Our Publications

Systemic steroid treatment of grade I acute GVHD increases steroid-refractory GVHD and NRM

Blood ICT, 2026; 2:100044

The use of systemic corticosteroids is recommended only for grades II to IV acute graft-versus-host disease (GVHD), but many patients are often treated at the onset of grade I in real-world practice. We retrospectively analyzed outcomes of 1143 patients with grade I GVHD from 24 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers. Approximately half received “up-front” systemic steroids, whereas the remainder received topical steroids alone; GVHD progressed to grade II to IV in only one-third of these patients. Up-front steroids decreased the risk for grade II to IV GVHD but not grade III to IV acute GVHD or the need for a second line of treatment. Systemic steroids were equally effective at treating grade I or II GVHD; however, up-front therapy exposed 3 times more patients to systemic steroids, with a corresponding threefold increase in GVHD that required additional therapy and a threefold rise in infection-related deaths. In multivariable analyses, up-front steroids were significantly associated with higher nonrelapse mortality (NRM; P = .026). MAGIC biomarkers identified most patients with grade I GVHD as low risk and unlikely to progress to severe GVHD regardless of treatment. Nevertheless, low-risk patients who received up-front steroids experienced a threefold increase in infectious deaths compared with those treated topically. This study supports the consensus recommendation of topical therapy for patients with low-risk grade I GVHD, a strategy that can be supported by biomarkers to avoid unnecessary steroid exposure and increased NRM.

Differential effects of GVHD therapies on intestinal epithelium

Blood Advances, 2026; 10:2431-2440

Graft-versus-host disease (GVHD), an often-fatal complication of allogeneic hematopoietic cell transplantation, is driven by inflammatory injury that damages target organs of the gastrointestinal (GI) tract, skin, and liver. Effective therapies must not only suppress GVHD reactivity of donor lymphocytes but also permit regeneration of the damaged epithelium, particularly in the GI tract. Systemic corticosteroids are the standard first-line treatment for GVHD because of their powerful immunosuppressive and anti-inflammatory properties but may retard epithelial repair. Ruxolitinib, a selective JAK1/2 inhibitor, is an approved therapy for steroid-refractory GVHD, although its direct effects on epithelial repair are unknown. Intestinal stem cells (ISCs), which are critical for maintaining gut integrity and barrier function, are key cellular targets of GVHD. We used both ileal and colonic organoid cultures to study the direct effects of methylprednisolone and ruxolitinib under conditions that controlled the strength of the GVH reaction. Ruxolitinib prevented inflammatory apoptosis in both human and murine organoids and preserved ISC function and proliferation, whereas corticosteroids offered no protection and in fact suppressed proliferation. This study highlights the importance of GVHD therapies that facilitate epithelial repair and regeneration, protect target tissues, and suppress alloreactivity of donor T cells.

The MAGIC Composite Response: A Novel Endpoint Integrating Clinical and Biomarker Parameters for Acute GVHD

Blood Advances, 2025; 9:5763-5773

Changes in the clinical symptoms of acute graft-versus-host disease (GVHD) are currently used to assess treatment responses. The Mount Sinai Acute GVHD International Consortium (MAGIC) consortium has recently revealed that the integration of serum biomarkers with clinical symptoms at the onset of treatment in a MAGIC composite score (MCS) more accurately predicts treatment response and 6-month nonrelapse mortality (NRM) than clinical symptoms alone. In this study, we evaluated whether the integration of serum biomarkers and clinical symptoms on day 28 (D28) would also better predict NRM than clinical response only (CRO). We analyzed data from 1135 patients receiving systemic treatment for acute GVHD and created a fourth MCS category for patients with complete resolution of symptoms and low-risk clinical biomarkers on D28. Using a classification and regression tree model with 6-month NRM as the end point, we identified status of MCS 0 or MCS 1 at D28 as responses, which we termed the MAGIC composite response (MCR). In the validation cohort (n = 309), MCR more accurately predicted 6-month NRM than CRO (area under the curve: 0.77 vs 0.69; P = .014) and demonstrated higher negative and positive predictive values. MCR correctly reclassified both clinical nonresponders and responders: 28 of 213 clinical responders (13%) became nonresponders with fivefold higher NRM (34.3% vs 6.8%, P < .001) and a larger group (29/96, 30%) of clinical nonresponders became responders with sixfold lower NRM (7.6% vs 50.7%, P < .001). These findings support the use of MCR as a superior surrogate end point for long-term GVHD control and survival in future clinical trials.

Serial Clinical and Biomarker Monitoring during Graft-Versus-Host Disease Treatment Identifies Distinct Risk Strata Including an Ultra-Low Risk Group

Transplant Cell Ther, 2025; 31:10.e1-10.e9

Recipient of the 2025 Ernest McCulloch and James Till Award

Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD

Blood, 2024; 144:1010-1021

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. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar nonrelapse mortality (NRM); we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs 0.64, P = .009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish 3 MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs 0.70, P = .010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs 63% vs 30%, P < .001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long-term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design.

Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects

Sci. Transl. Med. 2023 Dec 20;15(727)

Graft-versus-host disease (GVHD) remains the major cause of morbidity and nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT). Inflammatory cytokines mediate damage to key GVHD targets such as intestinal stem cells (ISCs) and also activate receptor interacting protein kinase 1 (RIP1; RIPK1), a critical regulator of apoptosis and necroptosis. We therefore investigated the role of RIP1 in acute GVHD using samples from HCT patients, modeling GVHD damage in vitro with both human and mouse gastrointestinal (GI) organoids, and blocking RIP1 activation in vivo using several well-characterized mouse HCT models. Increased phospho-RIP1 expression in GI biopsies from patients with acute GVHD correlated with tissue damage and predicted NRM. Both the genetic inactivation of RIP1 and the RIP1 inhibitor GNE684 prevented GVHD-induced apoptosis of ISCs in vivo and in vitro. Daily administration of GNE684 for 14 days reduced inflammatory infiltrates in three GVHD target organs (intestine, liver, and spleen) in mice. Unexpectedly, GNE684 administration also reversed the marked loss of regulatory T cells in the intestines and liver during GVHD and reduced splenic T cell exhaustion, thus improving immune reconstitution. Pharmacological and genetic inhibition of RIP1 improved long-term survival without compromising the graft-versus-leukemia (GVL) effect in lymphocytic and myeloid leukemia mouse models. Thus, RIP1inhibition may represent a nonimmunosuppressive treatment for GVHD.

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract remains the major cause of morbidity and nonrelapse mortality after BM transplantation (BMT). The Paneth cell protein regenerating islet-derived 3α (REG3α) is a biomarker specific for GI GVHD. REG3α serum levels rose in the systematic circulation as GVHD progressively destroyed Paneth cells and reduced GI epithelial barrier function. Paradoxically, GVHD suppressed intestinal REG3γ (the mouse homolog of human REG3α), and the absence of REG3γ in BMT recipients intensified GVHD but did not change the composition of the microbiome. IL-22 administration restored REG3γ production and prevented apoptosis of both intestinal stem cells (ISCs) and Paneth cells, but this protection was completely abrogated in Reg3g^−/− mice. In vitro, addition of REG3α reduced the apoptosis of colonic cell lines. Strategies that increase intestinal REG3α/γ to promote crypt regeneration may offer a novel, nonimmunosuppressive approach for GVHD and perhaps for other diseases involving the ISC niche, such as inflammatory bowel disease.

Effective treatment of low-risk acute GVHD with itacitinib monotherapy

Blood, 2023; 141:481-489

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. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.