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Dear Editor, Blastic plasmacytoid dendritic cell neoplasm (BPDCN), formerly known as agranular CD4 SP + sp /CD56 SP + sp hematodermic neoplasm or blastic natural killer (NK) cell lymphoma was officially recognized as a distinct entity in the 2016 revision of the World Health Organization (WHO) classification of myeloid malignancies [[1]]. In an open-label clinical trial with tagraxofusp in 47 patients with BPDCN, response rates were 90 and 67% among treatment naïve and relapsed patients, respectively [[5]]. 1Overall survival of Mayo Clinic patients with blastic plasmacytoid dendritic cell neoplasm.a Overall survival of 55 patients with blastic plasmacytoid dendritic cell neoplasm stratified by allogeneic stem cell transplant. b Overall survival of 36 patients with blastic plasmacytoid dendritic cell neoplasm stratified by normal vs abnormal karyotype. [Extracted from the article]

To evaluate the impact of killer immunoglobulin-like receptor (KIR) genotyping in allogeneic hematopoietic stem cell transplantation for myeloid disorders at our institution, retrospective KIR genotyping was performed on 77 patients and their 10/10 matched unrelated donors. In a multivariate model including donor age, HLA-DPB1 permissiveness, and presence of donor KIR B/x, an association with overall survival was observed (p =.047). Within the model, increasing donor age increased risk (RR 1.03 [1.00–1.06]/year, p =.046), while donor KIR and HLA-DPB1 permissiveness were not associated with risk (RR 0.51 [0.26–1.03] and RR 0.68 [0.34–1.36]). Grouping recipients by conditioning regimen or limiting the analysis to recipients of peripheral blood stem cells, no association between donor KIR and survival or relapse was identified. No significant associations were observed between overall survival, relapse, grade III-IV acute, or chronic graft versus host disease and presence of KIR B (B/x), quantity of donor KIR B haplotype motifs, or centromeric KIR type (all p >.05). [ABSTRACT FROM AUTHOR]

The article presents a study, discussing immunophenotypic and molecular comparison between allogeneic and autologous graft-vs-host disease (GVHD) of the skin. Topics include Interferon-mediated processes implicated in early pathogenesis of GVHD; using microdissection-assisted liquid chromatography-based tandem mass spectrometry method; and CD8-predominance over CD4 revealed in immunohistochemistry.

Objective HLA- DPB1 matching may impact allogeneic hematopoietic stem cell transplantation ( ASCT) outcomes; however, this locus is not in linkage disequilibrium with the remainder of the HLA genes. After classifying HLA- DPB1 mismatches based on T-cell epitope, avoiding non-permissive mismatches may impact survival. We tested this hypothesis at a single academic institution. Methods Retrospective HLA- DPB1 genotyping was performed on 153 adult patients who underwent ASCT and unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 loci (10/10). Using the ImMunoGeneTics/ HLA T-cell epitope matching algorithm, mismatch status was classified as permissive or non-permissive. Results Of 153 donor-recipient pairs, 22 (14.4%) were HLA- DPB1 matches, 64 (42.8%) permissive mismatches, and 67 (43.8%) non-permissive mismatches. DPB1 mismatch increased risk of chronic graft-versus-host disease ( cGVHD; RR 2.89 [1.19-9.53], P=.016) compared with DPB1-matched transplants, but there were no differences in overall mortality, risk of relapse, or acute GVHD ( aGVHD). Combining matches and permissive mismatches and comparing to non-permissive mismatches, there was no significant difference in overall survival or relapse; however, patients receiving non-permissive mismatched transplants experienced greater risk of aGVHD overall and severe aGVHD ( RR 1.66 [1.13-2.44], P=.010 and RR 1.97 [1.10-3.59], P=.024, respectively). Conclusion In this single-center study, HLA- DPB1 matching influenced outcomes of patients undergoing ASCT for hematologic malignancy. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a common complication of hematopoietic stem cell transplantation (HSCT). Graft-versus-host disease (GVHD) is another complication of HSCT that may modify the risk of VTE. Our objective was to explore the incidence of VTE (deep venous thrombosis and pulmonary embolism) following HSCT and to evaluate its association with GVHD. A comprehensive search of Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus was conducted to search for both retrospective and prospective HSCT studies which had reported VTE. Random-effects meta-analysis was used to pool incidence rates. We included 17 studies reporting on allogeneic- and 10 on autologous-HSCT; enrolling 6693 patients; of which 5 were randomized. The overall incidence of VTE after HSCT was 5 % (4-7 %). Incidence in allogeneic-HSCT was 4 % (2-6 %) and in autologous-HSCT was 4 % (1-15 %). Eleven and nine studies reported data on acute and chronic GVHD, respectively. The incidence of VTE in chronic GVHD was 35 % (20-54 %), whereas in acute GVHD it was 47 % (32-62 %). Based on the results of this meta-analysis, VTE is a fairly common complication after HSCT, emphasizing the importance of assimilating guidelines for both treatment and prophylaxis in this patient population. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) of the right forearm demonstrated fasciitis and myositis, involving the deep and superficial flexor muscles and tendons. Based on his clinical presentation in the absence of preceding trauma, nerve dysfunction, or tissue ischemia, the patient was diagnosed with pseudo-Volkmann contracture. Pseudo-Volkmann contracture must also be differentiated not only from Volkmann ischemic contracture and finger joint contracture but also from nerve dysfunction, which can present similarly. [Extracted from the article]

Highlights • ECP favorably impacts overall survival in HCT patients with BOS. • This survival benefit is independent of the ECP effect on measured pulmonary function. • The corticosteroid-sparing effect of ECP may be responsible for the improved survival. Abstract We carried out the first matched retrospective cohort study aimed at studying the safety and efficacy of extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT). Medical records of 1325 consecutive adult patients who underwent HCT between 2005 and 2015 were reviewed. Seventy-four patients (median age, 51 years) with a diagnosis of BOS were included in the study. After propensity-score matching for BOS severity, 26 patients who underwent ≥3 months of ECP were matched to 26 non–ECP-treated patients, who were assigned an index date corresponding to the ECP start date for their matched pairs. The rate of decline in FEV 1 percentage predicted (FEV 1PP) decreased after ECP initiation (and after index date in the non-ECP group), with no significant difference between the 2 groups (P =.33). On a multivariable analysis that included baseline transplant and pulmonary function test variables, matched related donor HCT (HR,.1; 95% CI,.03 to.5; P =.002), ECP (HR,.1; 95% CI,.01 to.3; P =.001), and slower rate of decline in FEV 1PP before the ECP/index date (HR,.7; 95% CI,.6 to.8; P =.001) were associated with a better overall survival. At last follow-up, non–ECP-treated patients were more likely to be on >5 mg daily dose of prednisone (54% versus 23%; P =.04) and had a greater decline in their Karnofsky performance score (mean difference, −9.5 versus −1.6; P =.06) compared with ECP-treated-patients. In conclusion, compared with other BOS-directed therapies, ECP was found to improve survival in HCT patients with BOS, without significantly impacting measured pulmonary functions. These findings need prospective validation in a larger patient cohort. [ABSTRACT FROM AUTHOR]

Background Matching at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci is important in donor selection for patients undergoing unrelated allogeneic hematopoietic stem cell transplantation (ASCT). Additional matching across the MHC gamma region may further improve outcomes. Methods The MHC gamma region was retrospectively genotyped in 66 adult recipients of ASCT and their 10/10 matched unrelated donors. A chart review was performed to determine whether MHC gamma matching impacted survival, relapse, or graft-versus-host disease. Results Of 66 donor-recipient pairs, 26(39.4%) were gamma-type matches, 34(51.5%) were mismatches, and 6(9.1%) were “indeterminate.” Matching status was not associated with overall survival (p = 0.43), relapse (p = 0.21), acute GVHD (p = 0.43), severe aGVHD (p = 0.31), or chronic GVHD (p = 0.23) in univariate analyses, nor in multivariate analyses (p = 0.28, 0.13, 0.29, 0.16, and 0.67, respectively), with or without adjusting for HLA-DPB1 matching status. Conclusions In our single institution study, gamma-type matching status was not associated with outcomes of adult ASCT recipients. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3a) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies. [ABSTRACT FROM AUTHOR]

Oral mucositis (OM) is a debilitating early adverse effect of allogeneic hematopoietic stem cell transplantation (HSCT). The intensity of the conditioning regimen correlates with the incidence and severity of OM, but no studies have analyzed this relationship among various conditioning regimens. We performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and analyzed this association. A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Cochrane CRCT, Cochrane DSR, Scopus) from 1990 to 2014 for studies of OM in allogeneic HSCT patients was conducted. Professional societies' meeting abstracts were also searched. Grade of OM was analyzed based on the World Health Organization (WHO) or National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events scales. Severe mucositis was defined as either grades 2 to 4 or grades 3 and 4, depending on the studies' definition of severity. Cohorts were analyzed based on regimen intensity; ie, reduced-intensity conditioning (RIC) (including nonmyeloablative) and myeloablative (MA). Random effect (RE) and standard logistic models weighted by the number of patients in each cohort were used for comparisons. A total of 624 studies were generated from the search. Of the 395 patients in 8 eligible MA regimen studies, 73.2% experienced any OM, whereas in 245 patients in the 6 eligible RIC regimen studies, 86.5% experienced any OM (chi-square P < .0001; RE, P = .05). Severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% of RIC patients (chi-square, P = .0421; RE, P < .01). In comparing graft-versus-host disease (GVHD) prophylaxis, only 55.4% of patients receiving nonmethotrexate regimens experienced OM; this was lower (chi-square, P < .0001; RE, P = .06) than that found among patients who received methotrexate (83.4%), either standard or reduced dose. Besides NCI and WHO grading scales, other scales included in the studies were Oral Mucositis Index, the Southwest Oncology Group Criteria, and Eastern Cooperative Oncology Group scale. To our knowledge, this is the first analysis on OM in allogeneic HSCT patients with respect to conditioning regimens, and we observed that RIC regimens led to a high incidence of OM similar to that of MA regimens. Clinical trials on treatment of OM are lacking, emphasizing the essential need for prospective studies in this arena. A significant variance in the criteria for grading OM underscores the importance of establishing a standard grading system for OM measurement in future allogeneic HSCT clinical trials. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation. [ABSTRACT FROM AUTHOR]

Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and s irolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There w as no difference in the probability of day 114 grades 2 -4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .0 0 1 ; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393. (Blood. 2014;124(8):1372-1377) [ABSTRACT FROM AUTHOR]

Many previous studies of immune reconstitution (IR) postallogeneic hematopoietic stem cell transplantation (HSCT) have focused on lymphocyte recovery. Recognizing that IR involves complex interactions between innate and adaptive immune networks, we hypothesized that patterns of both monocyte and lymphocyte recovery could provide additional prognostic information. To test our hypothesis, we analyzed data from 135 consecutive patients undergoing myeloablative allogeneic HSCT for acute myeloid (AML) and lymphoblastic leukemia (ALL) from 2001 to 2010. The absolute lymphocyte and monocyte counts (ALC and AMC, respectively) were determined longitudinally at days +15, +30, +60, and +100, and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC >0.3 × 109 cells/L were strongly associated with improved survival (overall survival [OS] 29.6 months versus 5.4 months, P = .006 and 25.3 months versus 5.1 months, P = .01 respectively), a pattern that generally continued through the day +100 evaluation. Multivariate analysis revealed the following independent prognostic factors: early disease status at transplantation, the development of chronic GVHD, the day +30 AMC, day +100 AMC, and day +100 ALC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort. Four clusters of patients were identified: clusters A-D. Patient clusters B and D both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters A and C (57.8 months versus 19.7 and 4.4 months, respectively, P < .001). Our data suggest that patients with poor lymphocyte and monocyte recovery beyond the day +60 time points may be at risk for poorer outcomes, and that further investigation into lymphoid/myeloid interactions in developing individualized immunotherapy is warranted. [Copyright &y& Elsevier]

Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease-free survival (DSF) after allogeneic hematopoietic cell transplantation (HCT). In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year overall survival (OS) rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients. [Copyright &y& Elsevier]

Introduction Reduced-intensity conditioning (RIC) regimens have expanded allogeneic hematopoietic stem cell transplantation (allo-HSCT) to patients (pts) with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who are unfit for myeloablative regimens. Several RIC regimens are typically used. We and others have previously shown that fludarabine-melphalan (FM) has a lower risk of relapse compared to fludarabine-busulfan (FB). Objectives Herein, we re-examine these findings with a larger cohort and longer follow-up. We also compare the composite endpoint graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS), and elucidate factors that predict for relapse and NRM. Methods After IRB approval, we conducted a study of pts (age ≥18) diagnosed with AML or MDS who underwent allo-HSCT from January 1st, 2008 to March 1st 2017 at Mayo Clinic Rochester. Only pts who received FM (melphalan 140 mg/m2) or FB (busulfan 0.8 mg/kg IV for 10 doses with therapeutic AUC target of 900-1500 mcmol/L[min]) were included. Grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death counted as events for GRFS. Statistical analyses were performed using JMP 13 and EZR 1.36. Results We identified 184 pts who underwent RIC allo-HSCT: 135 with AML and 49 with MDS. The median age for the entire cohort was 61 (range, 18-74). FM was used in 123 pts, while 61 received FB. Baseline characteristics were comparable (Table 1a). The median follow-up was 5 years (95% CI, 4-5.6). In line with previous findings, the cumulative incidence of relapse (CI-R) was significantly higher with FB compared to FM: 3-year CI-R was 31.7% for FB vs. 17.3% for FM (p=.04)(Figure 1a). On the other hand, there was a nonsignificant trend towards an increased CI-NRM in the FM group; at Day +100, CI-NRM was 6.5% for FM vs. 1.6% for FB (p=.24). Acute and chronic GHVD were comparable (Table 1b). The median GRFS for the entire cohort was 7.3 months (95% CI, 6.1-8.4); there was no difference between the two regimens (p=.94). Overall survival (OS) was comparable (p=.61), as were causes of death (Figure 1b). In a multivariate Fine-Gray proportional hazard model for relapse vs. NRM, which included factors in Table 2 ; disease status (CR1 vs. CR2 or active disease) predicted relapse (HR 0.42, 95% CI 0.21-0.84, p=.01). There was also a trend towards a decreased risk of relapse with FM (HR 0.54, 95% CI 0.28-1.03, p=.06). On the other hand, age was predictive of NRM (HR 1.05 per year, 95% CI 1.01-1.09, p=.01). Conclusion In the present follow-up study, there were no significant differences in GRFS or OS between FM and FB regimens for RIC allo-HSCT in AML/MDS, despite FB having a significantly higher risk of relapse. Likely, the OS was balanced by continuing NRM after FM conditioning, particularly in older pts. Further studies, ideally prospective, are required to elucidate the optimal RIC regimen matched to disease biology and pt fitness. [ABSTRACT FROM AUTHOR]

Acute GVHD biomarkers predict long-term outcomes after GVHD diagnosis. Our group has validated the MAGIC algorithm which uses the concentrations of 2 GVHD biomarkers, ST2+REG3a, to predict lethal GVHD (defined as death from GVHD without relapse) [Hartwell 2017]. Other published biomarker combinations that predict GVHD outcomes include ST2+ REG3a+TNFR1 [Levine 2015], ST2+TIM3 [Abu Zaid 2017], ST2+TNFR1 [McDonald 2015], TIM3+TNFR1+IL6 [McDonald 2015], as well as AREG alone [Holtan 2018]. It is not clear which biomarker combination best predicts lethal GVHD because these algorithms were developed using different patient cohorts with different endpoints. To answer this question, we compared the predictive accuracy of different biomarker combinations as well as these six specific combinations in the same patient cohort. We studied 522 patients with serum samples at GVHD diagnosis who were transplanted at 19 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 1, 2004 and April 30, 2017. Patients were divided into training (n = 253) and validation (n = 269) sets; validation patients were transplanted after November 1, 2015 and had not previously been used to generate an algorithm. Biomarkers were measured by ELISA and log-transformed values were used to predict 1-year lethal GVHD by competing risk regression. Four of the 6 biomarkers (ST2, REG3a, TNFR1, and TIM3) independently predicted lethal GVHD in the training set. We then developed algorithms that predicted lethal GVHD using all possible combinations of these 4 biomarkers as well as the published combination of TIM3+TNFR1+IL6 and AREG alone. The best algorithms of 1-4 biomarkers for predicting lethal GVHD were REG3a alone, ST2+REG3a, ST2+REG3a+TNFR1, and ST2+REG3a+TNFR1+TIM3. While ST2+REG3a was the most accurate combination based on the lowest Akaike Information Criterion (AIC), the other published biomarker combinations produced similar AICs. Therefore, we used the independent validation set to compare all six published algorithms. We generated area under the receiver operating characteristic curves (AUC) for each algorithm (FIG 1). We next determined the threshold that maximized sensitivity and specificity for each algorithm and calculated the cumulative incidence of lethal GVHD in the resulting high and low risk strata (FIG 2). Highly similar results were obtained when the cumulative incidence of non-relapse mortality was used as the endpoint. In a validation set of previously unanalyzed patients, several biomarker combinations reproducibly stratified patients with GVHD for risk of death. The best 4 algorithms, all of which included ST2, produced comparable outcomes. Adding TNFR1 to ST2+ REG3a did not improve accuracy. The ST2+REG3a algorithm best identifies patients at onset of GVHD for high risk of lethal GVHD and NRM, and thus remains a standard for biomarker-based risk prediction. [ABSTRACT FROM AUTHOR]

There are no validated biomarkers that measure a patient's response to therapy for acute graft-versus-host disease (GVHD), the leading cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP estimates GVHD-mediated damage to crypts throughout the lower GI tract at single time points (Hartwell et al., JCI Insight , 2017; Major- Monfried et al., Blood , 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker and would compare favorably to clinical response, the gold standard which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT , 2009; MacMillan et al., Blood , 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We computed MAPs and clinical responses for each patient. MAPs of patients who experienced 6 month NRM increased significantly compared to MAPs of patients who survived (p=0.0004). In patients whose initial MAPs were low (Ann Arbor 1, MAP < 0.141) or intermediate (Ann Arbor 2, 0.141 ≤ MAP ≤ 0.290), 6 month NRM clustered among those with the greatest increases in MAP after 28 days (Fig 1A,B). In patients with high initial MAPs (Ann Arbor 3, MAP > 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). We found that patients whose MAPs rose above the previously determined high-risk threshold MAP of 0.290 had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold had a large increase in mortality (Fig 2). When measured at day 28, MAPs predicted NRM more accurately than clinical responses, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p<0.0001). An algorithm that combined clinical response with biomarkers generated the same AUC as the MAP alone (0.83 v 0.86, p = NS). The same MAP threshold predicted risk of NRM within both clinical responders and non-responders after four weeks of treatment (Fig 3), and in those with and without significant lower GI symptoms (Fig 4). We conclude that the MAP is, to our knowledge, the first laboratory test validated as a response biomarker for acute GVHD treatment and more accurately predicts survival than clinical response after 28 days of treatment. The MAP may serve as a novel endpoint in future trials of GVHD treatment. [ABSTRACT FROM AUTHOR]