HR 1.46, CI 1.25-1.70, p < 0.001). Pre-transplantation diabetes and obesity did not influence the risk of developing acute GvHD, but pre-transplantation diabetes was associated with poorer survival after acute GvHD.

Metabolic Profiling Early Post-Allogeneic Haematopoietic Cell Transplantation in the Context of CMV Infection.

Immune dysfunction resulting from allogeneic haematopoietic stem cell transplantation (aHSCT) predisposes one to an elevated risk of cytomegalovirus (CMV) infection. Changes in metabolism have been associated with adverse outcomes, and in this study, we explored the associations between metabolic profiles and post-transplantation CMV infection using plasma samples collected 7-33 days after aHSCT. We included 68 aHSCT recipients from Rigshospitalet, Denmark, 50% of whom experienced CMV infection between days 34-100 post-transplantation. First, we investigated whether 12 metabolites selected based on the literature were associated with an increased risk of post-transplantation CMV infection. Second, we conducted an exploratory network-based analysis of the complete metabolic and lipidomic profiles in relation to clinical phenotypes and biological pathways. Lower levels of trimethylamine N-oxide were associated with subsequent CMV infection (multivariable logistic regression: OR = 0.63; 95% CI = [0.41; 0.87]; p = 0.01). Explorative analysis revealed 12 clusters of metabolites or lipids, among which one was predictive of CMV infection, and the others were associated with conditioning regimens, age upon aHSCT, CMV serostatus, and/or sex. Our results provide evidence for an association between the metabolome and CMV infection post-aHSCT that is independent of known risk factors.

Triple-Drug Graft-versus-Host Disease Prophylaxis after HLA-Matched Unrelated Donor Nonmyeloablative Allogenic Hematopoietic Stem Cell Transplantation.

Adding sirolimus to graft-versus-host disease (GVHD) prophylaxis with cyclosporin and mycophenolate mofetil (MMF) reduced the risk of grade II-IV acute GVHD after nonmyeloablative (NMA) allogenic hematopoietic stem cell transplantation (HSCT) with an HLA-matched unrelated donor in a randomized clinical trial. We analyzed real-life data to investigate the impact of implementing the triple-drug regimen with cyclosporin, MMF and sirolimus as standard GVHD prophylaxis after NMA HSCT with an HLA-matched unrelated donor at our institution. We studied all adult patients (age ≥18 years) who underwent NMA HSCT with an HLA-matched unrelated donor at Rigshospitalet, Copenhagen University Hospital, Denmark between 2018 and 2021 and received GVHD prophylaxis with cyclosporin, MMF and sirolimus (triple-drug group [TDG]). Comparisons were made with a historical cohort who received tacrolimus and MMF as GVHD prophylaxis after HLA-matched unrelated donor NMA HSCT between 2014 and 2017 (control group [CG]). Outcomes were grade II-IV and grade III-IV acute GVHD, chronic GVHD, relapse, nonrelapse mortality (NRM) and overall survival (OS). A total of 264 patients were included (TDG, n = 137; CG, n = 127). Median age was 66 years (interquartile range [IQR], 58 to 69 years) in the TDG and 63 years (IQR, 57 to 68 years) in the CG. Acute myeloid leukemia and myelodysplastic syndrome were the most frequent indications for HSCT in both groups (TDG, 33% and 23%, respectively; CG, 36% and 22%, respectively). The cumulative incidence at day +110 of grade II-IV GVHD was 17% (95% confidence interval [CI] 11% to 23%) in the TDG versus 29% (95% CI, 21% to 37%) in the CG (P = .02, Gray's test) and that of grade III-IV acute GVHD was 3% (95% CI, 0 to 6%) versus 5% (95% CI, 1% to 8%), respectively (P = .4, Gray's test). In a Cox regression model adjusted for age, donor age and female donor to male recipient the risk of grade II-IV acute GVHD was lower in the TDG compared to the CG (hazard ratio [HR], .51; 95% CI .30 to .86; P = .01). The 2-year OS was 77% (95% CI, 70% to 84%) in the TDG and 69% (95% CI, 61% to 77%) in the CG (P = .04), and this difference remained significant after adjustment for age and Karnofsky Performance Status (HR, .65; 95% CI, .42 to .99; P = .04). The 2-year cumulative incidences of chronic GVHD, relapse and NRM were 60% (95% CI, 51% to 69%), 21% (95% CI, 13% to 28%), and 12% (95% CI, 6% to 17%), respectively, in the TDG and 62% (95% CI, 54% to 71%), 27% (95% CI, 19% to 35%) and 14% (95% CI, 8% to 20%), respectively, in the CG. Multivariable analyses revealed no difference in the risk of chronic GVHD (HR, .91; 95% CI, .65 to 1.26; P = .56), relapse (HR, .70; 95% CI, .42 to 1.15; P = .16) or NRM (HR, .56; 95% CI, .31 to 1.05; P = .07). After changing the standard GVHD prophylaxis in patients undergoing NMA HSCT with an HLA-matched unrelated donor from tacrolimus and MMF to cyclosporin, MMF and sirolimus, we observed a reduction in the incidence of grade II-IV acute GVHD and improved 2-year OS.

Hypomethylating agent-based therapies in older adults with acute myeloid leukemia - A joint review by the Young International Society of Geriatric Oncology and European Society for Blood and Marrow Transplantation Trainee Committee.

Acute myeloid leukemia (AML) is associated with poor outcomes in older adults. A major goal of treatment is to balance quality of life and functional independence with disease control. With the approval of new, more tolerable regimens, more older adults are able to receive AML-directed therapy. Among these options are hypomethylating agents (HMAs), specifically azacitidine and decitabine. HMAs have become an integral part of AML therapy over the last two decades. These agents are used either as monotherapy or nowadays more commonly in combination with other agents such as the Bcl-2 inhibitor venetoclax. Biological AML characteristics, such as molecular and cytogenetic risk factors, play crucial roles in guiding treatment decisions. In patients with high-risk AML, HMAs are increasingly used rather than intensive chemotherapy, although further trials based on a risk-adapted approach using patient- and disease-related factors are needed. Here, we review trials and evidence for the use of HMA monotherapy and combination therapy in the management of older adults with AML. Furthermore, we discuss the use of HMAs and HMA combination therapies in AML, mechanisms of action, their incorporation into hematopoietic stem cell transplantation strategies, and their use in patients with comorbidities and reduced organ function.

Pretransplantation Plasma ST2 Level as a Prognostic Biomarker of 1-Year Nonrelapse Mortality in Allogeneic Hematopoietic Cell Transplantation.

Soluble ST2 is established as a prognostic biomarker of nonrelapse mortality (NRM) when measured early after allogeneic hematopoietic cell transplantation (HCT). However, less is known about the prognostic value of ST2 measured before transplantation. We hypothesized that pretransplantation plasma ST2 level was associated with 1-year NRM and could add to our current prognostic assessment. Moreover, we aimed to investigate the associations between pretransplantation plasma ST2 levels and patient characteristics and other plasma biomarkers and to reproduce previous associations between post-transplantation plasma ST2 levels and outcomes of HCT. We conducted this cohort study of 374 adults who underwent allogeneic HCT at our center between July 2015 and December 2019 (median age, 59 years; 55% with a nonmyeloablative conditioning regimen). ST2 levels were measured by enzyme-linked immunosorbent assay in stored plasma samples obtained at a median of 23 days before HCT and also in samples obtained on days +7 and +14 post-HCT. A logistic regression model of 1-year NRM was fitted using an a priori defined set of covariates consisting of age, Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), and conditioning intensity (myeloablative versus nonmyeloablative), to which the pretransplantation ST2 level was added as a variable to assess its incremental prognostic value. Models also were fitted of 1-year all-cause mortality, relapse, and grade II-IV acute graft-versus-host disease (GVHD) for pretransplantation and post-transplantation ST2 levels. The median pretransplantation plasma ST2 level was 20.4 ng/mL (interquartile range, 15.2 to 27.2 ng/mL). Pretransplantation ST2 levels were higher in males compared with females (median, 22.2 ng/mL versus 18.1 ng/mL; P < .001) and were correlated with HCT-CI (Spearman ρ = .18; P < .001), body mass index (ρ = .10; P = .05), and plasma levels of C-reactive protein (ρ = .34; P < .001), creatinine (ρ = .17; P = .001), and albumin (ρ = -.17; P < .001). Pretransplantation ST2 levels added prognostic information about 1-year NRM to age, HCT-CI, and conditioning intensity (adjusted odds ratio [OR] of 1-year NRM per 10 ng/mL increase in ST2, 1.32; 95% confidence interval [CI], 1.05 to 1.65; P = .02). Although adding pretransplantation ST2 levels did not notably improve model discrimination (.674 to .675, ΔAUC = .001), it increased the diversity of the predicted risks (P = .02, likelihood ratio test). Pretransplantation ST2 levels also were prognostic of 1-year all-cause mortality (adjusted OR per 10-ng/mL increase, 1.23; 95% CI, 1.02 to 1.48; P = .03), but not of relapse (P = .47) or acute GvHD (P = .81). Plasma ST2 levels at day +7 were prognostic of 1-year NRM, all-cause mortality, relapse, and acute GVHD, whereas levels at day +14 were prognostic of 1-year NRM and all-cause mortality. Our results show that pretransplantation plasma ST2 levels added prognostic information about 1-year NRM to age, HCT-CI, and conditioning intensity, and suggest that ST2 has potential as a biomarker of pretransplantation vulnerability and should be considered in future developments of prediction models of NRM after allogeneic HCT.

Sexual function of adult long-term survivors and their partners after allogeneic hematopoietic cell transplantation in Europe (S-FAST): a study from the Transplant Complications Working Party and Nurses Group of the EBMT.

Sexual dysfunction after allogeneic hematopoietic cell transplantation (allo-HCT) is a common long-term complication. We conducted a European multicenter cross-sectional study of adult allo-HCT recipients who had survived >2 years and their partners to investigate sexual functioning after HCT and to evaluate whether discussion about sexual functioning between the transplant team and the survivor and partner was perceived to have taken place. In total, 136 survivors (77 males, 59 females) and 81 partners (34 males, 47 females) participated. Median age was 56 and 54 years in male and female survivors, respectively. Forty-seven percent of male and 65% of female survivors and 57% of male and 59% of female partners reported clinically relevant sexual problems. Sixty-two percent of survivors and 79% of partners reported that sexual functioning had not been discussed with them during transplant. Standardized sexual functioning scores were correlated with self-reported health status in survivors (rho = 0.24, p = 0.009). The high prevalence of sexual dysfunction warrants additional studies focusing on the impact of changes in sexuality for patients as well as their partners. Future studies should also investigate which methods that are effective in preventing or treating sexual problems after allo-HCT.

Erratum: Author Correction: Early stimulated immune responses predict clinical disease severity in hospitalized COVID-19 patients.

[This corrects the article DOI: 10.1038/s43856-022-00178-5.].

Early stimulated immune responses predict clinical disease severity in hospitalized COVID-19 patients.

Background: The immune pathogenesis underlying the diverse clinical course of COVID-19 is poorly understood. Currently, there is an unmet need in daily clinical practice for early biomarkers and improved risk stratification tools to help identify and monitor COVID-19 patients at risk of severe disease. Methods: We performed longitudinal assessment of stimulated immune responses in 30 patients hospitalized with COVID-19. We used the TruCulture whole-blood ligand-stimulation assay applying standardized stimuli to activate distinct immune pathways, allowing quantification of cytokine responses. We further characterized immune cell subsets by flow cytometry and used this deep immunophenotyping data to map the course of clinical disease within and between patients. Results: Here we demonstrate impairments in innate immune response pathways at time of COVID-19 hospitalization that are associated with the development of severe disease. We show that these impairments are transient in those discharged from hospital, as illustrated by functional and cellular immune reconstitution. Specifically, we identify lower levels of LPS-stimulated IL-1ß, and R848-stimulated IL-12 and IL-17A, at hospital admission to be significantly associated with increasing COVID-19 disease severity during hospitalization. Furthermore, we propose a stimulated immune response signature for predicting risk of developing severe or critical COVID-19 disease at time of hospitalization, to validate in larger cohorts. Conclusions: We identify early impairments in innate immune responses that are associated with subsequent COVID-19 disease severity. Our findings provide basis for early identification of patients at risk of severe disease which may have significant implications for the early management of patients hospitalized with COVID-19.

Fitting parametric cure models in R using the packages cuRe and rstpm2.

BACKGROUND AND OBJECTIVE: Within medical research, cure models are useful for analyzing time-to-event data in the scenario where a proportion of the analyzed individuals are expected to never experience the event of interest. Cure models are also useful for modelling the relative survival in scenarios where a proportion of the individuals are expected to eventually experience a mortality rate similar to that of the general population. Here we present two R packages, cuRe and rstpm2, that provide researchers with several tools for performing statistical inference using parametric cure models. METHODS: Cure models are commonly used to estimate 1) the proportion of individuals that are cured and 2) the event-time distribution of individuals who are not cured. This can be done using simple parametric distributions for the event-time distribution of the uncured, but our implementations also enable fitting of more flexible spline-based cure models. The parametric framework of both packages ensures that cure models for the relative survival can easily be used. RESULTS: The cuRe package contains two main functions for estimating parametric mixture cure models; one based on simple parametric distributions (e.g. Weibull or exponential) and one utilizing a spline-based formulation of the cure model. The rstpm2 package enables estimation of spline-based latent cure models, i.e., cure models with no explicit parameters modelling the proportion of cured individuals. CONCLUSIONS: Through the R-packages cuRe and rstpm2, a wide range of different parametric cure models can be fitted. The cuRe package also contains a number of useful post-estimation procedures for computing the time to statistical cure and conditional probability of cure, which may spread the use of cure models in medical research.

Ocular Chronic Graft-versus-Host Disease and Its Relation to Other Organ Manifestations and Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Ocular chronic graft-versus-host disease (cGVHD) has been shown to significantly reduce quality of life after allogeneic hematopoietic stem cell transplantation (HSCT). To learn more about this bothersome complication, we investigated the relationship between ocular cGVHD and cGVHD in other organs. We also investigated the associations between ocular cGVHD and overall mortality, nonrelapse mortality, and relapse. In this single-center study, we retrospectively included 1221 consecutive adults who underwent allogeneic HSCT. Patients were examined by an ophthalmologist before HSCT and annually for 5 years after HSCT or more frequently if needed. Patients with dry eye disease before HSCT were excluded. The International Chronic Ocular GVHD Consensus Group criteria were used to diagnose ocular cGVHD. Nonocular cGVHD was diagnosed using the National Institute of Health criteria. Out of 601 patients who were diagnosed with systemic cGVHD during follow-up, 279 (46%) developed ocular cGVHD. Ocular cGVHD was more frequent in patients with extensive cGVHD compared to those with limited cGVHD (50% versus 29%; P < .0001) and was associated with cGVHD in skin (P < .0001), oral cavity (P = .0024), genitals (P = .0023), and nails (P = .031). The frequency of ocular cGVHD was higher in patients with skin cGVHD with sclerosis compared to those with skin cGVHD without sclerosis (70% versus 49%; P = .0003). In an adjusted time-dependent Cox model, ocular cGVHD was associated with increased nonrelapse mortality (adjusted hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.17 to 2.21; P = .003), whereas there was no support for an association with relapse (adjusted HR, .85; 95% CI, .53 to 1.36; P = .5). Special attention to eye problems after HSCT should be given to patients with extensive cGVHD and cGVHD in ectodermal-derived organs (skin, mouth, nails, and genitals). Furthermore, ocular cGVHD is a potential risk factor for nonrelapse mortality. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Pre-transplantation vitamin E levels and acute graft-versus-host disease after non-myeloablative allogeneic hematopoietic cell transplantation.

BACKGROUND: Low pre-transplantation plasma vitamin E levels have been associated with increased risk of acute graft-versus-host disease (GvHD) after myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to investigate the association between pre-transplantation plasma vitamin E levels and acute GvHD in patients undergoing allo-HCT with non-myeloablative conditioning. METHODS: In a cohort of 194 adults who underwent non-myeloablative allo-HCT at Rigshospitalet between July 2015 and December 2019, we measured pre-transplantation plasma vitamin E levels by high-performance liquid chromatography in stored plasma samples. Univariable ordinary least squares linear models were used to investigate associations between vitamin E levels and patient characteristics. A multivariable logistic regression model was used to estimate the association between vitamin E levels and grade II-IV acute GvHD, adjusted for recipient age, donor age, female-male donor-recipient pairing, and donor type. RESULTS: The median (Q1, Q3) pre-transplantation plasma vitamin E level was 32.3 (26.4, 40.4) µmol/L. No patients had a vitamin E level below the normal reference range. Vitamin E levels were higher in females (mean difference: 8.0 µmol/L, 95% confidence interval [CI]: 4.9, 11.1 µmol/L) and in patients transplanted for acute leukemia (mean difference: 6.2 µmol/L, CI: 3.0, 9.4 µmol/L). Grade II-IV acute GvHD developed in 33 (17%) patients. Patients who developed acute GvHD had similar pre-transplantation vitamin E levels compared with patients who did not develop grade II-IV acute GvHD (mean difference: 0.7 µmol/L, bootstrap CI: -3.3, 4.7 µmol/L). In the adjusted logistic regression model, an increase in the pre-transplantation vitamin E level from 26.4 (Q1) to 40.4 (Q3) µmol/L was associated with an odds ratio of grade II-IV acute GvHD of 1.17 (CI: 0.64, 2.12). CONCLUSIONS: Contrary to the previously reported association between pre-transplantation vitamin E levels and acute GvHD after myeloablative allo-HCT, we did not find support for an association in patients who received non-myeloablative conditioning. The potential protective effects of vitamin E may not be efficacious in the reduced inflammatory response following non-myeloablative conditioning.

Improved survival after allogeneic transplantation for acute lymphoblastic leukemia in adults: a Danish population-based study.

We investigated trends of survival in a population-based cohort study of all 181 adults who received HCT for ALL in Denmark between 2000-2019. Patients had a median (min-max) age of 36 (18-74) years at HCT and were followed for a median of eight years. Overall survival (OS) improved over time with an estimated 2-year OS of 49% (CI 27-66%) in year 2000 versus 77% (CI 59-88%) in year 2019. More patients achieved cure over time (OR for cure per year 1.07, CI 1.00-1.15), while the rate of death in non-cured patients remained stable (HR of excess mortality per year 0.99, CI 0.93-1.06). Relapse decreased over time (HR 0.92 per year, CI 0.87-0.98), whereas non-relapse mortality did not change notably (HR 0.98 per year, CI 0.93-1.04). In conclusion, survival after HCT in adults with ALL has improved over the past two decades, primarily due to more patients achieving cure.

Cytokine autoantibodies are stable throughout the haematopoietic stem cell transplantation course and are associated with distinct biomarker and blood cell profiles.

Cytokine-specific autoantibodies (c-aAbs) represent an emerging field in endogenous immunodeficiencies, and the immunomodulatory potential of c-aAbs is now well documented. Here, we investigated the hypothesis that c-aAbs affects inflammatory, immunoregulatory and injury-related processes and hence the clinical outcome of haematopoietic stem cell transplantation (HSCT). C-aAbs against IL-1α, IL-6, IL-10, IFNα, IFNγ and GM-CSF were measured in 131 HSCT recipients before and after (days + 7, + 14, + 28) HSCT and tested for associations with 33 different plasma biomarkers, leukocyte subsets, platelets and clinical outcomes, including engraftment, GvHD and infections. We found that c-aAb levels were stable over the course of HSCT, including at high titres, with few individuals seeming to acquire high-titre levels of c-aAbs. Both patients with stable and those with acquired high-titre c-aAb levels displayed significant differences in biomarker concentrations and blood cell counts pre-HSCT and at day 28, and the trajectories of these variables varied over the course of HSCT. No clinical outcomes were associated with high-titre c-aAbs. In this first study of c-aAbs in HSCT patients, we demonstrated that high-titre levels of c-aAb may both persist and emerge in patients over the course of HSCT and may be associated with altered immune biomarkers and cell profiles.

Platelet and Red Blood Cell Transfusions and Risk of Acute Graft-versus-Host Disease after Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Transfusion therapy is a critical part of supportive care early after allogeneic hematopoietic cell transplantation (allo-HCT). Platelet and RBC transfusions elicit immunomodulatory effects in the recipient, but if this impacts the risk of acute graft-versus-host disease (aGVHD) has only been scarcely investigated. We investigated if platelet and RBC transfusions were associated with the development of aGVHD following myeloablative allo-HCT in a cohort of 664 patients who underwent transplantation between 2000 and 2019. Data were further analyzed for the impact of blood donor age and sex and blood product storage time. Exploratory analyses were conducted to assess correlations between transfusion burden and plasma biomarkers of inflammation and endothelial activation and damage. Between day 0 and day +13, each patient received a median of 7 (IQR, 5 to 10) platelet transfusions and 3 (IQR, 2 to 6) RBC transfusions (Spearman's ρ = 0.49). The cumulative sums of platelet and RBC transfusions, respectively, received from day 0 to day +13 were associated with subsequent grade II-IV aGVHD in multivariable landmark Cox models (platelets: adjusted hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.06 to 1.51; RBCs: adjusted HR, 1.41; 95% CI, 1.09 to 1.82; both per 5 units; 184 events). For both platelet and RBC transfusions, we did not find support for a difference in the risk of aGVHD according to age or sex of the blood donor. Transfusion of RBCs with a storage time longer than the median of 8 days was inversely associated with aGVHD (HR per 5 units, 0.54; 95% CI, 0.30 to 0.96); however, when using an RBC storage time of ≥14 days as a cutoff, there was no longer evidence for an association with aGVHD (HR, 1.03 per 5 units; 95% CI, 0.53 to 2.00). For platelets, there was no clear association between storage time and the risk of aGVHD. The transfusion burdens of platelets and RBCs were positively correlated with plasma levels of TNF-α, IL-6, and soluble thrombomodulin at day +14. In conclusion, platelet and RBC transfusions in the first 2 weeks after myeloablative allo-HCT were associated with subsequent development of grade II-IV aGVHD. We did not find evidence of an impact of blood donor age or sex or blood product storage time on the risk of aGVHD. Our findings support restrictive transfusion strategies in allo-HCT recipients.

Pre-transplantation plasma vitamin D levels and acute graft-versus-host disease after myeloablative hematopoietic cell transplantation in adults.

BACKGROUND: The association between vitamin D and acute graft-versus-host disease (GvHD) remains controversial, especially for patients receiving myeloablative conditioning. METHODS: We measured pre-transplantation plasma vitamin D (25-hydroxyvitamin D3 + D2) levels by competitive electrochemiluminescence in plasma samples from 116 adult patients who underwent a myeloablative allogeneic transplantation at Rigshospitalet, Copenhagen between July 2015 and August 2018. RESULTS: The median (Q1, Q3) pre-transplantation plasma vitamin D level was 64 (47, 85) nmol/L (normal range: 50-160 nmol/L). Vitamin D insufficiency (<50 nmol/L) and moderate deficiency (<25 nmol/L) were observed in 29% and 8% of patients, respectively. No patients had a severe deficiency (<12 nmol/L). Pre-transplantation vitamin D levels were slightly higher in patients who later developed grade II-IV acute GvHD (mean difference: 8.1 nmol/L), but the 95% confidence interval [CI] encompassed clinically insignificant differences (CI: -2.2, 19.2 nmol/L). From multivariable logistic regression, we found that a patient with a pre-transplantation vitamin D level of 85 nmol/L (Q3) had 1.5 times higher odds of grade II-IV acute GvHD than a patient with a level of 47 nmol/L (Q1; CI of odds ratio: 0.84, 2.7; adjusted for patient age, donor type, use of anti-thymocyte globulin, and use of 12 Gy total-body irradiation). Patients with pre-transplantation vitamin D insufficiency (N = 34) had a cumulative incidence of grade II-IV acute GvHD similar to that of patients with vitamin D sufficiency (26% [CI: 11%, 42%] versus 35% [CI: 25%, 46%], respectively). CONCLUSIONS: Our data did not support an association between pre-transplantation vitamin D levels or vitamin D insufficiency and acute GvHD in adult patients receiving myeloablative conditioning.

Functional immune reconstitution early after allogeneic haematopoietic cell transplantation: A comparison of pre- and post-transplantation cytokine responses in stimulated whole blood.

We aimed to use a novel standardized whole-blood stimulation system to evaluate differences in the functional immune reconstitution in patients early after allogeneic haematopoietic cell transplantation (HCT). Between April and September 2018, 30 patients undergoing HCT had whole blood samples collected around day -21 (day 0 being the day of haematopoietic cell infusion) and day +28. Whole blood was transferred to TruCulture assays comprising prefilled incubation tubes with cell culture medium and a standardized stimulus. We used a panel of four stimuli (lipopolysaccharide, resiquimod, heat-killed Candida albicans and polyinosinic:polycytidylic acid) and a blank, designed to evaluate the function of critical extra- and intracellular immunological signalling pathways. For each stimulus, the cytokine response was assessed by the concentration of interferon-γ, interleukin (IL)-12p40, IL-10, IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A and tumour necrosis factor-α using a multiplex Luminex assay. Pre-HCT cytokine responses were globally decreased across several different stimuli. Despite patients receiving immunosuppressive prophylaxis at the time, post-HCT cytokine responses were higher and less intercorrelated than pre-HCT responses, also after adjusting for differences in the leukocyte differential counts. For the resiquimod and heat-killed Candida albicans stimuli, we identified a cluster of patients in whom post-HCT responses were lower than average across several cytokines, indicating a possible functional immune deficiency. Our findings suggest that the standardized whole blood stimulation system can be used to reveal heterogeneity in the in vitro cytokine responses to various stimuli after HCT. Larger studies are needed to address if the functional immune reconstitution after HCT can predict the risk of infections.

Vitamin E and acute graft-versus-host disease after myeloablative allogeneic hematopoietic cell transplantation.

OBJECTIVES: Vitamin E has antioxidant and immunomodulatory effects that might influence the development of acute graft-versus-host disease (GvHD). We investigated the association between plasma vitamin E levels and acute GvHD. METHODS: We studied 115 adults who underwent myeloablative allogeneic hematopoietic cell transplantation between July 2015 and August 2018. Vitamin E was measured by high-performance liquid chromatography in stored plasma samples obtained pre-transplantation at day -23 (±15 days) and post-transplantation at day +28 (±3 days). RESULTS: Pre-transplantation vitamin E levels were inversely associated with grade II-IV acute GvHD (hazard ratio 0.68 per 10 µmol/L increase, 95% confidence interval [CI]: 0.47-0.98). The association remained after adjustment for known prognostic factors for acute GvHD. Patients with levels below the median had a cumulative incidence of grade II-IV acute GvHD of 46% (CI: 33-59%) versus 21% (CI: 10-32%) in patients with levels above the median. No clear association with non-relapse mortality, relapse, or chronic GvHD was found. Post-transplantation vitamin E levels (measured in 72 [63%] patients) were correlated with pre-transplantation levels (ρ = .31) but were not associated with subsequent grade II-IV acute GvHD. CONCLUSIONS: High pre-transplantation vitamin E levels were associated with less acute GvHD.