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

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.

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): The Mayo Clinic experience.

Not available.

The MAGIC algorithm probability predicts treatment response and long-term outcomes to second-line therapy for acute GVHD.

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.

Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD.

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.

Pulmonary function as a continuum of risk: critical care utilization and survival after allogeneic hematopoietic stem cell transplantation - a multicenter cohort study.

Abnormal pre-transplant pulmonary function tests (PFTs) are associated with reduced survival after allogeneic HCT. Existing scoring systems consider risk dichotomously, attributing risk only to those with abnormal lung function. In a multicenter cohort of 1717 allo-HCT recipients, we examined the association between pre-transplant PFT measures and need for ICU admission (120d), frequency of mechanical ventilation (120d) and overall survival (5 y). Predictive models were developed and validated using Cox proportional hazards, incorporating age, FEV1 (forced expiratory volume in 1-second) and diffusing capacity (DLCO). In univariate analysis, hazard ratios for each outcome (95% CI) were: mechanical ventilation (FEV1: 0.60 [0.52-0.69], DLCO: 0.69 [0.61-0.77], p < 0.001), ICU admission (FEV1: 0.74 [0.67-0.82], DLCO: 0.79 [0.72-0.86], p < 0.001) and overall survival (FEV1: HR 0.87 [0.81-0.94], DLCO: 0.83 [0.77-0.89], p < 0.001). A multivariable Cox model was developed and compared to the HCT-CI Pulmonary score in a validation cohort. This model was better at predicting need for ICU admission and mechanical ventilation, while both models predicted overall survival (p < 0.001). In conclusion, the risk conferred by pre-transplant pulmonary function should be considered in a continuous rather than dichotomous manner. A more granular prognostication system can better inform risk of critical care utilization in the early post-HCT period.

Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.

The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RSMLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (P<0.01) but not between MDS-RS with and without SF3B1 mutation (P=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (hazard ratio=1.8, 95% confidence interval: 1.1-2.8; P=0.01) and also identified age (P<0.01), transfusion need at diagnosis (P<0.01), and abnormal karyotype (P<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (P<0.01), RUNX1 (P=0.02) and IDH1 (P=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDS-SF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutation-based, disease classification for MDS-RS might be prognostically more relevant.

A Validated Risk Stratification That Incorporates MAGIC Biomarkers Predicts Long-Term Outcomes in Pediatric Patients with Acute GVHD.

Acute graft versus host disease (GVHD) is a common and serious complication of allogeneic hematopoietic cell transplantation (HCT) in children but overall clinical grade at onset only modestly predicts response to treatment and survival outcomes. Two tools to assess risk at initiation of treatment were recently developed. The Minnesota risk system stratifies children for risk of nonrelapse mortality (NRM) according to the pattern of GVHD target organ severity. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm of 2 serum biomarkers (ST2 and REG3α) predicts NRM in adult patients but has not been validated in a pediatric population. We aimed to develop and validate a system that stratifies children at the onset of GVHD for risk of 6-month NRM. We determined the MAGIC algorithm probabilities (MAPs) and Minnesota risk for a multicenter cohort of 315 pediatric patients who developed GVHD requiring treatment with systemic corticosteroids. MAPs created 3 risk groups with distinct outcomes at the start of treatment and were more accurate than Minnesota risk stratification for prediction of NRM (area under the receiver operating curve (AUC), .79 versus .62, P = .001). A novel model that combined Minnesota risk and biomarker scores created from a training cohort was more accurate than either biomarkers or clinical systems in a validation cohort (AUC .87) and stratified patients into 2 groups with highly different 6-month NRM (5% versus 38%, P < .001). In summary, we validated the MAP as a prognostic biomarker in pediatric patients with GVHD, and a novel risk stratification that combines Minnesota risk and biomarker risk performed best. Biomarker-based risk stratification can be used in clinical trials to develop more tailored approaches for children who require treatment for GVHD.

A Day 14 Endpoint for Acute GVHD Clinical Trials.

The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment.

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis.

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.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents.

Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.

Adjusting diffusing capacity for anemia in patients undergoing allogeneic HCT: a comparison of two methodologies.

BACKGROUND: Diffusing capacity (DLCO) measurements are affected by hemoglobin. Two adjustment equations are used: Cotes (recommended by ATS/ERS) and Dinakara (used in the hematopoietic stem cell transplantation comorbidity index [HCT-CI]). It is unknown how these methods compare, and which is better from a prognostication standpoint. STUDY DESIGN: This is a retrospective cohort of 1273 adult patients who underwent allogeneic HCT, completed a pre-transplant DLCO and had a concurrent hemoglobin measurement. Non-relapse mortality was measured using competing risk analysis. RESULTS: Patients had normal spirometry (FEV1 99.7% [IQR: 89.4-109.8%; FVC 100.1% [IQR: 91.0-109.6%] predicted), left ventricular ejection fraction (57.2[6.7]%) and right ventricular systolic pressure (30.1[7.0] mmHg). Cotes-DLCO was 85.6% (IQR: 76.5-95.7%) and Dinakara-DLCO was 103.6% (IQR: 90.7-117.2%) predicted. For anemic patients (Hb<10g/dL), Cotes-DLCO was 84.2% (IQR: 73.9-94.1%) while Dinakara-DLCO 111.0% (97.3-124.7%) predicted. Cotes-DLCO increased HCT-CI score for 323 (25.4%) and decreased for 4 (0.3%) patients. Cotes-DLCO was superior for predicting non-relapse mortality: for both mild (66-80% predicted, HR 1.55 [95%CI: 1.26-1.92, p < 0.001]) and moderate (<65% predicted, HR 2.11 [95%CI: 1.55-2.87, p<0.001]) impairment. In contrast, for Dinakara-DLCO, only mild impairment (HR 1.69 [95%CI 1.26-2.27, p < 0.001]) was associated with lower survival while moderate impairment was not (HR 1.44 [95%CI: 0.64-3.21, p = 0.4]). In multivariable analyses, after adjusting for demographics, hematologic variables, cardiac function and FEV1, Cotes-DLCO was predictive of overall survival at 1-year (OR 0.98 [95%CI: 0.97-1.00], p = 0.01), but Dinakara-DLCO was not (OR 1.00 [95%CI: 0.98-1.00], p = 0.20). CONCLUSION: The ERS/ATS recommended Cotes method likely underestimates DLCO in patients with anemia, whereas the Dinakara (used in the HCT-CI score) overestimates DLCO. The Cotes method is superior to the Dinakara method score in predicting overall survival and relapse-free survival in patients undergoing allogeneic HCT.

Reappraisal of mast cell leukemia based on a single institution review of 16 cases: Mast cell morphology determines clinical outcome.

Cytologic abnormalities of atypical mast cells in mastocytosis. The mature mast cells have oval-shaped nuclei, cytoplasmic hypogranulation and spindle-shaped cytology. or well-differentiated displaying a round nucleus with condensed chromatin, and abundant dense cytoplasmic granulations. Immature mast cells include promastocytes and metachromatic blast-like forms.

Venetoclax plus hypomethylating agents in DDX41-mutated acute myeloid leukaemia and myelodysplastic syndrome: Mayo Clinic series on 12 patients.

Venetoclax (VEN) is an FDA-approved selective inhibitor of B-cell leukaemia/lymphoma-2 (BCL-2), used for treating elderly or unfit acute myeloid leukaemia (AML) patients unable to undergo intensive chemotherapy. Combining VEN with hypomethylating agents (HMAs) has shown impressive response rates in high-risk myelodysplastic syndromes (MDS) and relapsed/refractory AML. However, the efficacy of VEN and HMAs in treating DDX41-mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.

Granularity in disease classification impacts survival prediction in advanced systemic mastocytosis: A single institution study of 329 informative cases.

The World Health Organization (WHO) classification system categorizes advanced systemic mastocytosis (SM-Adv) into aggressive SM (ASM), mast cell leukemia (MCL), and SM with associated hematological neoplasm (SM-AHN). By contrast, the International Consensus Classification (ICC) requires "immature" MC cytomorphology for the diagnosis of MCL and limits SM-AHN to myeloid neoplasms (SM-AMN). The current study includes 329 patients with SM-Adv (median age 65 years, range 18-88; males 58%): WHO subcategories SM-AHN (N = 212; 64%), ASM (N = 99; 30%), and MCL (N = 18; 6%); ICC subcategories SM-AMN (N = 190; 64%), ASM (N = 99; 33%), and MCL (N = 9; 3%); WHO-defined MCL with "mature" MC cytomorphology and SM-AHN associated with lymphoid neoplasms were operationally labeled as "MCL-mature" (N = 9) and SM-ALN (N = 22), respectively, and distinguished from ICC-defined MCL and SM-AMN. Multivariable analysis that included the Mayo alliance risk factors for survival in SM (age >60 years, anemia, thrombocytopenia, increased alkaline phosphatase) revealed more accurate survival prediction with the ICC versus WHO classification order: (i) survival was significantly worse with MCL-immature versus MCL-mature (hazard ratio [HR] 15; p < .01), (ii) prognostic distinction between MCL and SM-AHN/AMN was confirmed in the context of ICC (HR 9.3; p < .01) but not WHO classification order (p = .99), (iii) survival was similar between MCL-mature and SM-AMN (p = .18), and (iv) SM-AMN (HR 1.7; p < .01) but not SM-ALN (p = .37) was prognostically distinct from ASM. The current study provides evidence for the independent prognostic contribution of both the ICC system for SM-Adv and the Mayo alliance risk factors for survival in SM.