Ayuk, Francis

ABSTRACT 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. Key Points MAGIC Composite Scores that integrate clinical symptoms and biomarker scores predict outcomes of second-line therapy for acute GVHD more accurately than clinical symptoms alone. MCS identifies patients with high NRM despite treatment with ruxolitinib.

Abstract 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 &gt;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&lt;0.001) and the risk of 12-month NRM (8% vs 16% vs 39%, all P&lt;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.

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 &lt; .001) and a larger group (29/96, 30%) of clinical nonresponders became responders with sixfold lower NRM (7.6% vs 50.7%, P &lt; .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.

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 &lt; .001]; NPV, 92.0% vs 89.6% [P &lt; .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 &lt; .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.

Background Endpoints for GVHD treatment trials use early response (i.e, day (D)28 of treatment) as a surrogate for long term survival. Overall response (OR) that combines complete (CR) and partial responses (PR) at day (D) 28 is the conventional endpoint for primary acute GVHD trials because of similar survival outcomes between CR and PR. D28 OR ignores symptom severity at baseline and D28, however, and the PR category encompasses a wide range of responses from minimal improvement to near complete resolution of symptoms. D28 OR is the only endpoint currently approved by the FDA for efficacy, but it has not been re-evaluated as an endpoint for primary treatment (1L) in fifteen years and little is known regarding the prognostic value of D28 OR as an endpoint for second line treatment (2L) of GVHD. We hypothesized that refinement of the current D28 OR criteria, particularly through recategorization of PR in the GI tract, the main driver of nonrelapse mortality (NRM), would more accurately reflect disease control and better predict survival outcomes than current D28 response. Methods The Japanese Society for Transplantation and Cellular Therapy (JSTCT) collaborated with the Mount Sinai Acute GVHD International Consortium (MAGIC) to develop and validate D28 refined response (RR) criteria for 1L and 2L treatment (tx) in patients with Grades II-IV acute GVHD. To maximize the correlation between treatment success (i.e, response) with long term survival, our primary measured metric was the negative predictive value (NPV). We first randomly divided the 1L tx cohort of JSTCT into the training (n=2341) and validation sets (n=1156). In the training set we used a classification and regression tree (CART) algorithm to generate RR criteria that predicted 6-month (mo) NRM based on symptoms both at tx onset and D28. We then compared the two D28 response endpoints (RR vs OR) as surrogates for 6-mo NRM in two validation sets of both 1L tx (JSTCT: n=1156; MAGIC: n=1141) and 2L tx (JSTCT: n=510; MAGIC: n=196). Results The CART algorithm defined a RR as GVHD Grades 0/I at D28 without additional tx; all other D28 grades were considered refined nonresponses. As expected, RR successfully stratified the risk of 6-mo NRM in both 1L tx validation sets (JSTCT: 8% vs 38%, p&lt;0.01; MAGIC: 9% vs 37%, p&lt;0.01). We defined a discordant nonresponse as a nonresponse by RR criteria but a response by OR criteria, which accounted for the majority (~75%) of differences between RR and OR. 6-mo NRM in discordant nonresponders was four fold higher than in responders (JSTCT: 35%; MAGIC: 30%). The large majority (&gt;80%) of discordant nonresponders had persistent GI GVHD at D28. Because the proportion of discordant nonresponders was small (&lt;7% of the total population) in the 1L setting, the improvements of an already high NPV were small (JSTCT: 93% vs 91%; MAGIC: 91% vs 90%). In the 2L tx validation sets, RR also stratified the risk of 6-mo NRM (JSTCT: 26% vs 56%, p&lt;0.01; MAGIC: 13% vs 55%, p&lt;0.01). At the time of 2L tx, the discordant nonresponders are more common and half of the discordant nonresponders experienced 6-mo NRM (JSTCT: 45%; MAGIC: 59%); as a result, RR achieved much higher NPVs than OR (JSTCT: 75% vs 66%; MAGIC: 87% vs 76%). Deaths in responders from acute GVHD (vs. other causes such as infection) were more frequent in OR than RR in both 2L tx validation sets (JSTCT: 41% vs 20%; MAGIC: 41% vs 13%) and 1L tx validation sets (JSTCT: 25% vs 18%; MAGIC: 32% vs 29%). D28 RR is superior to OR because it more accurately reflects control of serious GVHD in four independent validation cohorts, particularly in patients with GI disease. Conclusion We conclude that RR is a more accurate endpoint than OR in patients with grade II-IV GVHD primarily because it classifies persistent GI GVHD at D28 as a non-response instead of a response, which correlates with 6-mo NRM and achieves a higher NPV. This validated RR metric can serve as a better endpoint than OR in assessing treatment efficacy in both primary treatment trials that enrich for high risk GVHD, e.g. GI involvement, and second line treatment trials.

Abstract 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 &lt; .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.

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 &lt; .001). Flares were more severe (grades 3/4, 41% vs 16%; P &lt; .001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs 32%; P &lt; .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 &lt; .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.

Introduction: Risk stratification approaches using clinical criteria or biomarkers in acute graft-versus-host disease (GVHD) have traditionally been implemented at diagnosis or initiation systemic treatment with corticosteroids. For patients who require second-line treatment, the significance of biomarkers at salvage therapy and the relationship between biomarker risk and choice of therapy are unknown. Methods: We studied adult patients who received second-line treatment for acute GVHD between January 2016 and December 2021 in the Mount Sinai Acute GVHD Consortium (MAGIC) database, which collects clinical data and longitudinal serum samples from allogeneic HCT recipients using a rigorous PRoBE study design. Exclusion criteria included relapse of underlying malignant disease prior to second-line therapy, missing response data, or missing serum sample. Serum samples collected from 7 days prior to 3 days after initiation of second-line therapy met criteria for biomarker analysis. The MAGIC algorithm probability (MAP) was calculated as a single value based on concentrations of ST2 and REG3α and was stratified at a threshold of 0.290 to define high MAP and low MAP groups. The primary objective evaluated the association between MAP and survival for patients receiving second-line therapy for acute GVHD. The key secondary objective was to investigate the MAP and choice of second-line systemic agent on Day 28 overall response rate (ORR) and survival. Results: In total, 316 adult patients received second-line treatment for acute GVHD; 149 patients (47%) were excluded for disease relapse (n=27), missing response data (n=48), or missing sample (n=74).Of the 167 evaluable patients, most had steroid-refractory acute GVHD (n=146, 87%), rather than steroid-dependent (n=8, 5%) or steroid-sensitive (n=14, 8%) disease. 62 patients received ruxolitinib while 102 received other systemic agents (best available therapy: BAT). Baseline clinical characteristics of the study population according to treatment choice were similar, except for donor type (Rux: MRD 15%, MUD 74%, haplo 11%; BAT: MRD 30%, MUD 67%, haplo 3%; P=0.014) and median days from corticosteroids to second-line treatment (Rux: 18, BAT: 12; P=0.02).In total, 81 patients had high MAPs and 86 patients had low MAPs, with similar distribution in each treatment cohort (P=0.53). For the entire cohort, the median follow-up for survivors was 22 months (range, 1.5-27).The MAP separated patients into 2 groups (high vs low) with significantly different mortality (NRM at 2 years, 76% vs 29%, P&lt;.0001) and survival (OS at 2 years, 12% vs 63%, P&lt;.0001). Patients who received ruxolitinib as second-line therapy had lower mortality (NRM at 2 years, 35% vs 60%, P&lt;.002) and improved survival (OS at 2 years, 51% vs 32%, P&lt;.008), compared to those who received other systemic agents. However, the outcomes of patients with high MAP were poor, regardless of second-line treatment choice ( Figure 1A). The MAP (low vs high), time from corticosteroids to second-line treatment (≥14 days vs &lt; 14 days), GVHD grade at second-line (0-2 vs 3-4), and choice of second-line therapy (Rux vs BAT) were all significant (P&lt;0.05) predictors of lower NRM and higher OS in multivariate analysis. The MAP also separated patients into 2 groups with significantly different D28 ORR (low: 49%, high: 30%, P&lt;.0001). In agreement with prospective trials, ruxolitinib resulted in higher D28 response rates compared to other systemic therapies (ORR 54.9% vs 30.5%, P=0.005), which was observed in both low MAP (ORR, 64.5% vs 38.5%, P=0.017) and high MAP cohorts (ORR, 42.9% vs 22.6%, P=0.06) ( Figure 1B). The MAP (low vs high), GVHD grade at second line (0-2 vs 3-4), and choice of second-line therapy (Rux vs BAT) were significant predictors (P&lt;0.05) of higher D28 ORR in multivariate analysis. Conclusion: The MAP measured at the initiation of second-line systemic treatment for acute GVHD predicts NRM and OS, as well as treatment response. The outcomes of patients with high MAP are poor, regardless of second-line treatment choice, and the higher CR rate in low MAP patients may drive higher survival rates. Incorporation of MAP into clinical trials in this setting warrants investigation. The results also support the current use of ruxolitinib as second-line treatment for acute GVHD, particularly in patients with low MAP.

[Background] The current standard first-line treatment for acute graft-versus-host disease (GVHD), systemic high-dose steroids, induces clinical responses in a majority of patients. Flares of GVHD after initial improvement often occur during tapering or discontinuation of immunosuppression. There is no consensus regarding the definition of GVHD flare and little has been published regarding its natural history. [Methods] We retrospectively evaluated clinical data and blood samples from 968 allogeneic hematopoietic cell transplantation (HCT) recipients from 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 acute GVHD treatment between 2014 and 2021. VGPR was defined as the complete resolution of acute GVHD manifestations except residual stage 1 skin disease. Flares were defined as a recurrence of acute GVHD after achievement of CR/VGPR if (1) patients had an increased symptom severity of at least 1 organ stage; (2) received intensified treatment (increase in steroid dose ≥ 0.25 mg/kg or initiation of additional systemic immunosuppression); and (3) had no prior history of primary disease relapse or donor lymphocyte infusion preceding the flare. Serum samples obtained at the time of CR/VGPR and at the time of flares were analyzed for ST2 and REG3α concentrations that generated MAGIC algorithm probabilities (MAPs) resulting in previously validated Ann Arbor (AA) scores (1, 2, and 3). [Results] The median recipient age at HCT was 55 years (range: 0 to 79); 18.6% of patients had grades III-IV acute GVHD before CR/VGPR. The median maximum daily dose of corticosteroids before CR/VGPR was 1 mg/kg methylprednisolone equivalent (range, 0.1 to 3.2 mg/kg). Flares developed within 6 months following CR/VGPR in 210/968 (21.7%) patients with a median onset of 28 days (range: 2 to 448). Symptom severity at the onset of flare symptoms varied widely (grade I: 22%; grade II: 38%; grade III-IV: 41%) and the development of a flare was associated with a five-fold increase in NRM (hazard ratio [HR], 4.84 [95% CI, 3.19-7.36], P &lt; 0.001) when considered as a time-dependent covariate in a multivariate regression model. The large majority of non-relapse deaths after flares (54/71, 76%) were due to acute GVHD or complications from its treatment. The AA scores at the time of first CR/VGPR successfully stratified patients for risk of six-month NRM (AA1: 5%, AA2: 11%, AA3: 34%, P &lt; 0.001) (Figure A). Increasing AA score at CR/VGPR was also associated with significantly increased risk of GVHD flares (Figure B). Not only did the risk of flare increase with each rising AA score, but the number of patients with severe (grade III/IV) symptoms at flare onset also increased (AA1: 34%, AA2: 43%, AA3: 54%). We next generated a multivariate regression model of risk factors for the development of flares. High AA scores at the time of CR/VGPR (AA2: HR, 1.81 [95% CI, 1.32-2.48], P = 0.001; AA3: HR, 3.14 [95% CI, 1.98-4.98], P &lt; 0.001), HCT from HLA mismatched unrelated donor (HR, 1.74 [95% CI, 1.00-3.02], P = 0.049), and interestingly, rapid achievement of CR/VGPR from the time of initial treatment (≤14 days) (HR, 1.84 [95% CI, 1.21-2.80], P = 0.004) were all identified as significant risk factors. Meanwhile, no other transplant, GVHD, or treatment characteristics associated with the development of flares including maximum GVHD severity, maximum steroid dose, and use of additional immunosuppressive agents other than steroids before CR/VGPR. AA scores measured at the onset of flare symptoms in 98 patients also predicted six-month NRM (AA1, 6%; AA2, 19%; AA3 42%, P = 0.01). [Conclusion] Despite advances in treatment, flares of GVHD symptoms following excellent (CR/VGPR) responses still occur in over one fifth of patients in current practice and are associated with a five-fold increase in six-month NRM. AA scores from serum biomarkers predict outcomes despite the absence of symptoms, suggesting that MAGIC biomarkers detect subclinical damage to GI crypts that can drive later recrudescence of clinical GVHD. Measurement of the MAP at the time of response to GVHD treatment may thus help to risk-stratify tapering strategies of immunosuppressive therapy.

The overall response rate (ORR) 28 days (D28) after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). ORR combines complete response (CR) and partial response (PR) because CR and PR have very similar non relapse mortality (NRM). D28 ORR has some disadvantages: first, physicians usually decide to modify immunosuppression much earlier than D28, and second, NRM does not always correlate well with ORR at D28, particularly for patients who present with intermediate risk or low risk disease. MAGIC serum biomarkers at day 14 (D14) of GVHD treatment have been shown to correlate better with NRM than clinical symptom response (Srinagesh et al, Blood Advances, 2019). We therefore hypothesized that a combination of clinical symptom severity and biomarkers at D14 of treatment would predict NRM at least as well and possibly better than clinical response at D28. We studied 1144 patients from 23 MAGIC sites who were systemically treated with at least 0.25 mg/kg/day of systemic steroids (prednisone equivalents) and had clinical data and serum samples available in the MAGIC database and biorepository. We divided the patients into a training set (n=764) and a validation set (n=380). We used 12-month NRM from the time of acute GVHD onset as the primary outcome of interest. We first trained a recursive partitioning algorithm in the training set to create a response model (MAGIC D14 clinical response) according to overall GVHD grade at both onset and D14 that predicted 12-month NRM and then applied it to the validation set. Patients that either progressed to grade III/IV GVHD, continued having grade III/IV GVHD, or only improved to grade II at D14 from grade III/IV at D0 had high NRM and were classified as non-responders. Patients with grade I/II GVHD at day 0 who had grade 0-II GVHD at day 14 and patients who improved to grade 0/I at day 14 from grade III/IV at day 0 had low NRM and were classified as responders. Although counterintuitive, responders included patients whose GVHD remained at grade II because the 12 month NRM of this group was only 20%. The new clinical model predicted NRM as well as the D28 standard response model in the validation set. When we integrated the D14 MAP biomarker score (low: ≤ 0.290 vs high: &gt;0.290) with the new D14 clinical response (D14 MAGIC integrated response), we observed three response groups of integrated response with strikingly different 12 month NRM (8%, 35%, 76%, p&lt;0.001), in contrast to the D28 standard response (Figure 1A, 1B). D14 complete response required MAGIC clinical response with low MAP; D14 partial response required either MAGIC clinical response with high MAP or MAGIC clinical non-response with low MAP; and D14 non-response required MAGIC clinical non-response with high MAP. The D14 response groups also displayed significant differences in 12 month OS (82%, 58%, 14% respectively, p&lt;0.001) We then compared the D14 integrated response with the D28 standard response for 12 month NRM prediction. This D14 integrated response model was superior for time-dependent AUC (0.78 vs 0.71, P=0.03), sensitivity (0.71 vs 0.54), positive predictive value (0.52 vs 0.48) and negative predictive value (0.92 vs 0.89), with minimal loss in specificity (0.85 vs 0.87) in the prediction of 12-month NRM compared to the D28 standard response model. Using decision curve analysis, the D14 integrated response displayed higher net benefit (correct identification of patients that will experience NRM by 12 months) over the whole range of threshold probabilities/preferences for changing immunosuppression when 12-month NRM was used as the outcome. We conclude first, that the definition of response that uses onset and D14 grades is as accurate as D28 ORR model; and second, that a model using clinical grades and biomarkers on D14 more accurately predicts long term NRM than the standard D28 definition and may be useful as a clinical trial endpoint.