Disease Risk Index Research Articles

Association of Neck Circumference with Body Composition and Cardiovascular Parameters in Young Healthy Adult Males

Background and Aim: Increased Neck circumference is the marker of upper body obesity and identified as an indicator of future cardiovascular disease risk (CVD). Hence, in this study, we assessed the relationship of Neck circumference (NC) with basal cardiovascular and body composition (BC) parameter in young adult males. Methods: Sixty three healthy young adult male volunteers of age between 18 to 25 years were enrolled for this study and they were divided into two groups based on neck circumference (NC). Control group (n = 32) comprises of individuals with normal neck circumference of ≤ 35.5 cm and study group (n = 31) includes individuals with increased neck circumference of ≥ 35.5 cm. The, BC parameters was assessed by Bioimpedance Analysis (BIA) method using Quadscan 4000. And the basal cardiovascular parameters such as systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) was measured by automated sphygmomanometer and the pulse pressure (PP), mean arterial pressure (MAP) and the rate pressure product (RPP) were derived. Results: Data was expressed in Mean ± SD. The groups were compared using Independent Student’s t test. The association between NC and various study parameters were assessed by Pearson’s correlation analysis. Our study, revealed increased body fat and reduced muscle mass in individuals with increased NC. Further, we observed a positive correlation of NC with body fat (%) and negative correlation with Lean Body Mass. Cardiovascular parameters SBP, DBP, MAP and PP were elevated in subjects with increased NC. Further, positive correlation is seen with SBP, DBP, RPP and NC. Conclusion: Neck circumference is a readily measurable screening tool of upper-body adiposity and increased NC is associated with CVD risk.

Optimized cyclosporine starting dose may reduce risk of acute GvHD after allogeneic hematopoietic cell transplantation: a single-center cohort study

Cyclosporine A (CsA) is commonly used for Graft versus Host Disease (GvHD) prophylaxis at a recommended starting dose of 3 mg/kg/d: Evidence for the effect of different CsA starting doses on GvHD risk is limited. We therefore estimated the association of 5 mg/kg/d (CsA5) and 3 mg/kg/d (CsA3) CsA starting doses with GvHD risk in two consecutive cohorts of allogeneic hematopoietic cell transplantation (allo-HCT) patients, exploring potential risk factors for incident acute GvHD, with a focus on CsA starting dose. We analyzed 519 patients within CsA5 (n = 153) and CsA3 (n = 366). The cumulative incidence function of acute GvHD grade ≥2 was higher in the CsA3 compared to the CsA5 group (41% vs. 33%, respectively; p = 0.043), without impacting chronic GvHD. In multivariable analysis, a CsA starting dose of 3 mg/kg/d, no ATG use, unrelated donor and high to very high disease risk index were significantly associated with acute GvHD grade ≥2. A higher CsA starting dose of 5 mg/kg/d was independently associated with lower acute GvHD risk, and higher CsA levels in the early period after allo-HCT were reached.

Intervention for a Digital, Cognitive, Multi-Domain Alzheimer Risk Velocity Study: Protocol for a Randomized Controlled Trial.

BackgroundIn the United States, more than 6 million adults live with Alzheimer disease (AD) that affects 1 out of every 3 older adults. Although there is no cure for AD currently, lifestyle-based interventions aimed at slowing the rate of cognitive decline or delaying the onset of AD have shown promising results. However, most studies primarily focus on older adults (>55 years) and use in-person interventions.ObjectiveThe aim of this study is to determine the effects of a 2-year digital lifestyle intervention on AD risk among at-risk middle-aged and older adults (45-75 years) compared with a health education control.MethodsThe lifestyle intervention consists of a digitally delivered, personalized health coaching program that directly targets the modifiable risk factors for AD. The primary outcome measure is AD risk as determined by the Australian National University-Alzheimer Disease Risk Index; secondary outcome measures are functional fitness, blood biomarkers (inflammation, glucose, cholesterol, and triglycerides), and cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status and Neurotrack Cognitive Battery). Screening commenced in January 2021 and was completed in June 2021.ResultsBaseline characteristics indicate no difference between the intervention and control groups for AD risk (mean −1.68, SD 7.31; P=.90).ConclusionsThe intervention in the Digital, Cognitive, Multi-domain Alzheimer Risk Velocity is uniquely designed to reduce the risk of AD through a web-based health coaching experience that addresses the modifiable lifestyle-based risk factors.Trial RegistrationClinicalTrials.gov NCT04559789; https://clinicaltrials.gov/show/NCT04559789International Registered Report Identifier (IRRID)DERR1-10.2196/31841

Post-Transplantation Cyclophosphamide After HLA Identical Compared to Haploidentical Donor Transplant in Acute Myeloid Leukemia: A Study on Behalf of GETH-TC

Post-transplantation cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT) and achieves low rates of GVHD in HLA-identical transplantation. To compare the outcomes of haploidentical versus HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. We conducted a retrospective study of 229 patients undergoing first HSCT for AML using PTCY with additional immunosuppression, 99 from matched sibling or unrelated donor (MSD/MUD) performed in 3 hospitals and 130 from haploidentical donors (haplo group) performed in 20 hospitals within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cellular Therapy. Peripheral blood stem cells were used as graft in 89% of patients; myeloablative conditioning was used in 56%. There were significantly more patients with active disease (5% versus 20%, P = .001), high/very high disease risk index (DRI) (32% versus 67%, P = .000) and prior auto-HSCT (2% versus 11%, P = .010) in the haplo group. Median follow-up was 27 and 62.5 months for MSD/MUD and haplo, respectively. At 2 years, no significant differences were observed in overall survival (OS) (72% versus 62%, P = .07), event-free survival (EFS) (70% versus 54%, P = .055), cumulative incidence of relapse (19% versus 25%, P = .13), non-relapse mortality (14% versus 19%, P = .145), and the composite endpoint of GVHD and relapse-free survival (49% versus 42%, P = .249). Multivariate analysis identified only age and active disease as significant risk factors for OS and EFS; reduced-intensity conditioning, high/very high DRI, and haplo donor were nearly statistically significant for these outcomes. Grade II-IV acute GVHD was lower in MSD/MUD (14% versus 47%, P = .000). Cumulative incidences of grade III-IV acute GVHD (4% versus 9%, P = .14) and moderate-severe chronic GVHD (22% versus 19%, P = .28) were similar. Limitations of our study include limited sample size, differences between haplo and MSD/MUD groups and heterogeneous additional immunosuppression and PTCY timing in MSD/MUD. The use of an HLA-identical donor with PTCY in patients with AML showed lower incidence of clinically significant grade II-IV acute GVHD compared to haplo donors. Further studies with larger sample sizes should be performed to establish a possible benefit of HLA-identical donor on survival.© 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Prediction and recommendation by machine learning through repetitive internal validation for hepatic veno-occlusive disease/sinusoidal obstruction syndrome and early death after allogeneic hematopoietic cell transplantation.

Using traditional statistical methods, we previously analyzed the risk factors and treatment outcomes of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after allogeneic hematopoietic cell transplantation. Within the same cohort, we applied machine learning to create prediction and recommendation models. We analyzed 2572 transplants using eXtreme Gradient Boosting (XGBoost) to predict post-transplant VOD/SOS and early death. Using the XGBoost and SHapley Additive exPlanations (SHAP), we found influential factors and devised recommendation models, which were internally verified by repetitive ten-fold cross-validation. SHAP values suggested that gender, busulfan dosage, age, forced expiratory volume, and Disease Risk Index were significant factors for VOD/SOS. The areas under the receiver operating characteristic curves and the areas under the precision-recall curve of the models were 0.740, 0.144 for all VOD/SOS, 0.793, 0.793 for severe to very severe VOD/SOS, and 0.746, 0.304 for early death. According to our single feature recommendation, following the busulfan dosage was the most effective for preventing VOD/SOS. The recommendation method for six adjustable feature sets was also validated, and a subgroup corresponding to five to six features showed significant preventive power for VOD/SOS and early death. Our personalized treatment set recommendation showed reproducibility in repetitive internal validation, but large external cohorts should prospectively validate our model.

Study on prevalence of obesity using different scales and its association with hypertension among the elderly in a district of Gujarat.

Introduction:In older adults, excess weight is associated with a higher prevalence of cardiovascular disease, metabolic disease, several important cancers, and numerous other medical conditions. Several indices such as body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) are used to classify general. Some studies also reported that WC and WHR is a better indicator of cardiovascular disease (CVD) risk than BMI and WHR.Aims and Objective:1. To estimate the prevalence of obesity among the elderly using three scale viz. BMI, WHR, and WHtR 2. To compare the results of these three-scale used for assessment of obesity 3. To determine the presence of association between obesity and hypertension if any.Material and Methods:For selection of the area, in both the urban and rural areas, the sampling units were enumerated and samples were collected from them. The estimated geriatric population combined in both Urban and Rural areas amounted to 12,220 (7% of geriatric population as per Census 2001), out of which 5% was selected as sample. This came out to be 611 elderly subjects which were selected equally from both urban and rural areas. For assessment of obesity BMI, WHR, and WHtR were measured. Assessment of hypertension was as per JNC classification.Result:Prevalence of obesity as per BMI in the urban area was found to be 40%, whereas that in rural areas was found to be 47.4%. WHR and WHtR showed higher prevalence in rural areas (70%) and also in urban areas (60%). BMI and WHR were significantly associated with hypertensive status of elderly.Conclusion:Anthropometric assessments of obesity like WHR and WHTR are more sensitive indicators of obesity among the elderly. BMI is found to be significantly associated with hypertension as well in the present study. Logistic regression showed that the association of BMI with hypertension was higher than other obesity assessments.

Evaluation of association between potential stress markers and periodontal health in medical and dental students: A questionnaire-based study.

Aims and Objectives:Psychological conditions, particularly psychosocial stress, have been implicated as risk indicators for periodontal disease. The aim of the present study was to explore the role of psychosocial stress on periodontium through questionnaire and serum cortisol level.Subjects and Methods:Two hundred medical and dental undergraduates were recruited for the study. Case group included 82 examination going and control group had 79 nonexam going students. Their stress level was evaluated using a standard questionnaire (perceived stress scale). Gingival index, periodontal disease index, bleeding on probing index, serum cortisol level, and serum alpha-amylase level were also measured.Statistical Analysis Used:Bivariate correlations and multiple regression tests were done.Results:A positive correlation was found among stress scores, salivary cortisol, alpha-amylase, and periodontal disease measures.Conclusion:Periodontitis can be related to immunologic changes related to psychological states

Evaluation of Aortic Elasticity Parameters in Survivors of COVID-19 Using Echocardiography Imaging

Objective: While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects lung tissue, it may cause direct or indirect damage to the cardiovascular system, and permanent damage may occur. Arterial stiffness is an early indicator of cardiovascular disease risk. The aim of our study was to establish the potential effects of SARS-CoV-2 on the vascular system evaluated by transthoracic echocardiographic examination. Subjects and Methods: This study compared arterial stiffness between the survivors of COVID-19 and those without a history of COVID-19 infection. The difference in aortic diameter was examined using echocardiography. Results: The study included 50 patients who survived COVID-19 in the last 3–6 months and 50 age- and gender-matched healthy volunteers. In surviving COVID-19 patients, aortic diastolic diameter in cm ([3.1 ± 0.2] vs. [2.9 ± 0.1], p < 0.001), pulse pressure (PP) ([43.02 ± 14.05] vs. [35.74 ± 9.86], p = 0.004), aortic distensibility ([5.61 ± 3.57] vs. [8.31 ± 3.82], p < 0.001), aortic strain ([10.56 ± 4.91] vs. [13.88 ± 5.86], p = 0.003), PP/stroke volume index ([1.25 ± 0.47] vs. [0.98 ± 0.28], p = 0.001), and aortic stiffness index ([2.82 ± 0.47] vs. [2.46 ± 0.45], p < 0.001) were statistically significant compared to the control group. Conclusion: SARS-CoV-2 may cause reduced or impaired aortic elasticity parameters linked to impaired arterial wall function in COVID-19 survivors compared with controls.

The Two-Step Allogeneic Stem Cell Transplantation Approach Results in Rapid Engraftment and Excellent Outcomes in Patients with Lymphoid Malignancies

The 2-step graft engineering approach has been the main platform for allogeneic hematopoietic cell transplantation (allo-HCT) at Thomas Jefferson University since 2005. We have previously described separating donor lymphocyte infusion followed by cyclophosphamide for bidirectional tolerization from CD34-selected hematopoietic grafts in haploidentical and matched related donors. Here we analyzed 60 patients with high-risk lymphoid malignancies who underwent a 2-step allo-HCT between 2008 and 2020. The majority of patients received haploidentical stem cell grafts (82%), and 20% of patients received matched related donor stem cell grafts. The patients underwent allo-HCT for diffuse large C cell lymphoma (n=17; 28%), chronic lymphoblastic leukemia (n=10; 17%), follicular lymphoma (n=8; 13%), and Hodgkin lymphoma (n=7; 12%). Eight patients (13%) had received prior high-dose chemotherapy. Thirty patients (50%) had a Hematopoietic Cell Transplantation Comorbidity Index ≥3, and 20 patients (33%) had a Center for International Blood & Marrow Transplant Research Revised Disease Risk Index of high risk or very high risk. The median patient age was 56 years (range, 24 to 75 years). Neutrophils engrafted at a median of 11 days (range, 9 to 16 days), and platelets engrafted at a median of 16 days (range, 13 to 37 days). With a median follow-up of 6 years, the 3-year probability of overall survival was 62.9% (95% confidence interval [CI], 49.3% to 73.8%), and that of disease-free survival was 60.2% (95% CI, 46.4% to 71.6%). The cumulative incidence of relapse at 3 years was 11.9% (95% CI, 5.2% to 21.6%). The cumulative incidence of nonrelapse mortality at 3 years was 30.1% (95% CI, 1.91% to 42.0%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at 1 year was 45% (95% CI, 32.2% to 57.0%), and that of grade III-IV acute GVHD at 1 year was 5% (95% CI, 1.3% to 12.6%). The cumulative incidence of cGVHD at 3 years was 15.2% (95% CI, 7.5% to 25.4%). The 2-step approach achieved excellent outcomes in high-risk lymphoid malignancies, with rapid neutrophil and platelet recovery.

Cardiometabolic risk factors predict executive function scores in high-risk individuals

Alzheimer’s disease (AD) is expected to triple by 2050, affecting 16 million Americans. As a result, it is essential to combat this alarming increase in cognitive impairment through early detection. Cardiometabolic risk factors have shown to be associated with higher risk of AD. The purpose of this study was to determine if cardiometabolic risk factors could predict executive function scores in a high-risk population. Fifty (60.9±8.8 years) high-risk adults (classified by the Australian National University Alzheimer’s Disease Risk Index) were enrolled in this study. Participants completed a 6-minute walking test, venous blood draw, blood pressure measurement, and the digit coding symbol test (DCS). Results were examined through a multiple linear regression with DCS as the dependent variable and age, sex, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), glucose, 6-minute walking test, systolic blood pressure (SBP), and diastolic blood pressure (DBP) as predictor variables. The model explained 42% of the variance of DCS (p = .04) with SBP (45%; p = .003) as a significant predictor. LDL (p = .087) and DBP (p = .123) accounted for 24% and 22% of the variance for this model, respectively. These results suggest cardiometabolic risk factors predict executive function values in high-risk individuals. Higher SBP was significantly associated with lower DCS scores indicating SBP as a valuable tool for practitioners when evaluating cognitive decline. Further research should expand sample size and track values longitudinally to substantiate these claims.

Differences of Sedentary Behavior, Physical Activity, and Metabolic Syndrome Severity Among Metabolic Syndrome Clusters

Background: Sedentary behavior (SB), physical activity (PA), and metabolic syndrome (MetS) are risk indicators for cardiometabolic diseases. Novel methods for researching MetS by the 16 unique clusters (i.e., WC+FBG+BP) and as a continuous severity z-score (MetS-Z) have emerged. This study examined how SB, PA, and MetS-Z differed among MetS clusters and SB and PA differences by MetS-Z tertiles. Methods: Using 2015-2016 National Health and Nutritional Examination Survey (NHANES) data, participants with MetS (N = 792) were identified. Subsequently, sex-, race-, and ethnicity-specific MetS-Z were calculated. SB and PA differences were compared between MetS clusters and MetS-Z tertiles. Additionally, MetS-Z was compared between MetS clusters. Results: The WC+FBG+BP MetS cluster was prevalent among 23.80% of participants (95% CIs, 18.41-30.18) and the overall mean MetS-Z was 1.16 (1.08-1.24). Participants reported over 6 daily hours of SB (393.41 minutes⋅day-1 [370.07-416.75]). The TRI+FBG+BP+HDL MetS cluster had less SB than the WC+TRI+FBG+HDL, WC+TRI+HDL, and WC+FBG+BP MetS clusters. PA did not differ between MetS clusters and no differences in SB or PA between MetS-Z tertiles. Conclusions: Limited differences in SB and PA were observed. Participants with 4 or more MetS criteria had worse MetS-Z. Efforts should support replacing SB with PA to improve cardiometabolic health.

Profiling the metabolic landscape of AD

Metabolic dysfunction, including perturbations in lipid, neurotransmitter, and polyamine metabolism, is an early indicator of cognitive impairment and Alzheimer disease (AD) risk. Further investigation is needed to elucidate the role of genetic heterogeneity in these metabolic disturbances. Here, we interrogate metabolomic signatures in the brains of carriers of pathological mutations in APP, PSEN1, and PSEN2 (Autosomal Dominant AD; ADAD), risk variants in TREM2, non-carrier sporadic AD cases (sAD), individuals with neuropathology but without clinical symptoms (Presymptomatic), and neuropathology-free controls (CO). Metabolomic data from parietal brain tissue of donors to the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network (ADAD, n=25; TREM2, n=21; sAD, n=305; Presymptomatic, n=15; CO, n=27) were generated using the Metabolon global metabolomics platform. A total of 627 metabolites passed our QC process. Differential abundance between AD strata and controls was tested using linear regression corrected for sex, age, and post-mortem interval. Age was excluded from ADAD models. Benjamini-Hochberg multiple testing correction was applied, and pathway analysis was performed with MetaboAnalyst and IMPaLA. In total, we identified 138 metabolites associated with distinct genetic strata (FDR q-value<0.05). For sAD, these included tryptophan betaine (β=-0.55) and N-acetylputrescine (β=-0.14). Metabolites associated with both sAD and ADAD were ergothioneine (β=-0.22 and -0.26 respectively) and serotonin (β=-0.34 and -0.57). TREM2 and ADAD showed association with α-tocopherol (β=-0.12 and -0.12). β-citrylglutamate abundance decreased in sAD, ADAD, and TREM2 versus controls (β=-0.14; -0.22; and -0.29). Pathways identified included glutamate, vitamin, and antioxidant metabolism. A 16-metabolite subset showed consistent direction of effect among the genetic strata with the magnitude of effect of ADAD greater than that of TREM2, in turn greater than sAD. A representation of these (eigengene) is associated with disease duration in sAD (p=5.65x10-03 ), possibly driven by tau accumulation. Hierarchical clustering identified 41 "early stage" sAD individuals with Braak tau stage similar to Presymptomatic (p=0.35), but lower than other sAD individuals (β=-0.56, p=3.09x10-04 ) (Figure 1). Our findings suggest distinct and characteristic metabolic perturbations in ADAD and TREM2 brains. Investigation of these differentially abundant metabolites may lead to greater insight into the metabolic etiology of AD and its impact on clinical presentation.

Cardiovascular Risk Screening and Pregnancy Complications: A Comparison of Two Canadian Maternal Health Clinic Populations.

This study compared pregnancy-related cardiovascular disease risk indicators between women who attended 2 different postpartum screening and education clinics: 1 at an urban tertiary care centre and 1 at a northern, rural community hospital. Risk differences associated with ethnicity were also examined. We conducted a retrospective record review that compared data from an urban clinic in Kingston, Ontario (n=675) with those from a rural clinic in Prince Rupert, British Columbia (n=65). Patients who had a hypertensive disorder of pregnancy, gestational diabetes, intrauterine growth restriction, idiopathic preterm birth, or placental abruption attended the clinics at 6 months postpartum. Demographic information, personal and family history, physical examination findings, and laboratory results were collected and used to generate cardiovascular risk estimates using validated scoring systems. These estimates were compared between clinic populations and between ethnic subsets. Fifty-five percent of the Prince Rupert cohort were Indigenous, while 87% of the Kingston cohort were White (P < 0.001). A greater proportion of the Kingston cohort had experienced hypertensive disorders of pregnancy (P=0.002), while a greater proportion of the Prince Rupert cohort had developed gestational diabetes (P=0.010). The Prince Rupert population had higher lifetime and 30-year cardiovascular disease risk scores (P=0.008 and P=0.005, respectively). Indigenous patients had more major cardiovascular risk factors as well as higher lifetime and 30-year cardiovascular risk scores (P=0.001 and P=0.008, respectively) than White and Asian patients. The increased cardiovascular disease risk in both rural and Indigenous women supports the need for better postpartum care, long-term follow-up, and early promotion of cardiovascular health in these populations.

Impact of Vitamin D Deficiency on Survival for Patients Received Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT)

BackgroundBeyond its role in bone health, vitamin D is known to have immunomodulatory effects including cell proliferation, differentiation and apoptosis. Delays in immune reconstitution following HSCT increase transplant-related toxicity. Several studies have explored the role of vitamin D deficiency after HSCT with mixed results regarding its impact on survival outcomes. Our aim in this study was to examine the impact of vitamin D deficiency prior to HSCT on transplant outcomes in patients who received a haplo-HSCT.MethodsThis retrospective study included consecutive patients who underwent haplo-HSCT at our institution between 02/2009 and 01/2021. Primary objectives were to assess progression-free survival (PFS) and overall survival (OS) by vitamin D status at the time of transplant. Vitamin D deficiency was defined as vitamin D levels < 20 nmol/L within 6 months prior to transplant. Survival estimates were calculated using Kaplan-Meier method. Proportional cox hazards analysis was used to adjust for multivariable analysis (MVA).ResultsFour-hundred and eighty-four patients out of 508 patients had vitamin D checked at baseline and were included in the final analysis. Table 1 summarizes patient, disease, and transplant characteristics for all study patients, and by vitamin D status. Median age for all study patients was 48 (18-72) years, of which 237 (49%) had vitamin D deficiency and 247 (51%) had normal vitamin D level. Overall, the two groups were comparable, except that patients in the vitamin D deficiency group were younger in age. Furthermore, we adjusted for disease subtype heterogeneity by using the validated disease risk index (DRI). With a median follow-up of 35.4 (range, 1.4-132.8) months, the 3-year PFS and OS for all study patients were 44% and 48%, respectively. The respective 3-year PFS and OS for the vitamin D deficiency group were 42% and 47% compared to 46% and 50% for patients with adequate vitamin D (p=0.773 for PFS; p=0.704 for OS). Furthermore, we found no difference in non-relapse mortality at 3 years (each for 30%; p=0.6682). Univariate analysis (UVA) was performed for the following variables: vitamin D, age, gender, KPS, DRI, HCT-CI, and intensity of conditioning regimen. MVA included only the factors with p value<0.1 in in the UVA (plus vitamin D). In UVA for PFS, age ≥55, KPS <90, high/very-high DRI, HXT-CI >3 and reduced intensity conditioning were associated with inferior outcome. Same factors were significantly associated with inferior OS, but the reduced conditioning regimen. In MVA, age ≥55 (HR 1.627, 95% CI: 1.212-2.212; p=0.0013), high/very-high DRI (HR 1.865, 95% CI: 1.427-2.437; p=<0.0001), and HCT-CI >3 (HR 1.314, 95% CI: 1.001-1.726; p=0.0493) were associated with decreased PFS. Patients in the vitamin D deficiency group had a trend towards decreased PFS (HR 1.292, 95% CI: 0.975-1.712; p=0.0746), but this didn't reach statistical significance. In regard to OS, age ≥55 (HR 1.727, 95% CI: 1.278-2,334; p=0.0004), high/very-high DRI (HR 1.855, 95% CI: 1.396-2.467; p=<0.0001), and HCT-CI >3 (HR 1.411, 95% CI: 1.058-1.882; p=0.0191) were again associated with decreased OS, while vitamin D deficiency patients showed a trend for decreased OS (HR 1.312, 95% CI: 0.973-1.77; p=0.0753).ConclusionOur study demonstrates that serum vitamin D levels prior to haplo-HSCT have no significant impact on either progression-free or overall survival, albeit with a trend for worse outcomes in the vitamin D deficient group. Prospective controlled studies are needed to assess the impact of vitamin D deficiency on transplant outcomes, and on the role of vitamin D supplementation to improve the outcomes. [Display omitted] DisclosuresQazilbash: Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Angiocrine: Research Funding; Amgen: Research Funding; Biolline: Research Funding; NexImmune: Research Funding; Janssen: Research Funding. Shpall: Navan: Consultancy; Novartis: Honoraria; Axio: Consultancy; Magenta: Honoraria; Takeda: Patents & Royalties; Bayer HealthCare Pharmaceuticals: Honoraria; Adaptimmune: Consultancy; Affimed: Patents & Royalties; Magenta: Consultancy; Novartis: Consultancy.

Outcomes for Allogeneic Stem Cell Transplantation in Secondary AML Are Inferior to De Novo AML and Are Independent of the Disease Risk Index

BackgroundPatients with secondary acute myeloid leukaemia (sAML), defined as AML that follows a diagnosis of myelodysplastic syndrome or myeloproliferative neoplasm, are known to have a poor prognosis with conventional chemotherapy alone, when compared to de novo AML (dnAML). Allogeneic stem cell transplant offers the best chance of cure due to the often chemo-resistant nature of sAML, although there are limited studies assessing the outcome of allografting in this patient population. The Disease Risk Index (DRI) is a clinical decision tool which assists in determining the balance of transplant risk versus benefit, however validation studies to date have not evaluated the DRI in patients with sAML.MethodsA retrospective analysis of 211 patients with dnAML or sAML who underwent allogeneic stem cell transplant between 1 st January 1998 and 31 st July 2015 at St Vincent's Hospital or Royal North Shore Hospital in Sydney Australia, was undertaken. Cases were identified from the Australasian Bone Marrow Transplant Recipient Registry, with additional data collected by medical record review.Overall survival (OS) probability was calculated by the Kaplan-Meier method. Non-relapse mortality (NRM) and relapse incidence (RI) were estimated by cumulative incidence with “death without relapse” and “relapse” as competing risks. A Cox proportional hazards model was used for multivariate regression, with results expressed as hazard ratio (HR) with 95% confidence intervals.ResultsOf the 211 eligible patients, 63 (30%) had a diagnosis of sAML, compared to 148 with dnAML. Of those with sAML, 74% had antecedent MDS and 26% an MPN. Patients with sAML had an older median age (55 vs 44 years, p<0.001), more often had HCT-CI >3 (p=0.003), and more commonly had at least one cytogenetic abnormality (p=0.026). A myeloablative conditioning regimen was used in 35.3% and 66.0% of s- and dn- AML respectively. Grade II or greater acute graft-versus-host disease (GVHD) occurred in 39.7% of sAML and 29% of dnAML, with chronic GVHD reported in 60.3% and 64.5% respectively. OS at 1 year was 48.5% in sAML and 71.6% in dnAML (HR 1.93 [95%CI 1.32-2.97, p=0.0001]). Multivariate analysis accounting for disease risk index (DRI) as a co-factor identified sAML as an independent adverse risk factor for OS (HR 2.13 [95%CI 1.31-3.45], p=0.002). Compared to dnAML, sAML was associated with higher rates of disease relapse (HR 2.21 [95%CI 1.20-4.05], p=-0.011).Figure 1: Transplant outcomes (A) Overall survival dnAML vs sAML (B) Cumulative incidence of relapse at 1 year dnAML vs sAMLConclusionsPatients with sAML experience poorer outcomes following allogeneic stem cell transplant than those with dnAML. Whilst the DRI stratifies AML based on cytogenetic risk and stage, our study identifies sAML as a prognostic marker independent of risk ascribed by the DRI. This has not been reported previously and if replicated, suggests the need for development of an independent prognostic model to capture the adverse risk in the sAML patient cohort. Importantly, despite poor outcomes, the lack of alternate management strategies still makes allogeneic stem cell transplant the only potential curative therapy. [Display omitted] DisclosuresHamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Greenwood: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Severe Cytokine Release Syndrome Associated with Worse Outcomes in Recipients of a Haploidentical Stem Cell Transplant

Introduction: The utilization of haploidentical (haplo) donors for allogeneic hematopoietic stem cell transplant (HCT) recipients has allowed more donor options to treat a multitude of hematopoietic malignancies and disorders. However, there are substantial complications and morbidities associated with haplo HCT. Cytokine release syndrome (CRS), a manifestation of alloreactive T cell expansion, has posed an obstacle early after stem cell infusion. CRS is well described among chimeric antigen receptor (CAR) T cell therapy recipients, where anti-interleukin (IL) 6 therapy and glucocorticoids to abrogate cytokine activity depends on objective physiologic markers and neurologic changes. In 2019, the American Society of Transplantation and Cellular Therapy (ASTCT) developed a consensus CRS grading scale for CAR T cell therapy that has since been widely adopted for these recipients (Lee et al, Biol Blood Marrow Transpl 2019). While the etiology of CRS differs between haplo HCT and CAR T cell recipients, severe CRS (grade 3 or 4) is seen in both patient populations, defined by ASTCT CRS grading as non-fluid responsive hypotension and/or capillary leak necessitating increased ventilatory support. We investigated whether the newly adopted ASTCT CRS grading could apply to a haplo HCT population in predicting overall survival (OS) and progression-free survival (PFS) at 1 year as well as the 2-year probability of graft-versus-host disease (GVHD).Methods: This IRB-approved retrospective analysis assessed 64 patients who underwent haplo HCT at Colorado Blood Cancer Institute from July 2015 to December 2018. All but one patient received peripheral blood-derived stem cells, and all patients received post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil for GVHD prophylaxis. Variables of birth sex, primary disease, disease risk index (DRI), blood type, degree of HLA-mismatching, presence of donor-specific antibodies, Hematopoietic Cell Transplant Comorbidity Index (HCT-CI), conditioning regimen, and cell dose were assessed. In all patients, fever, blood pressure, and oxygen supplementation were used to identify the maximum CRS grade between 0-5 days after HCT using ASTCT CRS grading. Patients with other etiologies (i.e. infection, cardiomyopathy) were excluded from the analysis. CRS grading was then dichotomized to mild (CRS grades 0-2) or severe (grades 3-4), reflecting the physiologic changes that align with minimal compared to intensive cardiopulmonary support. As all patients had complete follow-up to 2 years, logistic regression was used to estimate association between severe CRS and outcome.Results: When adjusted for age, DRI and HCT-CI, development of severe CRS was associated with an inferior PFS at 1 year (odds ratio (OR) 0.22, (95% Confidence Interval (CI) 0.07, 0.69), p = 0.01). Inferior OS was also seen in those who developed severe CRS but the magnitude of the effect was smaller and not considered definitive (OR 0.38, (95%CI 0.13, 1.13), p=0.082). Increased non-relapse mortality (NRM) was also seen with severe CRS. Due to the low number of events, adjustment for only one factor at a time was necessary. When adjusted for age (OR 2.94, (95%CI 0.82, 11.1), p=0.101), DRI (OR 3.23, (95%CI 0.91, 11.1), p=0.069), HCT-CI (OR 2.94, (95%CI 0.85, 10), p=0.089), and conditioning regimen (OR 3.23, (95%CI 0.91, 11.1), p=0.071), consistent results were demonstrated, although not definitive. This was also observed with the risk of relapse, adjusted for conditioning regimen (OR 2.56, (95%CI 0.76, 9.09), p=0.126) and DRI (OR 2.56, (95%CI 0.75, 8.33), p=0.132). There was no demonstrable association between CRS and the probability of acute GVHD. However, severe CRS was associated with a reduction in the development of any chronic GVHD at 2 years (OR 0.24, (95%CI 0.08, 0.72), p=0.011).Conclusion: This analysis suggests that an adapted ASTCT CRS grading, dichotomizing into those with mild (grades 0-2) or severe (grades 3-4) CRS may identify haplo HCT recipients at risk for inferior outcomes. Haplo HCT recipients with severe CRS demonstrated an inferior PFS. The data also showed numerical decreases in overall survival, higher relapse, and higher NRM. On the other hand, severe CRS was associated with a decreased probability of chronic GVHD. As the analysis was limited to a single site, validation of adapted ASTCT grading in a larger haplo HCT population is necessary. DisclosuresNo relevant conflicts of interest to declare.

Validation of Different Prognostic Scores in Allogeneic Hematopoietic Cell Transplantation in the Post-Transplant Cyclophosphamide Era

INTRODUCTIONThe use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis has decreased the rates of this complication, resulting on an improvement of transplant-related toxicity and survival. Secondary to its efficacy, the use of PTCy has been almost universally integrated for allogeneic hematopoietic cell transplantation (alloHCT), independently of the selected donor source.Clinical decisions in alloHCT are supported by the use of prognostic scores for outcome prediction. However, capability of prediction by diverse scores can vary depending on their features and on the composition of the study cohort. Additionally, the continuous innovation on alloHCT techniques and practices leads to an ongoing need to update risk indices aimed at improving risk stratification of patients undergoing alloHCT. This study explores the predictive capacity of different prognostic scores routinely used in alloHCT, in a contemporaneous cohort of adults undergoing peripheral blood (PB) alloHCT using PTCy-based GvHD prophylaxis.METHODSBetween 2014 and 2020, 230 consecutive adults with hematological malignancies underwent PB-alloHCT with PTCy-based GvHD prophylaxis at our Institution. Data related to Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), Karnosfky Performance Status (KPS), Disease Risk Index (DRI), European Bone Marrow Transplantation (EBMT) score, and Endothelial Activation and Stress Index (EASIX) were collected retrospectively. Complete information was available for 216 patients. Overall survival (OS) was considered the main outcome variable. Patients were grouped into two risk groups based on the optimal cut-off value for each score. In the case of EASIX, 1.578 was the most discriminating cut-off for OS. The score discrimination for OS was measured independently for each index using the receiver operating characteristic curve (AUC) calculated using receiver operating characteristic (ROC) curves, and determined at different time-points after alloHCT.RESULTSOf the 216 patients included, the median age was 52 years (range: 18-70), acute myeloid leukemia (36.1%) was the most prevalent baseline diagnosis, 42.1% of adults underwent reduced-intensity conditioning alloHCT, 69.4% received grafts from unrelated donors, and 23.0% from haploidentical donors. With a median follow-up of 22.6 months, 24.1% patients relapsed, and 2-y OS and non-relapse mortality were 67.3% and 19.9%.DRI, HCT-CI, KPS, and EASIX successfully grouped patients into higher and lower risk strata, supporting their use for risk classification. HCT-CI [(score>3 (vs 0-3): HR 2.02, p<0.01], DRI [High - Very High risk (vs Low - Int): HR 2.08, p<0.01], and EASIX [>1.578 (vs ≤ 1.578): HR 1.73, p<0.02], maintained an optimal discrimination capacity during the entire post-transplant follow-up (median AUC ranges > 55%).DRI was the most accurate prognostic index during the entire post-transplant period (median AUC ranges > 60%). KPS score was found to be a useful predictor of mortality up to the first year after alloHCT and with the highest prognostic accuracy at 3 months (AUC 67.09%). HCT-CI score was found to present a better discrimination capacity once elapsed 6 months after alloHCT and with a peak of prediction capacity at 2 years (AUC 60.3%). EASIX, when measured at the pre-transplant evaluation, demonstrated to have acceptable predictive ability during the entire post-transplant period (median AUC > 55%), and with a peak of prediction at 3 months (AUC 62.6%). The EBMT score had the lowest predictive capacity in our analysis (Figure 1). CONCLUSIONThis study validates, for the first time, the risk stratification capacity for OS of DRI, HCT-CI, KPS, and EASIX in PB-alloHCT with PCTy-based prophylaxis. Interestingly, the prediction accuracy of the prognostic scores differed depending on the time-period. This result can be taken into consideration to enhance the applicability of these scores and refine the clinical decisions taken based on the information provided from their use in routine clinical practice. [Display omitted] DisclosuresLozano: Terumo BCT: Honoraria, Research Funding; Macopharma: Research Funding; Grifols: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Esteve: Novartis: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.

HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

A Tale of Two Centers: Access to Private Care Improves Outcomes in Allogeneic Transplant Recipients

IntroductionAllogeneic bone marrow transplantation (BMT) is a potentially curative treatment for many hematological diseases. However, lack of availability of specialized centers and high costs limit access to the procedure in low and middle income countries. Previous research has shown that Latin-American patients with hematological malignancies have worse outcomes when treated in public health systems compared to patients treated in the private setting. Healthcare in Mexico is provided by three systems: the private sector (financed by a private insurance or out of pocket), social security (government-run health systems) and a public system (partially funded by the government), where the most vulnerable population is treated. To date, disparities in outcomes of BMT between patients in public and private health systems have not been widely studied.ObjectivesPrimary: to determine the impact of access to private healthcare in BMT recipients by comparing the outcomes of patients treated in two centers that are led by a single team. Secondary objectives were to determine differences in the overall treatment population and transplantation strategies in each context.Patients and MethodsWe performed a retrospective analysis of consecutive patients aged 15 and older who underwent BMT regardless of diagnosis form 2015-2021 in two Institutions: 1) A private hematology practice treating insured patients in conventional BMT units similar to those in high-income countries (Private) and 2) A public academic institution where an outpatient transplant strategy is common in the context of significant limitations in access to quality supportive care and high-cost medications (Public). Both programs are led by the same team of hematologists following similar transplant strategies with the salient features being the frequent use of peripheral blood stem cells, chemotherapy-based conditioning regimens, and the preferred use of haploidentical donors vs. matched unrelated donors. We excluded second transplants from this analysis and patients who received them were censored at the time of infusion. We compared baseline characteristics, overall survival (OS), event free survival (EFS), non-relapse mortality (NRM), and the incidence of GVHD in the two different treatment systems.ResultsA total of 219 patients underwent BMT from January 2015 to June 2021, n=166 (76%) were performed in the Public setting, and n=53 (24%) in the Private setting. Patients in the Private group were older, with a higher proportion of high/very high disease risk index (DRI), hematopoietic cell comorbidity index (HCT-CI) and more frequent use of myeloablative conditioning (Table 1). A similar proportion haploidentical donor grafts were performed (61 vs 57%) with a single matched unrelated donor transplant in the Private center. Median follow-up was 9.7 (0.2-71), and 10.3 (0.7-67.6) months, for Public and Private centers respectively (p=0.38). Median time to neutrophil and platelet engraftment were similar. Seventy patients (42%) in Public, and 15 patients (28%) in Private groups relapsed (p=0.049), with a median time to relapse of 17.5 vs. 47.6 months (p<0.017); there were no significant differences in non-relapse mortality at 2 years (27 vs. 18%) (Fig.1) and primary failure (9% vs 2%). Grade 2-4 aGVHD occurred in 31% patients in the Public setting vs. 19% in Private (p=0.08), without differences in grade 3-4 aGVHD (12% vs 8%). Moderate/severe cGVHD incidence was similar for both groups with (19 vs. 18%). Estimated 2-year EFS was 34% in Public vs. and 54% in Private (Fig. 2), with a median EFS of 8.8 vs 25.7 months (p= 0.024). There were no statistically significant differences in OS (p=0.65), with estimated 2-year OS of 51% for Public and 68% for Privately treated patients, and a median OS of 21.1 months vs. not reached (Fig. 3). When stratified by DRI, patients with Public BMT and a high/very high DRI had a median OS of only 9.7 months vs. not reached for the Private group (Fig. 4). Patients with high/very high DRI in the Private setting had similar outcomes to those with low/intermediate disease in the Public group with the best outcomes achieved by patients with low/intermediate disease treated privately.ConclusionPatients who undergo BMT in the public health system are at risk for significantly worse outcomes when compared to patients cared for in private systems even if a similar strategy is followed and are led by the same team. [Display omitted] DisclosuresGonzález López: AMGEN: Honoraria; JANSSEN: Honoraria. Gomez-Almaguer: Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Gomez-De Leon: ASH: Research Funding; Abbvie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria.