Amphiregulin, ST2,and REG3α Biomarker Risk Algorithms as Predictors of Non-Relapse Mortality in Patients with Acute GVHD.

Graft-vs-host disease (GVHD) is a major cause of non-relapse mortality (NRM) following allogeneic hematopoietic cell transplant (HCT). Algorithms containing either the GI GVHD biomarker amphiregulin (AREG) or a combination of two GI GVHD biomarkers, (ST2+REG3α) when measured at GVHD diagnosis are validated predictors of NRM risk, but have never been assessed in the same patients using identical statistical methods. We measured serum concentrations of ST2, REG3, and AREG by ELISA at the time of GVHD diagnosis in 715 patients divided by date of transplant into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n=341) was used to develop algorithms for predicting probability of 12 month NRM that contained all possible combinations of 1-3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for risk of NRM. Algorithms were compared to each other based on several metrics including the area under the receiver operating characteristics curve (AUC), proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n=374). All algorithms were strong discriminators of 12 month NRM, whether or not patients were systemically treated (n=321). An algorithm containing only ST2+REG3α had the highest AUC (0.757), correctly classified the most patients (75%), and more accurately risk stratified those who developed Minnesota standard risk GVHD and for patients who received post-transplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk stratified patients with Minnesota high risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

The MAGIC algorithm probability predicts treatment response and long-term outcomes to second-line therapy for acute GVHD.

The significance of biomarkers at second-line treatment for acute graft-versus-host disease (GVHD) is not well characterized. We analyzed clinical data and serum samples at initiation of second-line systemic treatment of acute GVHD from 167 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC) between 2016 and 2021. Sixty-two patients received ruxolitinib-based therapy while 102 received other systemic agents. In agreement with prospective trials, ruxolitinib resulted in higher day 28 (D28) ORR compared to non-ruxolitinib therapies (55% vs 31%, P=0.003) and patients who received ruxolitinib had significantly lower non-relapse mortality (NRM) than those who received non-ruxolitinib therapies (point estimates at 2-year: 35% vs 61%, p=0.002). Biomarker analyses demonstrated that the benefit from ruxolitinib was observed only in patients with low MAGIC algorithm probabilities (MAPs) at the start of second-line treatment. Among patients with a low MAP, those who received ruxolitinib experienced significantly lower NRM than those who received non-ruxolitinib therapies (point estimates at 2-year: 12% vs 41%, p=0.016). However, patients with a high MAP experienced high NRM regardless of treatment with ruxolitinib or non-ruxolitinib therapies (point estimates at 2-year: 67% vs 80%, p=0.65). A landmark analysis demonstrated that the relationship between D28 response and NRM largely depends on the MAP level at initiation of second-line therapy. In conclusion, the MAP measured at second-line systemic treatment for acute GVHD predicts treatment response and NRM. Outcomes of patients with high MAP are poor, regardless of treatment choice, and ruxolitinib appears to primarily benefit patients with low MAP.

The Adverse Event Landscape of Stem Cell Transplant: Evidence for aGVHD Driving Early Transplant Associated Toxicities.

Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (aGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of aGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 aGVHD, only aGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 aGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified aGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between aGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant aGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).

A Validated Risk Stratification That Incorporates MAGIC Biomarkers Predicts Long-Term Outcomes in Pediatric Patients with Acute GVHD.

Acute graft versus host disease (GVHD) is a common and serious complication of allogeneic hematopoietic cell transplantation (HCT) in children but overall clinical grade at onset only modestly predicts response to treatment and survival outcomes. Two tools to assess risk at initiation of treatment were recently developed. The Minnesota risk system stratifies children for risk of nonrelapse mortality (NRM) according to the pattern of GVHD target organ severity. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm of 2 serum biomarkers (ST2 and REG3α) predicts NRM in adult patients but has not been validated in a pediatric population. We aimed to develop and validate a system that stratifies children at the onset of GVHD for risk of 6-month NRM. We determined the MAGIC algorithm probabilities (MAPs) and Minnesota risk for a multicenter cohort of 315 pediatric patients who developed GVHD requiring treatment with systemic corticosteroids. MAPs created 3 risk groups with distinct outcomes at the start of treatment and were more accurate than Minnesota risk stratification for prediction of NRM (area under the receiver operating curve (AUC), .79 versus .62, P = .001). A novel model that combined Minnesota risk and biomarker scores created from a training cohort was more accurate than either biomarkers or clinical systems in a validation cohort (AUC .87) and stratified patients into 2 groups with highly different 6-month NRM (5% versus 38%, P < .001). In summary, we validated the MAP as a prognostic biomarker in pediatric patients with GVHD, and a novel risk stratification that combines Minnesota risk and biomarker risk performed best. Biomarker-based risk stratification can be used in clinical trials to develop more tailored approaches for children who require treatment for GVHD.

Secondary bone marrow graft loss after third-party virus-specific T cell infusion: Case report of a rare complication.

Virus-specific T cells (VST) from partially-HLA matched donors have been effective for treatment of refractory viral infections in immunocompromised patients in prior studies with a good safety profile, but rare adverse events have been described. Here we describe a unique and severe adverse event of VST therapy in an infant with severe combined immunodeficiency, who receives, as part of a clinical trial (NCT03475212), third party VSTs for treating cytomegalovirus viremia following bone marrow transplantation. At one-month post-VST infusion, rejection of graft and reversal of chimerism is observed, as is an expansion of T cells exclusively from the VST donor. Single-cell gene expression and T cell receptor profiling demonstrate a narrow repertoire of predominantly activated CD4+ T cells in the recipient at the time of rejection, with the repertoire overlapping more with that of peripheral blood from VST donor than the infused VST product. This case thus demonstrates a rare but serious side effect of VST therapy.

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis.

ABSTRACT: The absence of a standardized definition for graft-versus-host disease (GVHD) flares and data on its clinical course are significant concerns. We retrospectively evaluated 968 patients across 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of treatment. The cumulative incidence of flares within 6 months was 22%, and flares were associated with a higher risk of nonrelapse mortality (NRM; adjusted hazard ratio [aHR], 4.84; 95% confidence interval [CI], 3.19-7.36; P < .001). Flares were more severe (grades 3/4, 41% vs 16%; P < .001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs 32%; P < .001) than the initial GVHD. At CR/VGPR, elevated MAGIC biomarkers predicted the future occurrence of a flare, along with its severity and LGI involvement. In multivariate analyses, higher Ann Arbor (AA) biomarker scores at CR/VGPR were significant risk factors for flares (AA2 vs AA1: aHR, 1.81 [95% CI, 1.32-2.48; P = .001]; AA3 vs AA1: aHR, 3.14 [95% CI, 1.98-4.98; P < .001]), as were early response to initial treatment (aHR, 1.84; 95% CI, 1.21-2.80; P = .004) and HLA-mismatched unrelated donor (aHR, 1.74; 95% CI, 1.00-3.02; P = .049). MAGIC biomarkers also stratified the risk of NRM both at CR/VGPR and at the time of flare. We conclude that GVHD flares are common and carry a significant mortality risk. The occurrence of future flares can be predicted by serum biomarkers that may serve to guide adjustment and discontinuation of immunosuppression.

A Day 14 Endpoint for Acute GVHD Clinical Trials.

The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment.

Overlap chronic GVHD is associated with adverse survival outcomes compared to classic chronic GVHD.

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.

D-dimer and sinusoidal obstructive syndrome-novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022. Patients were universally screened for TA-TMA and intermediate and high-risk patients were immediately treated with eculizumab. Sub-distribution cox-proportional hazards models were used to identify sub-distribution hazard ratios (sHR)  for multi-organ dysfunction (MOD) and non-relapse-related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA-TMA and 21/36 (58%) developed MOD, significantly more than those without TA-TMA, (p < .0001). Of those with TA-TMA, 18 (50%) had high-risk TA-TMA (HR-TA-TMA), 11 (31%) had intermediate-risk TA-TMA (IR-TA-TMA), and 8 (22%) had standard risk (SR-TA-TMA). Twenty-six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D-dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8-32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA-TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA-TMA patients (sHR 10.54, 95% CI 3.8-29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA-TMA patients included SOS (HR 2.89, 95% 1.07-7.80) and elevated D-dimer (HR 3.82, 95% CI 1.14-12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0-113.6 and OR 6.5, 95% CI 1.1-38.6 respectively). TA-TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D-dimer in TA-TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi-institutional clinical trials are needed to understand the impact of TA-TMA-targeted therapies.

Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.

Novel approaches to acute graft-versus-host disease prevention.

The field of graft-versus-host disease (GvHD) has experienced significant growth, with increased number of clinical trials and the approval of several agents by the US Food and Drug Administration for both acute and chronic GvHD treatment. In addition, the development of prognostic biomarker algorithms has enabled risk stratification in acute GvHD. However, prevention remains the cornerstone of GvHD management. Notable recent changes include the expansion of donor options with the increased use of haploidentical donor and unrelated donor transplantation, the development of ex vivo selective T-cell depletion strategies, recent approval by the Food and Drug Administration of abatacept for GvHD prevention, and the application of posttransplant cyclophosphamide in matched and mismatched donor settings. In this article, we review the results of recent clinical trials in GvHD prophylaxis and discuss the changes in clinical practice and promising emerging strategies driving the field forward.

Pulmonary microbiome and transcriptome signatures reveal distinct pathobiologic states associated with mortality in two cohorts of pediatric stem cell transplant patients.

Lung injury is a major determinant of survival after pediatric hematopoietic cell transplantation (HCT). A deeper understanding of the relationship between pulmonary microbes, immunity, and the lung epithelium is needed to improve outcomes. In this multicenter study, we collected 278 bronchoalveolar lavage (BAL) samples from 229 patients treated at 32 children's hospitals between 2014-2022. Using paired metatranscriptomes and human gene expression data, we identified 4 patient clusters with varying BAL composition. Among those requiring respiratory support prior to sampling, in-hospital mortality varied from 22-60% depending on the cluster (p=0.007). The most common patient subtype, Cluster 1, showed a moderate quantity and high diversity of commensal microbes with robust metabolic activity, low rates of infection, gene expression indicating alveolar macrophage predominance, and low mortality. The second most common cluster showed a very high burden of airway microbes, gene expression enriched for neutrophil signaling, frequent bacterial infections, and moderate mortality. Cluster 3 showed significant depletion of commensal microbes, a loss of biodiversity, gene expression indicative of fibroproliferative pathways, increased viral and fungal pathogens, and high mortality. Finally, Cluster 4 showed profound microbiome depletion with enrichment of Staphylococci and viruses, gene expression driven by lymphocyte activation and cellular injury, and the highest mortality. BAL clusters were modeled with a random forest classifier and reproduced in a geographically distinct validation cohort of 57 patients from The Netherlands, recapitulating similar cluster-based mortality differences (p=0.022). Degree of antibiotic exposure was strongly associated with depletion of BAL microbes and enrichment of fungi. Potential pathogens were parsed from all detected microbes by analyzing each BAL microbe relative to the overall microbiome composition, which yielded increased sensitivity for numerous previously occult pathogens. These findings support personalized interpretation of the pulmonary microenvironment in pediatric HCT, which may facilitate biology-targeted interventions to improve outcomes.

Tisagenlecleucel utilisation and outcomes across refractory, first relapse and multiply relapsed B-cell acute lymphoblastic leukemia: a retrospective analysis of real-world patterns.

Background: Tisagenlecleucel was approved by the Food and Drug Administration (FDA) in 2017 for refractory B-cell acute lymphoblastic leukemia (B-ALL) and B-ALL in ≥2nd relapse. Outcomes of patients receiving commercial tisagenlecleucel upon 1st relapse have yet to be established. We aimed to report real-world tisagenlecleucel utilisation patterns and outcomes across indications, specifically including patients treated in 1st relapse, an indication omitted from formal FDA approval. Methods: We conducted a retrospective analysis of real-world tisagenlecleucel utilisation patterns across 185 children and young adults treated between August 30, 2017 and March 6, 2020 from centres participating in the Pediatric Real-World CAR Consortium (PRWCC), within the United States. We described definitions of refractory B-ALL used in the real-world setting and categorised patients by reported Chimeric Antigen Receptor (CAR) T-cell indication, including refractory, 1st relapse and ≥2nd relapse B-ALL. We analysed baseline patient characteristics and post-tisagenlecleucel outcomes across defined cohorts. Findings: Thirty-six percent (n = 67) of our cohort received tisagenlecleucel following 1st relapse. Of 66 evaluable patients, 56 (85%, 95% CI 74-92%) achieved morphologic complete response. Overall-survival (OS) and event-free survival (EFS) at 1-year were 69%, (95% CI 58-82%) and 49%, (95% CI 37-64%), respectively, with survival outcomes statistically comparable to remaining patients (OS; p = 0.14, EFS; p = 0.39). Notably, toxicity was increased in this cohort, warranting further study. Interestingly, of 30 patients treated for upfront refractory disease, 23 (77%, 95% CI 58-90%) had flow cytometry and/or next-generation sequencing (NGS) minimum residual disease (MRD)-only disease at the end of induction, not meeting the historic morphologic definition of refractory. Interpretation: Our findings suggested that tisagenlecleucel response and survival rates overlap across patients treated with upfront refractory B-ALL, B-ALL ≥2nd relapse and B-ALL in 1st relapse. We additionally highlighted that definitions of refractory B-ALL are evolving beyond morphologic measures of residual disease. Funding: St. Baldrick's/Stand Up 2 Cancer, Parker Institute for Cancer Immunotherapy, Virginia and D.K. Ludwig Fund for Cancer Research.

Short-Course Empiric Antibiotics in Children Undergoing Allogeneic Hematopoietic Cell Transplantation.

Fever is common in children undergoing hematopoietic cell transplantation (HCT). Empiric antibiotic (EA) therapy is initiated and often continued until neutrophil engraftment. Prolonged antibiotic exposure reduces microbiome diversity and causes overgrowth of pathogenic organisms, leading to such complications as infections from antibiotic-resistant organisms and Clostridium difficile colitis. Shorter courses of EA therapy have been studied in adults undergoing HCT without significant safety concerns, but data in children are lacking. We instituted a single-center preintervention/ postintervention quality improvement (QI) project to assess the feasibility of short-course EA therapy for first fever in patients undergoing HCT. We aimed to reduce the median duration of broad-spectrum antibiotic use in eligible patients from 20 days in 2020 to 10 days in 2021. Patients were eligible for the intervention, limiting EAs to 7 days for first fever, if they were admitted for their first allogeneic HCT, were afebrile for >24 hours, had no infection requiring systemic treatment, and were hemodynamically stable. Outcome measures included days of EA therapy for first fever and total broad-spectrum antibiotic use during the period of hospitalization, defined as the time from the start of conditioning to 30 days after HCT or hospital discharge, whichever occurred first. Balancing measures included bloodstream infection (BSI), fever, and intensive care (ICU) admission within 3 days of stopping EA therapy. Project criteria were applied retrospectively to patients who underwent HCT in 2020 to construct a preintervention short-course-eligible cohort. During the intervention period, 41 patients underwent allogeneic HCT, of whom 17 (41%) were eligible for short-course EA therapy. Among eligible patients, the median age was 5.3 years, 47% had an underlying malignancy, and 88% received myeloablative conditioning. There were no differences in demographic or HCT characteristics between patients eligible for short-course EA during the intervention and preintervention period (n = 24). The short-course EA schedule was adhered to by 14 of the 17 eligible patients (82%). The duration of EA for first fever and total broad-spectrum antibiotic use was significantly decreased in the short-course EA-eligible patients compared to the preintervention cohort, from a median of 17 days to 8 days and from 20 days to 10 days, respectively (P < .01). Of the 14 patients adhering to short-course EA, 2 experienced a balancing measure of recurrent fever requiring resumption of EA, but no infection was identified. There were no BSIs, ICU admissions, or deaths during the hospitalization period in patients who received short-course EA. In this single-center QI project, short-course EA for initial fever was successfully applied to children undergoing allogeneic HCT using strict criteria and led to a significant decrease in broad-spectrum antibiotic use during hospitalization. These results should be validated in a prospective clinical trial to include the impact of short-course EA on antibiotic-resistant organisms, the intestinal microbiome, and HCT outcomes.

Diffuse alveolar hemorrhage after hematopoietic cell transplantation- response to treatments and risk factors for mortality.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of hematopoietic cellular therapy (HCT). This study aimed to evaluate the effect of DAH treatments on outcomes using data from consecutive HCT patients clinically diagnosed with DAH from 3 institutions between January 2018-August 2022. Endpoints included sustained complete response (sCR) defined as bleeding cessation without recurrent bleeding, and non-relapse mortality (NRM). Forty children developed DAH at a median of 56.5 days post-HCT (range 1-760). Thirty-five (88%) had at least one concurrent endothelial disorder, including transplant-associated thrombotic microangiopathy (n=30), sinusoidal obstructive syndrome (n=19), or acute graft versus host disease (n=10). Fifty percent had a concurrent pulmonary infection at the time of DAH. Common treatments included steroids (n=17, 25% sCR), inhaled tranexamic acid (INH TXA,n=26, 48% sCR), and inhaled recombinant activated factor VII (INH fVIIa, n=10, 73% sCR). NRM was 56% 100 days after first pulmonary bleed and 70% at 1 year. Steroid treatment was associated with increased risk of NRM (HR 2.25 95% CI 1.07-4.71, p=0.03), while treatment with INH TXA (HR 0.43, 95% CI 0.19- 0.96, p=0.04) and INH fVIIa (HR 0.22, 95% CI 0.07-0.62, p=0.005) were associated with decreased risk of NRM. Prospective studies are warranted to validate these findings.

Incidence, clinical presentation, risk factors, outcomes, and biomarkers in de novo late acute GVHD.

Late acute graft-versus-host disease (GVHD) is defined as de novo acute GVHD presenting beyond 100 days after allogeneic hematopoietic cell transplantation (HCT) without manifestations of chronic GVHD. Data are limited regarding its characteristics, clinical course, and risk factors because of underrecognition and changes in classification. We evaluated 3542 consecutive adult recipients of first HCTs at 24 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 2014 and August 2021 to better describe the clinical evolution and outcomes of late acute GVHD. The cumulative incidence of classic acute GVHD that required systemic treatment was 35.2%, and an additional 5.7% of patients required treatment for late acute GVHD. At the onset of symptoms, late acute GVHD was more severe than classic acute GVHD based on both clinical and MAGIC algorithm probability biomarker parameters and showed a lower overall response rate on day 28. Both clinical and biomarker grading at the time of treatment stratified the risk of nonrelapse mortality (NRM) in patients with classic and late acute GVHD, respectively, but long-term NRM and overall survival did not differ between patients with classic and late acute GVHD. Advanced age, female-to-male sex mismatch, and the use of reduced intensity conditioning were associated with the development of late acute GVHD, whereas the use of posttransplant cyclophosphamide-based GVHD prevention was protective mainly because of shifts in GVHD timing. Because overall outcomes were comparable, our findings, although not definitive, suggest that similar treatment strategies, including eligibility for clinical trials, based solely on clinical presentation at onset are appropriate.