The graft-versus-leukemia (GVL) effect after allogeneic hematopoietic cell transplant (HCT) can prevent relapse but the risk of severe graft-versus-host disease (GVHD) leads to prolonged intensive ...immunosuppression and possible blunting of the GVL effect. Strategies to reduce immunosuppression in order to prevent relapse have been offset by increases in severe GVHD and nonrelapse mortality (NRM). We recently validated the MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers. In this study we tested whether the MAP could identify patients whose risk for relapse is higher than their risk for severe GVHD and NRM. The multicenter study population (n = 1604) was divided into two cohorts: historical (2006-2015, n = 702) and current (2015-2017, n = 902) with similar NRM, relapse, and survival. On day 28 post-HCT, patients who had not developed GVHD (75% of the population) and who possessed a low MAP were at much higher risk for relapse (24%) than severe GVHD and NRM (16 and 9%); this difference was even more pronounced in patients with a high disease risk index (relapse 33%, NRM 9%). Such patients are good candidates to test relapse prevention strategies that might enhance GVL.
Congenital amegakaryocytic thrombocytopenia (CAMT) is an autosomal recessive disorder characterized by thrombocytopenia with an absence of megakaryocytes. It can lead to aplastic anemia or ...myelodysplastic syndrome (MDS). CAMT is linked to a mutation in the c-MPL gene on chromosome 1, which encodes the thrombopoietin receptor. In 2005, CAMT was categorized into three types based on the severity of c-MPL gene loss. Type 1 is the most severe, leading to early-onset pancytopenia and bone marrow abnormalities. Type 2 shows a temporary increase in platelets during infancy, followed by bone marrow failure at 3-6 years due to partial gene function. Type 3 has normal c-MPL function but produces ineffective megakaryocytes. We report a case of a patient with CAMT-like symptoms, without a c-MPL gene mutation, suggesting the presence of an alternative genetic defect. Methods Multi-institutional collaboration and review of medical records in addition to PubMed search for thrombocytopenia, bleeding complications, macrocytosis, trisomy 6, GATA2 variant, inherited bone marrow failure. Case Description A 12-year-old male with severe thrombocytopenia initially observed at 2 years of age. Bleeding complications included scalp hematoma, excessive bleeding during adenoidectomy, widespread petechiae, purpura, epistaxis, and gum bleeding. During this time platelet count ranged between 30-80,000 x10 3/uL. At 10 years of age, bleeding worsened with platelet counts of 6-20,000 x10 3/uL. Mean platelet volume (MPV) remained within the normal range. Simultaneously there was a decline in hemoglobin and the emergence of macrocytosis. Mother had moderate thrombocytopenia during pregnancy, older sibling with similar thrombocytopenia but asymptomatic. Clinical presentation made immune thrombocytopenia, autoimmune disorders, and immune dysregulation-induced platelet destruction unlikely. Inherited thrombocytopenia panel testing for 42 germline variants was negative. Bone marrow biopsy showed 60% cellularity and was remarkable for a decrease in megakaryocytes. Cytogenetic analysis revealed trisomy 6 in 7/20 metaphases. Molecular hematopathology identified a GATA2 variant in 50% of the alleles. Inherited BMF panel revealed heterozygosity for multiple variants of unknown significance (VUS), including c.5096A>G (p.Asp1699Gly) in BRCA2 gene, c.3898A>G (p.Ile300Val) in LYST gene, 1408A>G (p.Thr470Ala) in PALB2 gene, and c.7240G>A (p.Val2414Met) in tVPS13B gene. Another BMF panel revealed two additional heterozygous VUS - NBEAL2 and ADAMTS13. Testing for Fanconi anemia and dyskeratosis congenita were negative. Whole exome sequencing revealed heterozygosity for a 1.57 Mb duplication on chromosome 3q29. Additional molecular pathology panel testing for 468 genes, germline genetic testing for lysosomal disorders and mucopolysaccharidoses, were also negative. Repeat bone marrow testing demonstrated a progressive decrease in cellularity to 5-30% with trilineage hypoplasia. With extensive yet inconclusive diagnostic workup, worsening clinical presentation, and progressive hypocellularity of the bone marrow, he underwent an ABO incompatible stem cell transplantation (9:10, A HR) from a mismatched unrelated donor. The conditioning regimen was myeloablative with busulfan, cyclophosphamide, anti-thymocyte globulin, and post-transplant cyclophosphamide. Currently, he is 150 days post-transplant with peripheral blood chimerism demonstrating 97.7% donor on day 98. Platelet counts have normalized, and he has not required a transfusion for nearly 100 days. Discussion This case report highlights the concept of a “double hit” hypothesis. While homozygous mutations of PALB2 and BRCA2 are individually associated with Fanconi anemia and BMF syndromes, no hematological pathology has been documented in their heterozygous forms, raising the question of whether the co-expression of these variants in a heterozygous state could result in a similar disease phenotype as their homozygous counterparts. This finding prompts further exploration into the potential impact of combined variants on disease manifestation.
OBJECTIVES/SPECIFIC AIMS: The first aim of the study is to evaluate the accuracy of serum biomarkers of acute GVHD measured after four weeks of corticosteroid therapy to predict 6 month NRM. The ...second aim of this study is to compare the accuracy of the biomarker algorithm to that of clinical response to corticosteroids after four weeks. The third aim of the study is to develop a novel regression model that uses weekly biomarker measurements over the first month of corticosteroid therapy to predict 6 month NRM. METHODS/STUDY POPULATION:. Patients who received HCT at one of 22 IRB-approved centers and provided blood samples to the Mount Sinai Acute GVHD International Consortium (MAGIC) biorepository and developed GVHD between January 2008 to May 2018 are included in this study. Patients were divided by time into a training set (Jan 2008-Dec 2015, n=233) for model development and a validation set (Jan 2015-May 2018, n=357) to evaluate the predictive performance of the model. The later time of the validation set was chosen deliberately to model contemporaneous GVHD treatment practices. The size of each group was designed so that there would be roughly equal numbers of deaths in both groups. RESULTS/ANTICIPATED RESULTS:. Serum concentrations of GVHD biomarkers after one month of corticosteroid therapy were measured in the validation set, and the predicted probability of NRM (
$\hat{\rm p}$
) was computed according to the previously published algorithm:
$\log-\log(1 - \hat{\rm p})=-11.263 + 1.844({\rm logST}2)+ 0.577({\rm logREG}3\alpha)$
. The performance of the biomarker algorithm was evaluated by creating receiver operating characteristic (ROC) curves and calculating the area under the curve (AUC) in the validation set. The AUC of the biomarker algorithm was a significantly better predictor of 6 month NRM than clinical response to treatment after four weeks of corticosteroids (0.84 vs. 0.64, p<0.001), which is a clinically relevant improvement in accuracy. To evaluate serial biomarker monitoring, serum biomarker concentrations will be measured weekly at five time points from treatment initiation to one month after corticosteroid therapy. We will use these values in the training set to develop a regression model for 6 month NRM that accounts for repeated biomarker measurements. The performance of this model will be tested in the validation set and the accuracy of the serial biomarker measurements will be compared to the accuracy of measuring biomarkers at the single time point after four weeks of corticosteroid therapy. An AUC improvement of 0.05 would be considered clinically significant. DISCUSSION/SIGNIFICANCE OF IMPACT: Clinical response to treatment after four weeks has been the standard endpoint in GVHD interventional trials for decades. If biomarkers measured at the same time more accurately predict long term mortality, this study would provide the basis for a novel endpoint in GVHD trials and enable more accurate determination of effect size of experimental interventions. An accurate biomarker algorithm will prove useful in guiding immunosuppressive treatment decisions for patients with GVHD. Patients identified by the algorithm as low-risk may benefit from reduced-dose corticosteroid therapy, potentially reducing lethal opportunistic infections. Patients identified as high-risk will be candidates for more intensive immunosuppression or investigational therapies. This precision medicine approach tailors therapy to the individual patient’s biology.
Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after ...HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.
ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).
In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (
= .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo,
= .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%,
< .001), and the SGFS was better (97.7%
58.7%,
< .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.
Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
A disease risk index (DRI) that was developed for adults with hematologic malignancy who were undergoing hematopoietic cell transplantation is also being used to stratify children and adolescents by ...disease risk. Therefore, to develop and validate a DRI that can be used to stratify those with AML and ALL by their disease risk, we analyzed 2569 patients aged <18 years with acute myeloid (AML; n = 1224) or lymphoblastic (ALL; n = 1345) leukemia who underwent hematopoietic cell transplantation. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets, and separate prognostic models were derived for each disease. For AML, 4 risk groups were identified based on age, cytogenetic risk, and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (>8) risk groups was 78%, 53%, 40%, and 25%, respectively (P < .0001). For ALL, 3 risk groups were identified based on age and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups was 68%, 51%, and 33%, respectively (P < .0001). We confirmed that the risk groups could be applied to overall survival, with 5-year survival ranging from 80% to 33% and 73% to 42% for AML and ALL, respectively (P < .0001). This validated pediatric DRI, which includes age and residual disease status, can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.
•The pediatric DRI stratified children with AML and ALL into clinically distinct risk groups based on pretransplantation information.•Risk stratification was based on age at transplant, cytogenetics, and disease status including minimal residual disease at transplant.
Display omitted
A subset of patients with borderline hypoplastic left heart may be candidates for single to biventricular conversion, but long-term morbidity and mortality persist. Prior studies have shown ...conflicting results regarding the association of preoperative diastolic dysfunction and outcome, and patient selection remains challenging.
Patients with borderline hypoplastic left heart undergoing biventricular conversion from 2005 to 2017 were included. Cox regression identified preoperative factors associated with a composite outcome of time to mortality, heart transplant, takedown to single ventricle circulation, or hemodynamic failure (defined as left ventricular end-diastolic pressure >20 mm Hg, mean pulmonary artery pressure >35 mm Hg, or pulmonary vascular resistance >6 international Woods units).
Among 43 patients, 20 (46%) met the outcome, with a median time to outcome of 5.2 years. On univariate analysis, endocardial fibroelastosis, lower left ventricular end-diastolic volume/body surface area (when <50 mL/m
), lower left ventricular stroke volume/body surface area (when <32 mL/m
), and lower left:right ventricular stroke volume ratio (when <0.7) were associated with outcome; higher preoperative left ventricular end-diastolic pressure was not. Multivariable analysis demonstrated that endocardial fibroelastosis (hazard ratio, 5.1, 95% confidence interval, 1.5-22.7, P = .033) and left ventricular stroke volume/body surface area 28 mL/m
or less (hazard ratio, 4.3, 95% confidence interval, 1.5-12.3, P = .006) were independently associated with a higher hazard of the outcome. Approximately all patients (86%) with endocardial fibroelastosis and left ventricular stroke volume/body surface area 28 mL/m
or less met the outcome compared with 10% of those without endocardial fibroelastosis and with higher stroke volume/body surface area.
History of endocardial fibroelastosis and smaller left ventricular stroke volume/body surface area are independent factors associated with adverse outcomes among patients with borderline hypoplastic left heart undergoing biventricular conversion. Normal preoperative left ventricular end-diastolic pressure is insufficient to reassure against diastolic dysfunction after biventricular conversion.
•Itacitinib monotherapy is as effective as systemic corticosteroids for the treatment of low-risk acute GVHD.•Itacitinib monotherapy resulted in fewer serious infections compared with systemic ...corticosteroids.
Display omitted
The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.
Primary therapy for acute graft vs host disease (aGVHD) is systemic corticosteroids. Etra et al report on the results of a nonrandomized study of monotherapy with the selective JAK1 inhibitor itacitinib in 70 patients with low-risk aGVHD, compared to a contemporaneous cohort of steroid-treated patients. Responses to itacitinib were comparable to steroids (89% vs 86% at 28 days), with fewer serious viral and fungal infections with itacitinib, providing support for a randomized clinical trial in low-risk GVHD.
Multisystem inflammatory syndrome in children (MIS‐C) is a syndrome associated with coronavirus disease 2019. Various phenotypes of MIS‐C have been described including Kawasaki disease (KD). Although ...perineal desquamation is a known early sign of KD, to our knowledge, this rash has not yet been described in the KD phenotype of MIS‐C. In this article, we report two patients in whom perineal desquamation was an early clue for the KD phenotype of MIS‐C.
The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP), derived from 2 serum biomarkers, measures damage to crypts in the gastrointestinal tract during ...graft-versus-host disease (GVHD). We hypothesized that changes in MAP after treatment could validate it as a response biomarker. We prospectively collected serum samples and clinical stages of acute GVHD from 615 patients receiving hematopoietic cell transplantation in 20 centers at initiation of first-line systemic treatment and 4 weeks later. We computed MAPs and clinical responses and compared their abilities to predict 6-month nonrelapse mortality (NRM) in the validation cohort (n = 367). After 4 weeks of treatment, MAPs predicted NRM better than the change in clinical symptoms in all patients and identified 2 groups with significantly different NRM in both clinical responders (40% vs 12%, P < .0001) and nonresponders (65% vs 25%, P < .0001). MAPs successfully reclassified patients for NRM risk within every clinical grade of acute GVHD after 4 weeks of treatment. At the beginning of treatment, patients with a low MAP that rose above the threshold of 0.290 after 4 weeks of treatment had a significant increase in NRM, whereas patients with a high MAP at onset that fell below that threshold after treatment had a striking decrease in NRM that translated into clear differences in overall survival. We conclude that a MAP measured before and after treatment of acute GVHD is a response biomarker that predicts long-term outcomes more accurately than change in clinical symptoms. MAPs have the potential to guide therapy for acute GVHD and may function as a useful end point in clinical trials.
•The MAGIC algorithm probability, computed from 2 serum biomarkers, predicts mortality in all GVHD grades after 4 weeks of treatment.•Dynamic changes in the MAGIC algorithm probability occur within all biomarker risk groups and can guide therapy.
Display omitted
PDF
