allo-HCT Patients Research Articles

Toxoplasma qPCR kinetics to guide pre-emptive treatment of toxoplasmosis after allogeneic hematopoietic stem cell transplantation.

Recent ECIL-guidelines recommend a quantitative PCR (qPCR) guided pre-emptive treatment approach to toxoplasmosis in seropositive recipients of allogeneic hematopoietic cell transplantation (allo-HCT). While qPCR might serve as a sensitive tool for early Toxoplasma detection, its role in treatment follow-up remains unknown. We analyzed the qPCR kinetics of allo-HCT recipients experiencing either Toxoplasma infection (TI, n=71) or disease (TD, n=14) in relation to different parameters. We included 85 patients with available qPCR values expressed as quantitative cycle (Cq) from four large hematological centers from 2009 to 2023, and kinetic analysis was performed in a selection of 74 patients screened at least weekly with blood qPCR. Day 0 (D0) was the day of anti-Toxoplasma treatment start or (when untreated) day of diagnosis. Time to qPCR negativity was inversely proportional to the Cq value at D0 (p=0.0063). Not reaching negativity at D10 was associated with a significantly higher mortality at D30 (p=0.023). Patients with a high D0-parasitic load and patients with TD showed slower clearance (p<0.001, p=0.032). Time to negativity was not significantly different for patients started on prophylactic vs curative doses as first-line treatment regimen (p=0.16). This study underscores the predictive value of qPCR kinetics monitoring in allo-HCT patients with toxoplasmosis. With the aforementioned risk factors, clinicians can identify patients at high-risk for worse outcome. Our results support to consider a therapeutic change or reinforcement if the parasitic load does not decrease after 10 days, supplementing existing clinical guidelines.

Surrogates of Endothelial Injury Predict Survival After Post-transplant Cyclophosphamide

Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. We evaluate the prognostic ability of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy-based GVHD prophylaxis. Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease, and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 year after alloHCT (34.5% versus 12.3%, P = .003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 to 6.17, P = .005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 to 4.36, P = .034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 to 4.33, P = .005) and high-risk (HR 5.77, 95% CI 2.31 to 14.39, P < .001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

Oral and Gut Microbiome Alterations in Oral Chronic GVHD Disease: Results from Close Assessment and Testing for Chronic GVHD (CATCH Study).

Whether and how the oral microbiome and its changes in allogeneic hematopoietic cell transplantation (alloHCT) recipients may contribute to oral chronic GVHD (cGVHD) pathogenesis is unknown. In addition, although the oral and colonic microbiota are distinct in healthy adults, whether oral microbes may ectopically colonize the gut in alloHCT patients is unknown. To address these knowledge gaps, longitudinal oral and fecal samples were collected prospectively in the multicenter Close Assessment and Testing for Chronic GVHD study (NCT04188912). Through shotgun metagenomic sequencing of the samples collected at baseline, oral cGVHD onset, first post-cGVHD onset visit, and 1-year post-HCT time points in patients with oral cGVHD (cases; N = 29) or without any cGVHD (controls; N = 51), we examined whether (i) oral and/or gut microbiomes and their longitudinal trajectories differ between cases and controls and (ii) oral and gut microbiomes overlap in alloHCT recipients, especially those developing cGVHD. A total of 195 samples were analyzed. The onset of oral cGVHD was characterized by an expansion of Streptococcus salivarius and Veillonella parvula in the oral microbiome. High levels of oral/gut microbiota overlap were observed, particularly in patients with oral cGVHD, suggesting ectopic colonization of the gut by oral bacteria. The unusual coalescence of two distant niches in these patients may result in short- or long-term consequences for the host, a novel avenue for future research. In addition, this study suggests a contribution of the oral microbiome to oral cGVHD pathogenesis.

Impact of cytomegalovirus (CMV) seroconversion pre-allogeneic hematopoietic cell transplantation on posttransplant outcomes.

Cytomegalovirus (CMV) reactivation post-allogeneic hematopoietic cell transplantation (post-alloHCT) increases morbidity and mortality. We sought to determine the frequency of CMV seroconversion in patients pre-alloHCT and to investigate the impact on posttransplant outcomes. We retrospectively investigated 752 adult patients who underwent alloHCT at our center from January 2015 to February 2020 before the adoption of letermovir prophylaxis. CMV serology was assessed at consult and pretransplant. The cohort was divided into four groups based on pretransplant CMV seroconversion: negative to positive (Group 1), positive to negative (Group 2), consistently negative (Group 3), and consistently positive (Group 4). Eighty-nine patients (12%) had seroconverted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently seronegative, and 495 (66%) were consistently seropositive pretransplant. For the four CMV serostatus groups, cumulative incidence of CMV reactivation at 6 months posttransplant was 4.5%, 47.1%, 6.6%, and 76.6% for Groups 1, 2, 3, and 4, respectively (p < .0001). No differences between groups were seen regarding Grade III-IV acute graft-versus-host disease (GVHD) (p = .91), moderate/severe chronic GVHD (p = .41), or graft failure (p = .28). On multivariable analysis, there was no impact of CMV serostatus group on overall survival (p = .67), cumulative incidence of relapse (p = .83) or non-relapse mortality. alloHCT patients who demonstrate CMV seroconversion pretransplant from negative to positive have a very low risk of CMV reactivation posttransplant. The observed seroconversion may be due to passive CMV immunity acquired through blood products. Quantitative CMV immunoglobulin G/immunoglobulin M pretransplant may help differentiate between true seroconversion and passively transmitted CMV immunoglobulin.

The Prevalence of Pretransplant Frailty and Mental Distress in Hematopoietic Cell Transplantation and Association with Clinical Outcomes

Frailty is a phenotype of decreased physiologic reserve associated with increased risk of toxicities and nonrelapse mortality (NRM) in hematopoietic cell transplant (HCT) recipients. The incidence, predictors, and adverse effects of pre-HCT frailty are not well known. We evaluated the association of pre-HCT frailty, defined using Fried's criteria, with age and baseline characteristics in patients ≥18 years undergoing autologous (auto) or allogeneic (allo) HCT for hematological malignancies. Assessments were performed as part of routine pre-HCT evaluations and then retrospectively analyzed. We additionally investigated the association of mental health distress indicators with frailty and the association between frailty and transplant outcomes including NRM and overall survival (OS) plus healthcare utilization. Patients undergoing HCT for hematological malignancies were analyzed (total n = 300; 162 auto, 138 allo). The overall prevalence of frailty was 18%, 21.7% among alloHCT, and 14.8% among autoHCT recipients, with similar distributions of frailty domains. Logistic regression analysis of the overall cohort revealed that older age was associated with an increased risk of frailty (odds ratio [OR] 1.37, 95% confidence interval [CI] [1.02-1.82]; P = 0.04). AlloHCT (OR 2.03, CI [1.07-3.84]; P = .03), and patient health questionnaire-9 (PHQ-9) (health depression) score ≥10 (OR 6.28, CI 1.93-20.43; P < .01) were each independently associated with pre-HCT frailty. In alloHCT patients, older age (OR 1.44, CI [1.00-2.06]; P = .05) was the only significant risk factor for pre-HCT frailty, while for autoHCT patients, only a higher PHQ-9 score was associated with frailty (OR 6.43, CI [1.34-30.82]; P = .02). For the whole cohort OS at 1 year was lower in frail recipients at 83% (95% CI, 70-91%) versus 92% (95% CI, 88-95%) in nonfrail (P = .04); with multivariate analysis showing higher risk of death in the frail group (hazard ratio [HR] 2.31, CI 0.97-5.46; P = .06). In the alloHCT cohort, multivariate analysis showed greater 1-year mortality in frail recipients (HR 2.55, CI [0.99-6.56]; P = .053). In the alloHCT recipients, we observed a 1-year NRM of 20% in frail patients versus 9% in nonfrail, and multivariate analysis showed a marginally higher risk of NRM in the frail group (HR 2.70, CI 0.90-8.10; P = .08). Frailty was not associated with higher risk of relapse in alloHCT or autoHCT recipients. Frail alloHCT patients experienced a longer initial hospital stay following HCT compared to nonfrail recipients (P < .01). We observed a high prevalence of pre-HCT frailty across all age groups, and identify older age is a risk factor for frailty, particularly in alloHCT recipients. Frailty is associated with a greater risk of NRM and lower survival which needs investigation in a larger cohort. Frailty associates with greater HCT complexity suggesting a need for early assessments and targeted interventions for this vulnerable population. Our findings suggest the utility of frailty and mental distress screening along with multidisciplinary interventions in pre-HCT to limit the morbidity of HCT.

Increasing access to transplantation through telemedicine and patient navigation

BackgroundHematopoietic cell transplantation (HCT) is a promising treatment for hematological diseases, yet access barriers like cost and limited transplant centers persist. Telemedicine-based patient navigation (PN) has emerged as a solution. This study presents a cost-free PN telemedicine clinic (TC) in collaboration with the National Marrow Donor Program. Aim: to assess its feasibility and impac on HCT access determined by the cumulative incidence of transplantation. MethodsIn this single-center cohort study, patients of all ages and diagnoses referred for HCT participated. Two transplant physician-navigators established patient relationships via video calls, collecting medical history, offering HCT education and recommending pretransplant tests. The analysis involved descriptive statistics and intent-to-transplant survival assessment. ResultsOne hundred and three patients were included of whom n = 78 were referred for allogeneic HCT (alloHCT), with a median age of 28 years. The median time from initial contact to the first consult was 5 days. The cumulative incidence of transplantation was 50% at 6 months and 61% at 12 months, with varying outcomes based on HCT type. Notably, 49 patients were not transplanted, primarily due to refractory disease, progression or relapse (57.1%). Autologous HCT candidates and physician referrals were correlated with higher transplant success compared to alloHCT candidates and patients who were not referred by a physician. ConclusionOur pretransplant TC was feasible, facilitating access to HCT. Disease relapse posed a significant barrier. Enhancing timely physician referrals should be a focus for future efforts.

Letermovir Primary Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: Real-Life Data from a University Hospital in Argentina.

Cytomegalovirus (CMV) infection remains the most common clinically significant infection after allogeneic hematopoietic stem cell transplantation (allo-HCT) and is associated with considerable morbidity and mortality. The present study was designed to describe and compare the incidence of untreated CMV reactivation (uCMVr), clinically significant infection (cs-CMVi) and disease (CMVd), as well as CMV-related hospitalization and outcome of allo-HCT patients, either treated with letermovir (LET) primary prophylaxis or managed with preemptive therapy (PET). This is a prospective observational cohort study of adult CMV seropositive allo-HCT patients who either received primary prophylaxis with LET within the first 100 days after HCT or were managed with PET. The study population comprised 105 patients (28 in the LET group and 77 in the PET group). Compared to the PET group, patients in the LET group received more allo-HCT from alternative donors (54.5% vs. 82.14%, P=0.012). More than half of the patients in both groups were classified as high risk for CMVd. In the LET vs. PET group, cs-CMVi and CMVd developed respectively in 0 vs. 50 (64.94%), P=<0.0001, and 0 vs. 6 (7.79%), P=0.18. In the LET group, uCMVr occurred in 5 (17.8%) and were all considered blips. Hospital admissions related to cs-CMVi or CMVd in the PET group vs. LET group were 47 (61.04%) vs. 0, respectively, P=<0.0001. No differences were observed in 100-day mortality. LET primary prophylaxis proved effective in preventing cs-CMVi and CMVd and reducing hospitalizations in allo-HCT adults. Blips can occur during prophylaxis and do not require LET discontinuation.

Abstract 2794: Consumption of dietary fiber correlates with a significant increase in a-diversity in the intestinal Microbiome of allo-HCT recipients and with lower GVHD-lethality in pre-clinical models

Abstract Background: Graft-versus-host disease (GVHD) is associated with a decrease in intestinal microbiota and beneficial short-chain fatty acids (SCFAs). Dietary fiber can modulate the intestinal microbiome and SCFA production which effect intestinal epithelium health and immunity. Therefore, we hypothesized that a high-fiber diet in recipients of an allogeneic hematopoietic cell transplantation (allo-HCT) could result in an increase of beneficial commensals, concentrations of SCFAs, and decreased risk of GVHD. Methods: We evaluated dietary data and fecal samples of allo-HCT patients receiving unmodified grafts (n=95) at MSKCC (day -10 to day +30 relative to allo-HCT) and correlated microbial α-diversity (16s rRNA, n=568 samples) with fiber intake and acute GVHD in No-GVHD (n=30), Non-LGI-GVHD (GVHD except lower gastrointestinal tract, n=41), and LGI-GVHD patients (lower gastrointestinal tract GVHD, n=24).We tested concentrations of cellulose fiber (0%, 6%, 12% and 40%) in a GVHD mouse model (C57BL/6J into BALB/c) to assess survival, microbial composition (shotgun sequencing n=180; n=30 per group), cecal SCFAs concentrations (GC-MS n=24, n=8 per group), and lastly, T cell subsets (Th1/Th17/Tregs) and colonic epithelial MHC-II expression (flow cytometry n=54, n=18 per group). Results: In allo-HCT patients, fiber intake correlated positively with microbial α-diversity (R=0.3, p=0.04), especially in the LGI-GVHD group (p=0.007). Additionally, patients with high fiber intake had higher microbial α-diversity compared to the low fiber cohort (p&amp;lt;0.0001).GVHD mice receiving a fiber-rich diet (12%), compared to 0% and 6%, had a higher microbial α-diversity (p=0.01); reduced GVHD lethality (p=0.02); and a decrease in the Enterococcus sp. (p=0.004) and Akkermansia sp. (p=0.01) abundance; taxa which are associated with worse overall survival and increased risk of lethal GVHD. In contrast, compared to 12%, the 40% fiber diet resulted in worse survival (p=0.002), lower α-diversity (p=0.05) and a higher abundance of Bifidobacterium sp. (p&amp;lt;0.0001).Cecal butyrate in GVHD mice was higher in response to the 12% vs. the 0% (p=0.01) and 6% (p=0.05) fiber diets. Mice treated with12% fiber displayed higher number of Tregs (CD4+CD25+FOXP3+), than those with 0% (p=0.001) and 6% (p=0.02); and a lower expression of MHC-II in epithelial cells (EpCAM+CD45-) vs. 0% fiber (p=0.02). Conclusions: We demonstrated that a higher fiber intake in allo-HCT patients is associated with an increase in α-diversity; especially in LGI-GVHD patients. In a pre-clinical GVHD-model, optimal fiber consumption (12% cellulose) leads to an increase in α-diversity, a decrease in pathogen relative abundance, increased T-regulatory cells, and a decrease in GVHD lethality. These results suggest that dietary fiber could be utilized to prevent GVHD. Citation Format: Jenny Paredes, Anqi Dai, Ruben J. Faustino Ramos, Peter Adintori, Teng Fei, Chi Nguyen, Harold Elias, Kristen Victor, Romina Ghale, Charlotte Pohl, Ana Gradissimo, Justin Cross, Oriana Miltiadous, Jonathan Peled, Marina Burgos da Silva, Marcel RM van den Brink. Consumption of dietary fiber correlates with a significant increase in a-diversity in the intestinal Microbiome of allo-HCT recipients and with lower GVHD-lethality in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2794.

Nephrons and non-relapse mortality: simplified comorbidity index and acute kidney injury are associated with NRM in adults undergoing allogeneic hematopoietic cell transplant.

The Simplified Comorbidity Index (SCI) is a recently published 5-component, pre-transplant tool to predict non-relapse mortality (NRM) in allogeneic hematopoietic cell transplantation (alloHCT) patients. The SCI captures chronic kidney disease (CKD) using estimated glomerular filtration rate (eGFR) based on the CKD-EPI equation (KDIGO 2021 CKD-EPI), which may be more sensitive to predict risk of NRM than the creatinine cut-off in the 16-component, Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI). We retrospectively assessed the ability of the SCI to risk-stratify patients and the impact of acute kidney injury (AKI) to NRM in adults who underwent alloHCT at the University of Minnesota. We included 373 patients who underwent their first alloHCT between 2015 and 2019. Through multivariate analysis, we found that patients with an SCI of greater than 4 had a higher risk of NRM. Additionally, we noted that AKIs stages 2-3 prior to day +100 was independently associated with a 3-fold greater NRM than patients who did not experience clinically significant AKI.

Temporal trends in critical care utilization and outcomes in allogeneic hematopoietic stem cell transplant recipients.

Historically, the prognosis of allogeneic hematopoietic stem cell transplant (allo-HCT) recipients who require intensive care unit (ICU) admission has been poor. We aimed to describe the epidemiological trends of ICU utilization and outcomes in allo-HCT patients. We conducted a retrospective cohort study including adults (≥ 18) undergoing allo-HCT between 01/01/2005 and 31/12/2020 at Mayo Clinic, Rochester. Temporal trends in outcomes were assessed by robust linear regression modelling. Risk factors for hospital mortality were chosen a priori and assessed with multivariable logistic regression modelling. Of 1,249 subjects, there were 486 ICU admissions among 287 individuals. Although older patients underwent allo-HCT (1.64 [95% CI: 1.11 to 2.45] years per year; P = 0.025), there was no change in ICU utilization over time (P = 0.91). The ICU and hospital mortality rates were 19.2% (55/287) and 28.2% (81/287), respectively. There was a decline in ICU mortality (-0.38% [95% CI: -0.70 to -0.06%] per year; P = 0.035). The 1-year post-HCT mortality for those requiring ICU admission was 56.1% (161/287), with no significant difference over time, versus 15.8% (141/891, 71 missing) among those who did not. The frequency and duration of invasive mechanical ventilation (IMV) declined. In multivariable analyses, higher serum lactate, higher sequential organ failure assessment (SOFA) scores, acute respiratory distress (ARDS), and need for IMV were associated with greater odds of hospital mortality. Over time, rates of ICU utilization have remained stable, despite increasing patient age. Several trends suggest improvement in outcomes, notably lower ICU mortality and frequency of IMV. However, long-term survival remains unchanged. Further work is needed to improve long-term outcomes in this population.

P06 The effect of ciprofloxacin prophylaxis during haematopoietic cell transplantation on infection episodes, exposure to treatment antimicrobials and antimicrobial resistance: a single-centre retrospective cohort study

Abstract Background Fluroquinolone prophylaxis during haematopoietic cell transplantation (HCT) remains contentious. Objectives To determine the effectiveness of ciprofloxacin prophylaxis across different HCT indications and its association with exposure to treatment antimicrobials and antimicrobial resistance. Methods All admission episodes for HCT (N=400) in a tertiary centre between January 2020 and December 2022 were studied. Allogeneic haematopoietic cell transplantation (allo-HCT) recipients received prophylaxis with ciprofloxacin during chemotherapy-induced neutropenia, while autologous haematopoietic cell transplantation (auto-HCT) recipients did not. Results Allo-HCT was performed for 43.3% (173/400) of patients, auto-HCT for 56.7% (227/400). Allo-HCT was associated with an average of 1.01 fewer infection episodes per 100 admission days (95% CI 0.62–1.40, P&amp;lt;0.001) compared with auto-HCT. In allo-HCT, the total exposure to all antimicrobials was higher (+24.8 days of therapy [DOT]/100 admission days, P&amp;lt;0.001), as was exposure to ciprofloxacin (+40.5 DOT/100 admission days, P&amp;lt;0.001). In contrast, exposure to meropenem (−4.5 DOT/100 admission days, P=0.02), piperacillin/tazobactam (−5.2 DOT/100 admission days, P&amp;lt;0.001), aminoglycosides (−4.5 DOT/100 admission days, P&amp;lt;0.001), glycopeptides (−6.4 DOT/100 admission days, P&amp;lt;0.001), was reduced. Enterobacteriaceae isolated during allo-HCT were more resistant to ciprofloxacin (65.5%, 19/29 versus 6.1%, 2/33, P&amp;lt;0.001), ceftriaxone (65.5%, 19/29 versus 9.1%, 3/33, P&amp;lt;0.001), and other antimicrobial classes. Vancomycin-resistant enterococci were more common in allo-HCT recipients (11%, 19/173 versus 0.9%, 2/227, P&amp;lt;0.001). Inpatient mortality during allo- and auto-HCT was 9.8% (17/173) and 0.4% (1/227) respectively (P&amp;lt;0.001). An invasive bacterial infection was documented in 31.3% (125/400) of cases. Allo-HCT patients were more likely to have an invasive Gram-positive bacterial infection (23.1% versus 12.8%, P=0.01), while a difference was not observed for invasive Gram-negative bacterial infections (19.7% versus 18.5%, P=0.77). Among auto-HSCT recipients, patients with germ cell tumours had the highest probability (P for trend 0.03) of recording an invasive bacterial infection (12/23, 52.2%, 95% CI 31.3–74) compared with other indication for auto-HCT. Conclusions Ciprofloxacin prophylaxis in allo-HCT was associated with fewer infection episodes and reduced exposure to treatment antimicrobials. Mortality in auto-HCT remained low. A significant burden of antimicrobial resistance was detected in allo-HCT recipients. HCT recipients due to germ cell tumours, not receiving ciprofloxacin prophylaxis, recorded the highest incidence of invasive bacterial infections and represent a possible target group for this intervention.

Evaluation of prolonged magnesium infusion after allogeneic hematopoietic cell transplant.

Calcineurin inhibitor use after allogeneic hematopoietic cell transplantation (allo-HCT) is associated with significant magnesium wasting. Utilization of a prolonged magnesium infusion is thought to lead to a lower serum peak concentration and therefore, decreased renal wasting of magnesium. In November 2017, our institution implemented a modification to our inpatient electrolyte replacement protocol for allo-HCT recipients that extended the magnesium infusion rate from 4g/2h to 4g/4h based on this theoretical advantage. The primary objective of this study was to compare the median magnesium requirements per day of admission between patients who received magnesium 4g/2h to patients who received magnesium 4g/4h. Secondary objectives included a comparison of the per-patient median serum magnesium concentration during admission, as well as the median incremental difference in serum magnesium concentration after intravenous replacement per patient per admission. Allo-HCT recipients who received prolonged infusion magnesium infusions were compared to a historical cohort of allo-HCT patients who received shorter IV magnesium infusions. Admissions were included if the patient had received an allo-HCT within 100days prior, was admitted to the Transplant and Cellular Therapy Unit at WVU Medicine J.W. Ruby Memorial Hospital, and received at least one magnesium infusion and one dose of cyclosporine or tacrolimus. Admissions were excluded if the patient received oral magnesium, total parenteral nutrition, aminoglycosides, amphotericin, carboplatin, cisplatin, or foscarnet. The pre-implementation group consisted of 81 admissions (n = 64 patients), while the post-implementation group consisted of 90 admissions (n = 60 patients). Median magnesium requirements per day of admission were not different between groups at 1.4g of magnesium in the pre-implementation group and 1.9g of magnesium in the post-implementation group (P = 0.25). Median serum magnesium concentrations and median incremental difference in serum magnesium concentration after intravenous replacement were also not different between groups: 1.65mg/dL vs 1.60mg/dL (P = 0.65) and 0.30mg/dL vs 0.28mg/dL (P = 0.67), respectively. Prolonged infusion of magnesium in allo-HCT recipients receiving CNI therapy does not result in improvement in magnesium retention.

Out-of-Pocket Costs and Financial Hardship Among Participants of the BMT CTN 1102 Study

Introduction The Blood and Marrow Transplant Clinical Trials Network 1102 study (BMT CTN 1102, NCT02016781) was a multicenter, biologic assignment trial, where patients aged 50-75 with intermediate-2 or high risk de novo myelodysplastic syndrome (MDS) were assigned to reduced-intensity allogeneic hematopoietic cell transplantation (alloHCT) or best supportive care (non-alloHCT) based on donor availability. A parallel economic evaluation was performed alongside BMT CTN 1102. Here, we report on the financial impact of the treatment protocol on patients using a prospective cost diary study conducted within the trial. Methods BMT CTN 1102 enrollees were offered the option to participate in the parallel cost diary study at the same time of primary study enrollment. The cost diary survey instrument, comprised of 19 questions, covered the domains of out-of-pocket (OOP) costs of healthcare and financial hardship indicators. Surveys were distributed at 1- (1M), 7- (7M), and 19-months (19M) after enrollment. Study participants were grouped by actual treatment received, rather than group assignment. Responses were analyzed using univariate Fisher's exact and Wilcoxon rank sum tests for association. Results Out of 216 enrollee invitations, 138 patients (64%) returned at least one survey. Total completed surveys at the 1M, 7M, and 19M timepoints were 103 (39%), 93 (35%), and 71 (27%), respectively. 50 (36%) completed only one survey, while 41 (39%) completed surveys at all three timepoints. Of all respondents, median age was 67.7 years (IQR: 64.8-70.3), 88 (64%) were male, 128 (93%) white, and 126 (91%) were non-Hispanic. Among respondents of the 1M, 7M and 19M surveys, 82 (80%), 78 (84%), 65 (92%) received alloHCT, respectively. Mean OOP costs by category are presented in Table 1. While alloHCT patients experienced higher OOP costs compared to non-alloHCT patients across all categories (outpatient services, prescription medications, and accommodations for healthcare), none of the comparisons were statistically significant. However, total OOP costs were significantly higher among alloHCT patients at 1 and 7 months (mean over past 30 days, 1M: $889 vs. $217, p=0.046; 7M: $678 vs. $349, p=0.03; 19M: $328 vs. $103, p=0.15). Financial hardship indicators are presented in Table 2. While alloHCT patients experienced greater financial hardship compared to non-alloHCT patients across all categories (mobilized reserve funds, borrowed money to pay for care, developed debt due to care), none of the comparisons were statistically significant. However, alloHCT patients were significantly more likely to experience at least one of these factors of financial hardship at 7 months (1M: 38% vs. 19%, p=0.13; 7M: 42% vs. 13%; p=0.04; 19M: 37% vs. 0%, p=0.08). Discussion Patients with MDS who received alloHCT incurred substantially more OOP costs overall compared to patients who did not receive alloHCT, most notably for accommodations related to alloHCT. Similarly, alloHCT patients were more likely to develop financial hardship, including mobilizing reserve funds, borrowing money, and developing debt. These findings demonstrate that treatment-related OOP expenditures associated with alloHCT are substantial and may pose significant burdens for some populations receiving alloHCT. Financial navigation and assistance, which have been shown to help patients address cost burden in solid tumor settings, should be considered for MDS patients prior to alloHCT. Small final sample sizes limited our analyses significantly; further research into OOP costs and financial hardship among larger cohorts of alloHCT patients are necessary to confirm these findings. Acknowledgement Support for this study was provided by grants #U10HL069294 and #U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Preliminary Safety Results of the Open-Label Phase of a 2-Part Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of an Investigational Microbiome Therapeutic, SER-155, in Adults Undergoing Hematopoietic Cell Transplantation

Background: In patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), low gastrointestinal (GI) microbial diversity is associated with risk of bloodstream infections (BSIs), acute graft-versus-host disease (aGvHD), and death. SER-155 is an investigational cultivated microbiome therapeutic rationally designed to improve clinical outcomes in allo-HCT patients by preventing pathogen domination, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a 2-part, Phase 1b study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SER-155 in adults undergoing allo-HCT. Here, we present preliminary safety and tolerability data from the open-label Cohort 1 through Day 100 post HCT. Study Design and Methods: Adult recipients of allo-HCT were eligible for screening. Patients were excluded if they: a) were planned for umbilical cord blood or ex vivo T-cell depletion, b) had received a fecal microbiota transplant or any live biotherapeutic product within 3 months prior to screening, and/or c) had evidence of relapse or progression of hematologic malignancy (minimal residual disease was allowed). HCT conditioning and aGvHD prophylaxis were per investigator discretion. Following screening, patients received two treatment courses (before conditioning and after neutrophil engraftment) comprised of microbiome conditioning with 4 days of oral vancomycin (to facilitate engraftment of SER-155 strains) followed by 10 days of oral SER-155 (see study design schematic, Figure 1). The primary endpoint was the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), designated as invasive infection, BSI, and GI infection. Results: Fifteen adult patients were enrolled and 13 received study drug (safety population). Of these 13 patients, the median age was 67.0, all were White, and 54% were male. Underlying diseases included acute myeloid leukemia (6 patients [46.2%]); myelodysplastic syndromes and myeloproliferative neoplasms (2 patients each [15.4%]; and acute lymphoblastic leukemia, chronic myeloid leukemia, and classic Hodgkin's lymphoma (1 patient each [7.7%]). Ten patients (76.9%) received peripheral blood stem cells; 9 (69.2%) had an unrelated donor, 8 (61.5%) underwent a reduced-intensity conditioning regimen, and 3 (23.1%) received myeloablative conditioning. Eleven patients received allo-HCT, all patients had neutrophil engraftment within the expected timeframe and 10 had 100-day follow-up data available. Nine of these patients (81.8%) received tacrolimus/methotrexate-based GvHD prophylaxis. SER-155 was generally well-tolerated ( Table 1). Treatment-emergent AEs (TEAEs) were observed in all patients as is expected in this patient population. One TEAE considered unrelated to study drug, resulted in study discontinuation. Most AEs were gastrointestinal in nature with diarrhea being the most common AE. No SAEs were considered related to SER 155, and most SAEs and AESIs occurred after HCT and before starting the second course of SER-155. No deaths occurred prior to Day 100. Three deaths occurred after Day 100, all deemed to be unrelated to study drug by the investigators. No BSIs attributable to organisms in SER-155 occurred. Commencement of the double-blind, randomized, placebo-controlled Cohort 2 (n=60) was initiated following approval of the Data Safety Monitoring Committee. Conclusions: In patients enrolled in this open-label Cohort 1 of this Phase 1b study, SER-155 was well-tolerated through Day 100. Although sample size is limited, the observed safety and tolerability profile of SER-155 in this patient population is consistent with multiple preclinical assessments supporting the safety of SER-155 for therapeutic use. Enrollment in the double-blind, randomized, placebo-controlled second cohort to assess safety, efficacy, and changes in microbiome composition and function is ongoing.

Graft-Versus-Host Disease after Anti-CD19 Chimeric Antigen Receptor T-Cell Infusion Post Allogeneic Hematopoietic Cell Transplantation: A Transplant Complications and Paediatric Disease Working Parties EBMT Joint Study

Background Anti-CD19 chimeric antigen receptor T-cells (CART) have been incorporated into the therapeutic landscape of B-acute lymphoblastic leukemia (B-ALL) and B-non-Hodgkin's lymphoma (B-NHL). The manufacturing process of commercially available autologous CART in patients relapsing after allogeneic hematopoietic cell transplant (allo-HCT) might include T-cells of donor origin. In this setting, there is limited data on graft-versus-host disease (GvHD) as an off-target effect in patients treated with CART after allo-HCT. We hereby report on a large, retrospective, EBMT registry-based study on GvHD in patients treated with CART therapy after allo-HCT. Methods Inclusion criteria were B-ALL and B-NHL adult and pediatric allo-HCT patients, treated with a first anti-CD19 CART (axicabtagene ciloleucel [axi-cel] and tisagenlecleucel [tisa-cel]) from 2018 to August 2022. The primary study endpoints were the cumulative incidences (CI) of new acute GvHD (aGvHD) and chronic GvHD (cGvHD). Secondary endpoints were the 1-year GvHD relapse-free survival (GRFS), non-relapse mortality (NRM), and overall survival (OS). Overall data was analyzed in a descriptive manner. Results A total of 257 allo-HCT patients treated with anti-CD19 CART were included. One hundred seventy-two patients (66.9%) were ≥18 years old. Tisa-cel was the therapy of choice in 184 patients (71.6%), whereas axi-cel was used in 73 patients (28.4%). More than half of the cohort (57.6%) underwent allo-HCT from unrelated donors. Notably, 109 patients (46.6%) and 38 patients (15%) had previously develop aGvHD and cGvHD between allo-HCT and CART infusion. Table 1 describes data on baseline patient, allo-HCT and CART characteristics of the whole cohort and of patients developing aGvHD and cGvHD. In total, 3 patients developed new aGvHD and 6 patients developed new cGvHD after CART therapy. The 100-day CI of new aGvHD was 1.6% (95% CI, 0.4-4.2) and the 12-month CI of new cGvHD was 2.8% (95% CI, 1.1-5.7). No GvHD was observed in the pediatric cohort. The median time from allo-HCT to CART infusion was 15.8 months (range, 3.8-220.3) and the median times from CART to the development of aGvHD and cGvHD were respectively 44 days (range, 8-81) and 144 days (range, 5-182). The 1-year GRFS and NRM were 52.1% (95% CI 45.6-59.4) and 4.7% (95% CI 2.5-8.1) respectively (Figure 1). With a median follow up of 18.8 months (95% CI, 16.2-23.7), the 1-year OS was 76.8% (95% CI 71.5-82.4). The most frequent cause of death was disease-related in 56 patients (74.6%). Conclusion Together, in this large cohort including adult and pediatric allo-HCT patients treated with tisa-cel and axi-cel after allo-HCT, these data show that the incidence of both aGvHD and cGvHD is very low. Of note, GvHD was not observed in the pediatric cohort. Furthermore, no excessive NRM was observed compared to previously published methods of treating relapse post allo-HCT, being disease progression a major hurdle to optimal outcomes in this cohort of patients.

Caregiver Perspectives on Housing, Finances and Employment Post-Allogeneic Hematopoietic Cell Transplant

Background: Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for individuals diagnosed with blood cancers and disorders. Most transplant centers (TCs) require a caregiver for 24 hours per day, seven days per week, for at least 100 days post-alloHCT. However, there is limited knowledge of the evidence behind this requirement. Additionally, these requirements can have implications for caregivers in multiple aspects of their lives. This study aimed to learn more about alloHCT caregiver experiences in the first 100 days post-alloHCT to explore the impact of caregiver requirements. Methods: Web-based interviews were conducted from May 2022-February 2023 with a convenience sample of adult caregivers of adult alloHCT patients in the United States (US). Caregivers' patients were 100 days to 1-year post-alloHCT, with no relapse. Interviews were recorded and transcribed; thematic analysis was conducted by two independent reviewers. These results focus on the themes of housing, finances and employment, which arose during the interviews. Results: Sixteen caregivers participated, and included spouses (n=12, 75%), parents (n=3, 19%), and a fiancé (n=1, 6%). They generally cared for patients who received an unrelated alloHCT (n=14, 87.5%), and there was representation from all regions in the US.. The median distance from the caregiver's home to the TC was 55 miles (range: 3 to 2000 miles). Caregivers who needed to relocate described staying with family, in hotels, transplant housing, or renting an apartment. Caregivers also described the stressor of having to figure out where to stay, with a tight timeline and requirements for cleanliness and distance to the TC, as well as the difficulty of relocating to a new city without knowing anyone, the area or traffic patterns, and described the need for affordable options. Those with access to housing with other alloHCT caregivers/patients found support from others going through similar experiences. Of the caregivers who did not need to relocate, one noted the convenience of family living nearby; and another described household emergencies that resulted in financial and logistical challenges. Financial challenges mentioned by caregivers included medication, transportation, unexpected expenses, the importance of navigating finances, and the experience of not making enough money to meet their needs, while making too much money to qualify for financial assistance. Some also learned about financial assistance when it was too late or when it would have been helpful earlier and were not sure how they were expected to find these opportunities. Those who received financial assistance, regardless of the amount, were very grateful and noted it made a difference in their experience. Though caregivers shared their financial challenges, many noted they felt “lucky” or “privileged,” recognizing that if circumstances had been different, they, or others in less fortunate financial circumstances, may have had more difficulties. Caregivers were variably employed and included those who were retired, employed, self-employed, and not employed. Those who were employed mentioned the importance of the Family Medical Leave Act (FMLA), but also described the need to work to maintain income and health insurance. Employed caregivers also shared they were able to work effectively and provide care, despite some being told by their TC that they could not. The majority of those employed credited their ability to work to their employers' support and flexibility. Conclusions: This study interviewed adult caregivers of adults receiving alloHCT in the US to understand the caregiver experience and to explore the impact of caregiver requirements. The current caregiver requirement of most TCs can be a barrier not only to patients, but to caregivers. In this study, caregivers shared their housing, financial, and employment experiences. Knowledge of these experiences can help inform interventions to help support caregivers, and inform strategies to transform the caregiver requirement to allow for individual situations. Further information is needed on barriers faced by individuals unable to access alloHCT and patients who may not have had a caregiver. Results from this study will facilitate the development of programs to help improve patient and caregiver experiences.

ST2/ Rorγt-Dependent Th1/Th2-like CD4 + Trm Cells Mediate Cutaneous Chronic Gvhd

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for relapsed hematological malignances, but the same alloreactive T cells that eliminate malignant cells in the recipient also mediate graft-versus-host disease (GVHD), and in long-term Allo-HCT patients chronic GVHD (cGVHD) remains the major cause of morbidity and mortality. Th subsets (i.e., Th1, Th2, and Th17) have been associated with cGVHD in certain tissues, but the Th subsets involved in cutaneous cGVHD remain undefined. In the current studies, with a murine model of C57BL/6 donor to MHC-matched C3H.SW recipient, we observed that although IFN-γ + Th1 cells were dominant in the gut, liver, and skin during early acute GVHD, the skin showed a marked expansion of IFN-γ +IL-13 + Th1/Th2-like cells 30 days after HCT at the onset of cGVHD, while IFN-γ +IL-13 - Th1 cells remained dominant in the liver and intestines. The cutaneous Th1/Th2-like cells exhibited characteristics of Ly108 -CD69 + tissue resident memory T (Trm) cells. The expansion of cutaneous Th1/Th2-like cells was RORγt and ST2-dependent because T cells from RORγt -/- or ST2 -/- C57BL/6 donors did not show expansion of the cutaneous Th1/Th2-like cells or induce cutaneous cGVHD. These results indicate that 1) IFN-γ +/IL-13 + Th1/Th2-like CD4 + Trm cells likely play a critical role in the pathogenesis of cutaneous cGVHD; 2) the differentiation of IFN-γ +CD4 + Th1 cells into IFN-γ +IL-13 + Th1/Th2-like cells is RORγt and ST2-dependent. The molecular mechanisms that underpin this differentiation pathway are under investigation.

“Transplant Changes Your Life”: Communication Strategies of Transplant Hematologists in High Risk Decision Making Conversations

Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) offers a chance of cure for many patients with blood cancers including higher risk myelodysplastic syndromes (MDS) but carries many risks. In this high risk, high reward situation, shared decision making is essential to empower patients to make goal-concordant decisions. We detail communication strategies hematologists use to discuss treatment options including alloHCT and to facilitate shared decision making with patients. Methods: Our research team recruited hematologists who routinely perform alloHCT in the United States through email. Participants conducted a video-recorded virtual encounter lasting up to one hour with an actor portraying a 67-year-old man with recently diagnosed high risk MDS referred for specialty hematology consultation to discuss treatment options including alloHCT. We transcribed and qualitatively analyzed hematologists' communication approaches. Results: Participants (n=37) from 25 institutions were a median age of 44 years (range 33-73 years) and mostly male (65%) and white (65%). More than half spent &amp;gt;50% of their clinical time in managing alloHCT patients. Hematologists followed a similar conversation structure, though varied in the amount of detail they provided within each of the main sections (Figure 1). Their conversation routinely included an assessment of the patient's perception of his condition, information about MDS, and discussion of treatment options including transplant and chemotherapy and less commonly supportive care or a clinical trial. Many repeatedly highlighted that transplant was the only option with the potential for cure. Their discussion about transplant frequently followed a chronological approach from pretransplant considerations including donor issues, formal fitness testing, and disease control; to the peri-transplant period and hospital experience; and through the posttransplant course including need for dedicated caregiver support. Hematologists discussed risks, complications, and major outcomes at varying lengths. Decision making talk occurred at different points in the visit though was often concentrated in the latter part of the conversation. Hematologists referred to several elements that formed the basis of treatment decision making (Figure 2). While hematologists indicated that multiple factors should inform the patient's and hematologist's decision making, many honed in on transplant's position as the only chance for long-term survival. Although most hematologists acknowledged on a general level the importance of patients' goals and preferences in decision making, they elicited and incorporated the individual patient's specific goals into the discussion to varying degrees. Instead, in several conversations, hematologists' assessment of the patient's fitness and candidacy for transplant was prominent in their discussion about whether the patient could and should consider pursuing the curative option. Hematologists frequently recommended that the patient take time to think and talk with his family about the treatment decision in the immediate future. The strength of their longer-term recommendations ranged from strong recommendations for transplant or chemotherapy to conditional recommendations for transplant or deferral pending further information. These recommendations reflected a range of decision-making strategies, from a physician-led approach to a primarily patient-guided effort. In the middle, some hematologists described a collaborative effort with the patient, in which the patient and hematologist would work together to reach a shared decision. Within a single encounter, many hematologists expressed various statements suggesting that their approach to decision making did not fit tightly within a single domain but rather fell along a continuum which evolved as the encounter proceeded. Conclusions: The transplant decision making discussion is complex. The ways in which hematologists frame information and engage patients affect how they make decisions together. Hematologists consistently discuss similar major content areas as they navigate from beginning to end; identification of these key components can be used as the basis for creation of a communication tool to help hematologists discuss alloHCT with patients.

A Multicentre, Randomized, Double-Blinded, Phase 2b Study Evaluating the Efficacy and Safety of MaaT033, an Oral, Pooled Microbiome Ecosystem Therapy in Patients Undergoing Allogenic Hematopoietic Cell Transplantation to Improve Overall Survival: The Phoebus Trial

Background and significance: Allogenic hematopoietic cell transplantation (alloHCT) is a well-established therapy for various life-threatening hematologic malignancies. The use of alloHCT is constantly increasing, with nearly 20 000 transplantations reported to the European Society for Blood and Marrow Transplantation (EBMT) per year. However, this treatment is limited by high morbidity and mortality, mainly related to relapse, infection, graft-versus-host disease (GvHD), and conditioning-related toxicity. Several pioneering studies have shown that the diversity of the gut microbiota of patients not only correlates with the occurrence of medical complications after alloHCT, including GvHD (Jenq et al. 2012, Stein-Thoeringer et al. 2019) and bloodstream infections (Taur et al. 2012), but also with relapse of the underlying disease (Peled et al. 2017). Gut microbiota diversity restoration with fecal microbiotherapy could be an effective treatment to improve patients' clinical outcomes including overall survival (OS) after alloHCT, through the prevention and resolution of gut microbiota dysbiosis. MaaT033 is a freeze-dried, full-ecosystem, high-diversity, fecal microbiota medicinal product, formulated as delayed-release capsules and derived from pooled allogenic human fecal material. The PHOEBUS trial is a phase 2b study to evaluate the efficacy of MaaT033 in improving survival of adult alloHCT patients (Clinicaltrials.gov identifier: NCT05762211) Study design and Methods: 387 subjects aged ≥ 50 years with hematologic malignancies for which an alloHCT is indicated will be randomized 1:1 to receive either MaaT033 (experimental arm) or placebo (control arm) before initiation of the conditioning regimen and after hematopoietic recovery following alloHCT. Stratification of patients will be performed based on disease risk index (low-intermediate versus high-very high) and donor-host compatibility (HLA-identical versus HLA-mismatch). Inclusion criteria include age ≥ 50 years, alloHCT with a reduced-toxicity or reduced-intensity conditioning regimen, neutrophils &amp;gt; 0.5 G/L, and administration of broad-spectrum antibiotics within the last 90 days prior to inclusion. Exclusion criteria comprise non-myeloablative conditioning regimen, conventional myeloablative conditioning regimen, in-vitro T-cell depletion, alloHCT with cord blood cells, alloHCT from an unrelated donor with ≥ 3/10 HLA-mismatches, use of alemtuzumab, vedolizumab or abatacept for GvHD prophylaxis, history of chronic digestive disease. The primary endpoint is to evaluate OS at 12 months after randomization. Secondary endpoints will include evaluation of the safety of MaaT033, GvHD-free survival, cumulative incidence of acute GvHD and chronic GvHD, non-relapse mortality, relapse-free survival, GvHD-free, relapse-free survival, the proportion of patients with severe infections, gut microbiota composition, and quality of life. Exploratory endpoints will describe the impact of MaaT013 on immune recovery, the nutritional status of the patients, and resource utilization. Patients will receive MaaT033 or placebo (3 capsules per day) for 1 week before the start of the conditioning regimen. Experimental treatment (3 capsules per day) will be resumed at neutrophil recovery and pursued up to 90 days after alloHCT. Patients will be followed monthly up to 6 months post alloHCT and then every 3 months up to 12 months. The study is approved in France and Germany; expansion to other countries is planned for 2024. Study start is expected in September 2023.

Characterization of the calcineurin inhibitor pain syndrome in patients undergoing allogeneic hematopoietic cell transplantation

Calcineurin inhibitor pain syndrome (CIPS) is a rare complication of graft-vs-host disease prophylaxis following allogeneic hematopoietic cell transplant (alloHCT). CIPS presents as severe bilateral lower extremity pain, and the incidence, risk factors, and management of CIPS are poorly characterized. This is a single center retrospective study of patients who received tacrolimus (TAC) following alloHCT to describe the characteristics and management of CIPS and compare to a cohort who did not develop CIPS. Fifteen of 585 alloHCT patients (2.6%) developed CIPS at a median of 5 days following TAC initiation and a median level of 10.5 ng/mL. Severe bilateral foot, ankle, or leg pain were the primary symptoms. Patients with CIPS were younger and more frequently received myeloablative conditioning and total body irradiation compared to patients without CIPS. Analgesic regimens included dihydropyridine calcium channel blockers, gabapentinoids, topical diclofenac, and opioids. Clinicians should be aware of this uncommon but severe adverse effect.