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.

Approximately 30% of patients with acute graft-versus-host disease (GVHD) develop steroid-refractory disease and have very poor outcomes. Ruxolitinib has become the standard of care for steroid-refractory acute GVHD, but it is unclear which patients derive benefit. The MAGIC Composite Score (MCS), an algorithm that combines clinical symptoms and biomarkers, has been validated to predict outcomes at the start of primary GVHD treatment. Here, we evaluated its performance at the initiation of second-line treatment in 278 patients. MCS stratified patients into three risk groups (MCS1-3), with the majority (88%) classified as intermediate or high risk. Increasing MCS score was associated with progressively higher 1-year non-relapse mortality (NRM) rates (16%, 41%, and 73%; p<0.001), lower 1-year survival (77%, 56%, and 24%; p<0.001), and lower complete response (CR) rates at day 28 (47%, 38%, and 20%, respectively; p<0.01). The area under the receiver operating characteristic curve (AUROC) for 1-year NRM was significantly higher with MCS compared to clinical symptoms alone (0.70 vs. 0.63; p=0.023). Among patients treated with ruxolitinib, higher MCS similarly predicted higher NRM and lower survival and CR rates. Patients classified as MCS2/3 had poor outcomes despite ruxolitinib, underscoring the need for novel therapies in this patient population. In conclusion the MCS is an accurate predictor of outcomes for patients who require second-line treatment and may be of use as an eligibility criterion for future clinical trials in this high-risk population.

Chimeric antigen receptor (CAR)-T cells are considered a powerful therapeutic tool to reset the immune system in patients with autoimmune diseases. Innovative trial designs are needed to allow feasible testing of the safety and efficacy of CAR-T cells in clinical studies. CASTLE (CAR-T cells in systemic B cell mediated autoimmune disease) is a phase 1/2a two-stage optimal design basket study that investigated the safety and efficacy of zorpocabtagene autoleucel (Zorpo-cel, also known as MB-CART19.1), an autologous CD19 CAR-T cell product, in patients with treatment-resistant systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM). The primary safety outcome was the rate of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The secondary clinical efficacy outcomes were remission of SLE according to DORIS criteria, no progression of interstitial lung disease in SSc and American College of Rheumatology (ACR) major/moderate response in IIM after 24 weeks. A total of 24 patients were enrolled (10 with SLE, 9 with SSc and 5 with IIM), all receiving a single infusion of Zorpo-cel after stopping immunosuppressive treatments and receiving standard lymphodepletion with cyclophosphamide and fludarabine. Primary and secondary endpoints of CASTLE were met. Regarding safety, no CRS higher than grade 2 and no ICANS occurred. Regarding efficacy, 22 of the 24 patients achieved predefined efficacy endpoints, with 9 out of 10 patients with SLE reaching DORIS remission, 9 out of 9 patients with SSc showing no disease progression, and 4 out of 5 patients with IIM reaching ACR major/moderate response. Furthermore, all patients remained free of glucocorticoids and any other immunosuppressive treatment over the entire observation period of 24 weeks. CASTLE suggests the feasibility, safety and efficacy of Zorpo-cel in three different autoimmune diseases and paves the way for conducting a pivotal study. ClinicalTrials.gov identifier: NCT06347718, EudraCT identifier: 2022-001366-35.

Background Autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and antiphospholipid antibody syndrome (APLAS) are B cell-driven autoimmune diseases defined by pathogenic autoantibodies. CD19-directed chimeric antigen receptor (CAR)-T cells have recently demonstrated the ability to reset dysregulated B cells and induce long-lasting remission in refractory systemic autoimmune diseases. Evidence for efficacy in severe, treatment-refractory AIHA, however, is limited. Methods We report the clinical course of a 47-year-old woman with life-threatening cold- and warm-agglutinin AIHA refractory to nine prior treatment lines, accompanied by ITP and APLAS. In an uncontrolled flare, she received a fludarabine/cyclophosphamide-containing lymphodepletion followed by autologous CD19-directed, 4-1BB-costimulated CAR-T cells (zorpocabtagene-autoleucel [Zorpo-cel], 1 × 106/kg) on the basis of compassionate use. Treatment efficacy and safety were assessed over an 11-month follow-up period. Findings Zorpo-cel showed a rapid and sustained B cell depletion. Transfusion independence was achieved by day 7, with hemoglobin normalization by day 25, including resolution of hemolysis markers. Cold-agglutinin titers decreased, and previously elevated antiphospholipid antibodies normalized without recurrence throughout 11 months of follow-up. ITP stabilized. No cytokine release syndrome or neurotoxicity occurred. Mild transaminase elevation and thrombocytopenia were observed, most likely correlating with pre-existing severe iron overload due to erythrocyte transfusions. Conclusion This case demonstrates that CD19-directed CAR-T cell therapy can induce rapid, durable remission of severe, refractory cold-agglutinin AIHA and simultaneously improve coexisting APLAS and ITP on a favorable toxicity profile. However, more data from controlled clinical trials are needed for final conclusions. Funding This work was funded by Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe.

ABSTRACT:Chronic graft-versus-host disease (cGVHD) is characterized by dysregulation of the adaptive immune system, including an aberrant B-cell homeostasis after allogeneic hematopoietic stem cell transplantation (allo-SCT). It is uncertain, however, whether this B-cell dysregulation is a result of manifest cGVHD or develops as a sign of aberrant B lymphopoiesis after allo-SCT before cGVHD becomes apparent. To gain insight into the development of B-cell dysregulation before the onset of cGVHD, we analyzed B-cell subpopulations by multiparameter flow cytometry on days 90, 180, and 356 after allo-SCT in a prospective study design. After completion of follow-up, patients were assigned retrospectively to 3 groups according to onset of GVHD: (1) no GVHD (n = 17); (2) acute GVHD (aGVHD) without subsequent cGVHD (n = 32); and (3) cGVHD (n = 59). Although CD21lowCD11c+ B cells were increased in all groups, the frequency of CD20-CD38hi plasmablasts was significantly elevated already 90 days after allo-SCT in patients who subsequently developed cGVHD, compared to patients without GVHD or with aGVHD only (median of CD19+ cells, 5.9% vs 2.2% vs 2.2%; P = .0016 and .0304, respectively). Detailed molecular analysis of expanded plasmablasts revealed a dominance of the immunoglobulin A isotype, with molecular evidence for recent generation in mucosal sites and markers for intestinal homing. A large fraction of the clonally expanded plasmablasts produced antibodies that bound to subgroups of commensals known to produce short-chain fatty acids. In summary, our data suggest that dysregulated intestinal antibody responses against commensals contribute to the pathophysiology of cGVHD.

ABSTRACT:Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P < .001]; NPV, 92.0% vs 89.6% [P < .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P < .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials.

Introduction: Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM) are characterized by the activation of pathological B-cells and the formation of autoantibodies that trigger damage to cells and organs. Based on previous findings from pilot studies we found that zorpocabtagene-autoleucel (zorpo-cel, MB-CART19.1), an autologous T-cell product expressing the chimeric antigen receptor (CAR) against CD19, induce deep B-cell depletion e.g., in peripheral blood and in tissues such as lymph nodes achieving drug-free remission in these AIDs. Methods: CASTLE is a Phase I/II basket trial that tested the feasibility, safety, and efficacy of zorpo-cel in patients with severe, treatment-resistant SLE, SSc, and IIM. The primary enpoint was safety defined as the rate of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) within the first 4 weeks after zorpo-cel administration, the secondary clinical efficacy endpoints were DORIS remission in SLE, no progression of interstitial lung disease in SSc, and ACR Major/Moderate Response in IIM after 24 weeks. Dose-limiting toxicities were defined as CRS or ICANS of grade 3 or higher, or grade three or higher organ toxicities (including late immune effector cell-associated hematotoxicity, ICA-HT lasting beyond day 28).. Lastly, local immune effector cell associated toxicity syndrome (LICATS) was recorded according to Hagen et al 2025, Lancet Rheumatology. Patients were enrolled in 2 cohorts: 8 patients for Phase I, 16 patients for Phase II with a safety review between Phase I and Phase II. Results: All planned 24 patients with SLE, IIM or SSc were enrolled between July 2023 and February 2025. Ten SLE, nine SSc and five IIM patients had a median disease duration of 4.0 [1.3; 6.5] years and failed a median of 4 [3; 6] immunosuppressive treatments. For all patients, zorpo-cel was successfully produced and infused. CAR T cells peaked at a median of 140 [82; 360] cells/µl after 10 days. B cell depletion was achieved within 7 days and B-cell aplasia lasted a median of 83 [56; 113] days. B cells were mostly naïve in recurrence for all patients. The 8 patients of phase 1 fulfilled predefined safety and efficacy endpoints and 16 additional patients were included in Phase 2. The study met its primary endpoint of safety. No CRS > grade 2 and no ICANS occurred, there was no ICAHT persisting beyond day 28. One patient developed a CMV pneumonitis during a virus reactivation. Kidney biopsy due to reduced organ function showed thrombotic microangiopathy, possibly related to CMV. Persisting reduction of creatinine-clearance resulted in the only DLT of the trial. Twenty-two of 24 patients achieved efficacy endpoints, with 9/10 SLE patients fulfilling DORIS remission, all 9 SSc patients showing no disease progression, and 4/5 IIM patients reaching ACR/EULAR major response after 6 months. One patient with longstanding IIM did not adequately improve in muscle strength and failed ACR Moderate/Major Response Criteria. One patient with SLE did not achieve significant reduction of proteinuria (< 500 mg protein/g creatinine) and therefore did not meet DORIS remission at 6 months. Immunosuppressive therapy could be stopped in all patients. Conclusion: The CASTLE study is the first phase I/II basket trial to demonstrate feasibility, favorable safety, and high efficacy of zorpo-cel in three B-cell driven AIDs. These promising results provide strong rationale to further develop zorpo-cel in AID.

Chronic GVHD (cGVHD) following allogeneic stem cell transplantation (allo-SCT) is marked by disruption of the adaptive immune system, including aberrant B cell homeostasis, and numerous studies suggest that B cells play a role in cGVHD pathogenesis. However, which specific B cell populations contribute to cGVHD development, their pathogenic role in the disease, and how these cells could potentially be targeted remains uncertain. To gain insight into B cell dysregulations before onset of cGVHD, peripheral blood samples of 172 allo-SCT patients were examined at defined time points between 56 days and 365 days after allo-SCT using multiparameter flow cytometry in a prospective study design. Retrospective grouping categorized the patients into three cohorts: no GVHD (n=17), acute GVHD without later cGVHD (n=32), and cGVHD (n=59; de novo n=11; quiescent n=49), which emerged at a median of day 180. Patients who later developed cGVHD revealed a markedly higher frequency of antibody-producing CD21low CD20neg CD38hi plasmablasts at day 90 than those who never experienced GVHD or patients with only acute GVHD (median 5.9% vs 2.2% vs 2.2% of CD19+ cells; p=0.0016 and p=0.0304, respectively) and the elevation persisted until day 365. The expansion of the plasmablast population already occurred prior to the onset of cGVHD and a Cox proportional hazards model with cGVHD diagnosis as an endpoint identified an elevated frequency of plasmablasts higher than 3% of CD19+ cells 90 days after allo-SCT as an independent risk factor for subsequent cGVHD development taking into account multiple clinical transplant parameters as co-variables (hazard ratio, 3.07; 95% CI, 1.05 to 8.99; p value, 0.04). As demonstrated by scRNA sequencing data (n=5), expanded plasmablasts of cGVHD patients revealed clonal expansions, a high frequency of somatic mutations, and a selection of certain VH genes in their antibody repertoire. Most plasmablasts were found class switched to IgG and even more frequently to the mucosa-associated isotype IgA. Many IgA+ plasmablasts additionally expressed surface markers for mucosal homing like CCR9 or α4β7-integrin. Notably, 12 out of 24 IgA+ antibody clones derived from cGVHD plasmablasts recognized specific short-chain fatty acid-producing taxa of intestinal commensals such as Bacteroides, Blautia, Faecalibacterium, or Ruminococcus indicating a connection between peripheral plasmablasts and the microbiome. In a new patient cohort, we investigated whether plasmablast frequencies were elevated at disease onset and how first-line therapy for cGVHD affected B cell subpopulations. Samples from 20 patients (de novo, n=6; quiescent, n=14) were collected at the day of cGVHD onset (median day 183, range 98 to 402 days) and 4 and 8 weeks after disease onset and initiation of steroid therapy using prednisolone. At the day of cGVHD onset a remarkably elevated frequency of plasmablasts compared to patients 180 days after allo-SCT who never experienced GVHD was found by multiparameter flow cytometry (median 7.0% vs 1.9% of CD19+ cells; p=0.009). Steroid therapy led to a reduction of cGVHD severity with a concomitant decrease of plasmablast frequencies already 4 weeks after onset treatment (median 7.0% vs 1.6% of CD19+ cells; p=0.008). This was accompanied by a substantial decline in serum BAFF levels under steroid therapy (median 5.4 ng/ml vs 1.9 ng/ml; p=0.009). Interestingly, the frequency of other B cell subsets such as CD11c+ T-bet+ B cells remained unaltered in the first 8 weeks after treatment (median 3.1% vs 3.0% of CD19+ cells), suggesting a complex dynamic of B cell dysregulation at the onset of therapy. Overall, our new findings confirm the prominent role of plasmablasts as important predictors for the onset of cGVHD.

BACKGROUND:CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has advanced treatment strategies for severe autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis, and idiopathic inflammatory myopathy. Data regarding side-effects are mostly generated from patients with malignancies, but little is known about autoimmune disease-specific adverse events. This study aimed to describe autoimmune disease-specific adverse events that occur with CAR T-cell therapy. METHODS:In this observational study, patients of any age with autoimmune disease receiving CD19-targeting CAR T-cell therapy in two centres in Germany with a follow-up of at least 30 days were assessed for local organ-specific reactions occurring after CAR T-cell infusion. Observed reactions were documented according to localisation, time of onset, and duration, and were graded for severity (grade 1: spontaneous resolution; grade 2: glucocorticoid treatment due to symptoms lasting >1 week or presence of relevant inner organ involvement; grade 3: prolonged or new hospitalisation; grade 4: intensive care treatment). People with related lived experience were involved in the study design and implementation. FINDINGS:Between March 1, 2021, and Oct 31, 2024, 39 patients with autoimmune disease were treated with CD19-targeting CAR T cells (20 with SLE, 13 with systemic sclerosis, six with idiopathic inflammatory myopathy). 25 (64%) patients were female and 14 (36%) were male. Median age was 36 years (IQR 22-44). 54 local reactions, which we termed local immune effector cell-associated toxicity syndrome (LICATS), were recorded, affecting 30 (77%) patients with a median time of onset of 10 days (IQR 9-21) from CAR T-cell infusion and a median duration of 11 days (5-14). LICATS exclusively occurred during the B-cell aplasia phase and only involved organs previously affected by the respective autoimmune disease. The most frequently affected organs were the skin (19 [35%] of 54) and the kidneys (12 [22%]). Most cases of LICATS were mild (grade 1: 35 [65%]; grade 2: 16 [30%]). Only three cases were grade 3. All events of LICATS resolved without sequelae. INTERPRETATION:LICATS is a new form of toxicity in patients with autoimmune disease receiving CD19-targeting CAR T-cell therapy, most likely based on the cleansing of immune cells from the affected organs. It is self-limited, organ-specific, and usually mild in its intensity. FUNDING:Deutsche Forschungsgemeinschaft (DFG), German Cancer Aid, Bundesministerium für Bildung und Forschung, European Union, Staedtler Foundation, Lupus Research Alliance, and donations from the Bendel family and the Bleyl family.

Background Acute graft-versus-host disease (GVHD) is a major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). High-dose steroids are standard first-line therapy for grade II–IV acute GVHD, whereas systemic treatment (tx) is generally not recommended for grade I. However, in practice many patients (pts) with grade I GVHD receive systemic steroids. A prior GITMO randomized trial (n=173) of grade I GVHD to either systemic steroid tx or “watch and wait” found that preemptive steroid tx reduced progression to grade II but not grade III/IV GVHD, increased serious infections, and resulted in similar chronic GVHD, NRM and survival (Bacigalupo, Haematologica 2017). In this study we analyzed real world evidence for early systemic steroid use and the potential impact of serum biomarkers in grade I GVHD. Methods We analyzed clinical data and serum samples from pts with grade I acute GVHD at 24 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between 2014 and 2022 who were treated according to physician discretion. Pts were divided into a preemptive steroid tx group or a watch-and-wait group (systemic steroids administered only if progression to grade II–IV GVHD). Preemptive steroid use was treated as a time-dependent covariate and a frailty proportional hazards model with random effects was used to adjust for center effects to account for possible heterogeneity in clinical practices across transplant centers. Serum samples collected at the diagnosis of grade I GVHD were analyzed for ST2 and REG3α to calculate validated Ann Arbor (AA) scores (1, 2, 3). Results Grade I GVHD was diagnosed in 1143 pts; 591 (52%) received preemptive tx and 552 (48%) were treated by a watch-and-wait strategy. In the preemptive tx group, steroids were initiated at a median of 0 days and within 7 days for >90%. The median initial dose of steroids was 1 mg/kg of prednisone or its equivalent. In the watch and wait group, only 184 pts (33%) required systemic steroids for progression to grade II-IV GVHD at a median of 14 days from grade I diagnosis. Preemptive steroid tx reduced the risk of grade II–IV acute GVHD (HR, 0.71; 95% CI, 0.56–0.89; P=0.003), but not the risk of grade III/IV acute GVHD (HR, 1.03; 95% CI, 0.69–1.52; P=0.899) or chronic GVHD (HR, 1.03; 95% CI, 0.69–1.52; P=0.899), consistent with the GITMO trial. The 12-month incidence of NRM was higher for preemptive tx vs. watch and wait (13% vs 7%, P=0.002). In multivariate analysis preemptive steroid use independently predicted an increased risk of NRM (HR, 1.63; 95% CI, 1.06–2.50; P=0.026) as did several other known risk factors (older recipient age, umbilical cord blood donor, HCT-CI ≥3, and myeloablative conditioning). Greater NRM in the preemptive tx group was driven primarily by 3-fold more infectious deaths; deaths due to uncontrolled GVHD were similar for both tx groups. The risk for relapse was unexpectedly lower in the preemptive tx group (HR 0.64; 95% CI 0.47-0.88; P=0.006) and overall survival was therefore not different between groups, but risk factors for relapse such as minimal residual disease status were not available precluding further analysis of this finding. Serum was collected in 871 (76%) pts at onset of grade I GVHD for retrospective biomarker analysis. AA scores were AA1 (80%), AA2 (15%), and AA3 (5%). AA scores were highly predictive of progression to grade III/IV GVHD (AA1 vs AA2 vs AA3: 9% vs 14% vs 44%, all P<0.001) and the risk of 12-month NRM (8% vs 16% vs 39%, all P<0.001); this pattern was observed in both tx groups. The negative effect of preemptive steroid tx was most pronounced in pts with grade I/AA1 GVHD who experienced 5-fold more infectious related deaths compared to pts managed with a watch and wait approach. Conclusion Treatment of grade I GVHD with systemic steroids did not reduce the incidence of grade III/IV GVHD or deaths due to uncontrolled GVHD and instead increased the risk of NRM from infections compared to pts who were treated only after GVHD progressed. Importantly, 2/3 of the watch and wait pts never needed systemic steroid tx. These findings remained robust after adjusting for multiple confounders, including center effects, and were consistent with the GITMO trial. MAGIC biomarkers at the onset of grade I GVHD predicted outcomes and a watch and wait strategy may be best for the 80% of pts with AA1 GVHD. Better treatment options are needed for the 20% of pts with grade I and AA2/3 GVHD.

Background The standard treatment for acute graft-vs-host disease (GVHD), a common complication following allogeneic hematopoietic cell transplant, remains prolonged courses of high dose corticosteroids. Previous attempts to decrease corticosteroid exposure during GVHD therapy failed because physicians lack the tools necessary to safely reduce and shorten therapy and fear loss of GVHD control in responding patients. Prior studies have shown that a serum biomarker risk score, the MAGIC algorithm probability (MAP), provided prognostic value within groups with similar clinical severity and that patients with GVHD that is Minnesota standard risk by clinical symptoms and who have a low MAP at the start of corticosteroid treatment represent a low risk group with good outcomes. Objective This study tested the hypothesis that serial monitoring of GVHD symptoms and the MAP score in patients with low risk GVHD could provide further risk stratification, and would identify a subset with exceptionally low rates of failure with standard treatment, which we term ultra-low risk (ULR) GVHD who might benefit from reduced corticosteroid treatment. Study Design Weekly monitoring of clinical symptoms and MAPs from initiation to day 14 of treatment was used to further divide 450 patients with low risk GVHD into groups with different outcomes, such as overall response rates at day 28 and non-relapse mortality at six-months. Results 310/450 low risk patients (69%) who achieved clinical response by day 14 and had low MAPs at days 7 and 14 constituted an ultra-low risk (ULR) group. that experienced a significantly higher overall response rate at day 28 (93% vs 50%, p<0.001) that was sustained to day 56 (84% vs 45%, p<0.001) and significantly lower six-month NRM (4% vs 13%, p<0.001) compared to the non-ULR patients. Patients who achieved clinical response by day 14 but who developed a high MAP during monitoring (n=20) experienced six-fold higher six-month NRM than the ULR group (25% vs 4%, p<0.001). Among 120 patients who did not achieve a clinical response by day 14, the overwhelming majority (n=112) who maintained low MAPs at both days 7 and 14 of treatment experienced six-fold lower NRM at six months compared to patients with a high MAP at either time point (8% vs 50%, p<0.001). The majority of deaths within the ULR group were due to infections in patients with complete and sustained control of GVHD symptoms while the majority of deaths in the non-ULR group were due to poorly controlled GVHD. Conclusions Serial monitoring during treatment can identify a large subset of patients by day 14 who achieve excellent GVHD control but remain at risk for treatment complications with standard treatment and who might be suitable candidates for testing abbreviated corticosteroid courses.

ABSTRACT: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.

Acute graft-vs-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as 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 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=0.009) 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 three MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs. 0.70, P=0.010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs. 63% vs. 30%, P<0.001). 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.