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Introduction: Anti-BCMA CAR-T therapies like idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized RRMM treatment. However, the 6-8-week manufacturing period often leads to disease progression and/or death in up to 25% of patients (pts), necessitating effective bridging strategies. Talquetamab (talq), a bispecific antibody targeting GPRC5D, is approved for RRMM pts with four prior lines of therapy and offers rapid disease debulking without impacting BCMA. This study assesses the safety and efficacy of a short course of talq as a bridging therapy for pts receiving cilta-cel or ide-cel. Methods: This multicenter retrospective study involved 14 US academic medical centers within the US Multiple Myeloma Immunotherapy Consortium. We included pts with RRMM who underwent leukapheresis and received talq bridging therapy with the intent to proceed to commercial cilta-cel or ide-cel. We assessed the safety, feasibility, and efficacy of talq bridging therapy. Safety outcomes included cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), talq-related unique toxicities, and delayed neurotoxicity (NT). Efficacy outcomes included response rates to talq and CAR-T therapies. Results: Between June 2023 and May 2024, 77 pts received talq bridging therapy after apheresis with the intention to proceed to CAR-T. The median age was 66 years (range, 58-73); 14% were Black and 10% Hispanic. Poor prognostic features, including high-risk cytogenetics, were present in 45%, extramedullary disease (EMD) in 43%, and 72.7% were triple-class refractory. The median number of prior lines of therapy was 5 (range 3-11) and 10 pts (13%) had prior BCMA targeted therapy. Out of 77 pts, 10 pts were pending CAR-T infusion at the time of last follow up; 6 pts could not receive CAR-T infusion due to manufacturing failures. Of the remaining 61 patients who underwent successful CAR-T manufacturing, 58 (95%) pts were successfully infused with CAR-T therapy following talq bridging. Three (5%) pts died due to disease progression prior to CAR-T infusion. Talq was given 0.8 mg/kg biweekly in 59 (76%) pts and the median time on talq was 22 days (IQR: 10-41 days). Following talq bridging, none of the pts had grade >=3 CRS and 2 (2.5%) had grade 3 ICANS. Skin toxicities occurred in 32 (41%), nail toxicities in 19 (25%), and oral toxicities in 43 (56%) pts mainly grade 1. Most oral, skin, and taste changes resolved at the last follow-up (60%). Response to talq was evaluable in 72 out of 77 patients. An overall response was noted in 45/72 (62%) pts including unconfirmed CR in 14, VGPR in 10 and PR in 21 pts. There was no association of AEs and response to talq with high-risk cytogenetics, EMD and high baseline ferritin levels. Out of the 58 patients who went on to receive CAR-T therapy following talq bridging (45 cilta-cel and 13 ide-cel), 38 (65%) experienced CRS, with grade 3 CRS noted in 2 (3%) pts. ICANS occurred in 5 (8.6%) pts, with 1 (1.7%) grade 3 ICANS. Only 1 pt had delayed NT (facial nerve palsy) at the last follow up. No treatment related deaths were observed. Of these 58 pts, response was evaluable in 40 pts and a response at day +30 was noted in 39/40 (97.5%) pts (14 in CR, 10 in VGPR, 15 in PR). The median follow-up from CAR-T was 61 days (28-113). For the 58 pts who received CAR-T, the median time from the last talq dose to CAR-T infusion was 25 days (IQR: 19-36), and to lymphodepletion was 24 days (IQR: 18-33). There was no difference in the CAR-T related AEs by the duration of Talq washout (>4 weeks vs. =< 4 weeks). Conclusions: Talquetamab is an excellent bridging option before BCMA-targeted CAR-T therapy, showing high response rates even with short-term use and enabling most pts to receive CAR-T. Most oral, skin, and taste changes resolved post CAR-T. These findings underscore the effectiveness of a short course of talq bridging to maintain disease control and improve outcomes post CAR-T. Updated data with longer follow-up will be presented at the meeting.

Introduction CD19 CAR T cell therapies are highly effective for several aggressive B-cell malignancies. Emerging data suggest that these therapies may lead to durable, treatment-free responses in multiple autoimmune diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIMs), systemic sclerosis (SSc), and multiple sclerosis (MS). BMS-986353 (CC-97540) is an investigational CAR T cell therapy expressing the CD19-targeting CAR used in FDA-approved lisocabtagene maraleucel (liso-cel). BMS-986353 is manufactured using the NEX-TTM process, which shortens manufacturing time and optimizes phenotypic attributes of the CAR T cell product. Here, we report updated data on BMS-986353 in severe, refractory autoimmune diseases. Methods Two phase 1, multicenter, open-label studies are investigating BMS-986353 in patients (pts) with severe, refractory SLE, IIM, and SSc (CA061-1001; NCT05869955), and relapsing or progressive forms of MS (CA061-1006; NCT06220201). CAR T cells were manufactured using the NEX-T process and autoimmune-directed therapies were tapered before BMS-986353 infusion. Two to 9 d after lymphodepletion (3 d of fludarabine [30 mg/m2/d], cyclophosphamide [300 mg/m2/d]), a single infusion of BMS-986353 was administered. Pts were treated with 5 × 106 (MS only), 10 × 106, or 25 × 106 CAR+ T cells according to dose level. Pharmacokinetics were evaluated using droplet digital PCR to detect transgene copy numbers, and pharmacodynamics were measured using flow cytometry. Results As of Jul 12, 2024, 7 pts were treated with BMS-986353 (SLE, n=5; SSc, n=1; relapsing-remitting MS [RRMS], n=1). Seven pts were evaluable for safety; 4 pts were evaluable for efficacy (median follow-up of 167.5 d [range, 68-240]). All 5 pts with SLE had history of renal organ system involvement (BILAG category A) and disease refractory to multiple prior therapies (range 5-8); at screening, scores were (median [range]): SLE Disease Activity Index 2000 (SLEDAI-2K), 12.0 (7.0-22.0); Physician's Global Assessment (PGA), 2.3 (1.5-2.5). The pt with SSc was aged 43 y, and had history of progression of diffuse cutaneous SSc after 2 therapies and a modified Rodnan skin score of 18; the pt with RRMS was aged 33 y, and had history of active clinical disease despite 3 prior anti-CD20 therapies and an Expanded Disability Status Scale score of 3.0. Cytokine release syndrome was reported in 1 pt with SLE (grade [gr] 1) and 1 pt with SSc (gr 2), both resolved within 1 d. ICANS was reported in 1 pt with SSc (gr 1) and resolved in 1 d. Gr 3/4 transient lymphodepletion-related cytopenia occurred in 4 pts with SLE and 1 pt with MS. There were no prolonged gr ≥3 cytopenias or dose-limiting toxicities reported. In all efficacy evaluable pts, significant improvements in SLEDAI-2K (median, 4.0) and PGA (median, 0.55) were observed. dsDNA seroconverted and complements normalized for all pts who had abnormal values at screening. All pts remain off autoimmune-directed therapies without evidence of disease flare. Pts with SLE treated with 10 x 106 CAR+ T cell dose of BMS-986353 showed complete B-cell depletion and similar robust cellular expansion compared with pts with diffuse large B-cell lymphoma treated with liso-cel (TRANSFORM; NCT03575351) at the recommended phase 2 dose (RP2D; 100 x 106 CAR+ T cells). At the time of B-cell reconstitution following BMS-986353, re-emerging B cells were predominantly naive. Conclusions BMS-986353, a NEX-T investigational CD19-targeted CAR T cell therapy, has a more rapid manufacturing time and optimized phenotypic attributes. In pts with severe, refractory autoimmune diseases, BMS-986353 demonstrates a low rate of low gr CRS and ICANS events. Preliminary data suggest promising efficacy in pts with SLE despite discontinuation of all lupus therapies. Robust CAR T cell expansion comparable to the RP2D of liso-cel and complete B-cell depletion were observed after BMS-986353 at a dose of 10 x 106 CAR+ T cells despite being 1/10 of the RP2D of liso-cel. The studies continue to enroll pts in all autoimmune indications. Updated safety, efficacy, and translational data will be presented.

Abstract Ciltacabtagene autoleucel (cilta-cel) was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 1 March 2022 and 31 December 2022 at 16 US academic medical centers were included. Overall, 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel, of which 54% would not have met CARTITUDE-1 eligibility criteria. In treated patients (N = 236), cytokine release syndrome was seen in 75% (grade ≥3, 5%), immune effector cell–associated neurotoxicity syndrome in 14% (grade ≥3, 4%), and delayed neurotoxicity in 10%. Overall and complete response rates were as follows: all patients who received cilta-cel (N = 236), 89% and 70%; patients receiving conforming cilta-cel (n = 191), 94% and 74%; and conforming cilta-cel with fludarabine/cyclophosphamide lymphodepletion (n = 152), 95% and 76%, respectively. Nonrelapse mortality was 10%, most commonly from infection. After a median follow-up of 13 months from cilta-cel, the median progression-free survival (PFS) was not reached, with 12-month estimate being 68% (95% confidence interval, 62-74). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior B-cell maturation antigen–targeted therapy (P = .08). Second primary malignancies excluding nonmelanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard-of-care cilta-cel in RRMM, despite more than half the patients not meeting the CARTITUDE-1 eligibility criteria.

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 < .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 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. In agreement with prospective trials, ruxolitinib resulted in a higher day 28 (D28) overall response Frate than nonruxolitinib therapies (55% vs 31%, P = .003) and patients who received ruxolitinib had significantly lower nonrelapse mortality (NRM) than those who received nonruxolitinib therapies (point estimates at 2-year: 35% vs 61%, P = .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 nonruxolitinib therapies (point estimates at 2-year: 12% vs 41%, P = .016). However, patients with high MAP experienced high NRM regardless of treatment with ruxolitinib or nonruxolitinib therapies (point estimates at 2-year: 67% vs 80%, P = .65). A landmark analysis demonstrated that the relationship between the D28 response and NRM largely depends on the MAP level at the initiation of second-line therapy. In conclusion, MAP measured at second-line systemic treatment for acute GVHD predicts treatment response and NRM. The outcomes of patients with high MAP are poor regardless of treatment choice, and ruxolitinib appears to primarily benefit patients with low MAP.

Abstract 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. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, 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 area under the receiver operating characteristics curve (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 posttransplant 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.

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.

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<.0001) and survival (OS at 2 years, 12% vs 63%, P<.0001). Patients who received ruxolitinib as second-line therapy had lower mortality (NRM at 2 years, 35% vs 60%, P<.002) and improved survival (OS at 2 years, 51% vs 32%, P<.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 < 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<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<.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<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 < 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 < 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 < 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: >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<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<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.