Publications by authors named "James L M Ferrara"

Article Synopsis
  • * Researchers analyzed data from 450 patients, finding that 310 were classified as ultra-low risk (ULR) based on their rapid clinical response and low MAP scores, leading to significantly better outcomes.
  • * Patients in the ULR group had higher response rates at day 28 and lower non-relapse mortality at six months, suggesting that careful monitoring can guide safer, more effective GVHD treatment strategies.
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Acute graft-versus-host disease (GVHD) is a significant complication following hematopoietic stem cell transplantation (HCT). Although recent advancements in GVHD prophylaxis have resulted in successful HCT across HLA barriers and expanded access to HCT for racial minorities, less is known about how race affects the severity and outcomes of acute GVHD. This study examines differences in the clinical course of acute GVHD and the prognostic value of GVHD biomarkers for Black and White recipients.

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Acute graft-versus-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as the Minnesota risk identify standard and high-risk categories but lack a low-risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low-risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model's prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts.

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Background: Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.

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The significance of biomarkers in second-line treatment for acute graft-versus-host disease (GVHD) has not been well characterized. We analyzed clinical data and serum samples at the 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, whereas 102 received other systemic agents.

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Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [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 the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts.

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Article Synopsis
  • Acute graft versus host disease (GVHD) is a significant complication for children undergoing hematopoietic cell transplantation (HCT), and new tools have been developed to assess the risk of nonrelapse mortality (NRM) at the onset of treatment.
  • The study compared the Minnesota risk system and the MAGIC algorithm using biomarkers ST2 and REG3α, finding that MAGIC's probabilities (MAPs) were more effective in predicting outcomes in pediatric patients compared to Minnesota risk alone.
  • A combined model using both Minnesota risk and biomarker scores increased prediction accuracy further, demonstrating the potential for more personalized treatment approaches for children with GVHD.
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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.

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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).

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Article Synopsis
  • Graft-versus-host disease (GVHD) is a major complication after hematopoietic cell transplantation, causing significant morbidity and mortality, often mediated by inflammatory cytokines affecting crucial cells like intestinal stem cells.
  • The study explored the role of receptor interacting protein kinase 1 (RIP1) in acute GVHD, finding that high levels of phospho-RIP1 in patient biopsies indicated tissue damage and increased nonrelapse mortality, while blocking RIP1 helped protect stem cells and reduced inflammation in GVHD target organs.
  • Inhibiting RIP1, either genetically or with the compound GNE684, improved long-term survival in mouse models without compromising the beneficial graft-versus-leukemia effect, suggesting that RIP1
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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.

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Article Synopsis
  • GVHD in the GI tract is a leading cause of death after stem cell transplant, with higher Ann Arbor scores indicating worse outcomes and treatment resistance.
  • A phase 2 study tested natalizumab, a drug that targets T-cells, combined with corticosteroids for patients with severe GVHD, showing that it was safe and well-tolerated.
  • The results revealed no significant benefits of adding natalizumab, as patients had similar recovery and survival rates compared to those who only received corticosteroids.
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Acute GVHD occurs in nearly 50% of patients receiving hematopoietic cell transplantation (HCT), and is the major driver of mortality. However, progress in the development of new acute GVHD therapeutics has been slow, in part due to heterogeneity in acute GVHD data collection and interpretation among centers. Herein, we first describe the methods used by the Mount Sinai Acute GVHD International Consortium (MAGIC) to standardize acute GVHD data collection and curation.

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Intestinal microbiome diversity plays an important role in the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GVHD) and influences the outcome of patients after allogeneic stem cell transplantation (ASCT). We analyzed clinical data and blood samples taken preconditioning and on the day of ASCT from 587 patients from 7 German centers of the Mount Sinai Acute GVHD International Consortium, dividing them into single-center test (n = 371) and multicenter validation (n = 216) cohorts. Regenerating islet-derived 3α (Reg3α) serum concentration of day 0 correlated with clinical data as well as urinary 3-indoxylsulfate (3-IS) and Clostridiales group XIVa, indicators of intestinal microbiome diversity.

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The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS.

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We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort.

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Introduction: Acute Graft-versus-Host Disease (GVHD) is the major toxicity of allogeneic hematopoietic cell transplantation (HCT). Systemic steroids are the standard primary treatment but only half of the patients will respond completely and the survival of steroid-refractory patients is poor. The gastrointestinal (GI) tract is a key target organ that usually determines a patient's response to therapy.

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Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD.

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Cancer research has led to unprecedented advances in treatment in recent decades. Physician-scientists have played a crucial role in these advances given their unique perspective at the intersection between basic research and clinical care, though their representation in cancer research has been in progressive decline. Cancer research programs that feature strong mentorship at the medical student level are associated with increased likelihood of alumni choosing a cancer research career path.

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Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept "preemptive" treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD.

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Article Synopsis
  • Obesity negatively impacts outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly increasing the risk and severity of acute gut graft-versus-host disease (GVHD) in mice with diet-induced obesity (DIO).
  • Mice with obesity showed heightened gut permeability and inflammatory responses, leading to decreased survival rates due to acute gut GVHD, regardless of minor genetic mismatches.
  • Clinical data revealed that patients with a high body mass index (BMI) also experienced reduced survival and higher levels of the GVHD marker ST2, while using prophylactic antibiotics in DIO mice helped mitigate some damaging effects of obesity-related gut changes, although it didn't prevent chronic skin GVHD.
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The graft-versus-leukemia (GVL) effect after allogeneic hematopoietic cell transplant (HCT) can prevent relapse but the risk of severe graft-versus-host disease (GVHD) leads to prolonged intensive immunosuppression and possible blunting of the GVL effect. Strategies to reduce immunosuppression in order to prevent relapse have been offset by increases in severe GVHD and nonrelapse mortality (NRM). We recently validated the MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers.

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Hematopoietic cell transplantation (HCT) is a potentially curative therapy for hematologic malignancies that relies on the graft--leukemia (GVL) effect to eradicate malignant cells. GVL is tightly linked to graft--host disease (GVHD) however, in which donor T cells damage healthy host tissues. Acute GVHD occurs in nearly 50% of patients receiving HCT, and damages the skin, liver, and gastrointestinal (GI) tract.

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