Citations

e19023 Background: Acute GVHD (aGVHD) is a major cause of mortality and morbidity following stem cell transplantation (HCT). In effort to prognostic patients with aGVHD, the Mount Sinai Acute GVHD International Consortium (MAGIC) combined two biomarkers, ST2 and REG3α to generate an algorithm known as the Ann Arbor (AA) biomarker risk. This is now available as a commercial test to help predict risk for severe acute GVHD and non-relapse mortality when done at the onset of symptomatic aGVHD. Our institution began utilizing these lab values and here we report our “real world” experience. The primary aim was to correlate AA risk probabilities with recently defined endpoints including day 28 overall response rate (ORR) and 6 month freedom from treatment failure (6mFFTF) and overall survival (OS). Methods: 58 HCT patients who underwent HCT between October 2018 and November 2019 and had the biomarker assay at the onset of aGVHD were identified from the institutional database and clinical information about disease, transplant and outcomes was obtained from the medical records. Clinical staging of aGVHD was documented per standardized published guidelines. Day 28 ORR was defined as complete response by day 28. 6mFFTF was defined as a patient being alive, without relapse of underlying disease or addition of new systemic therapy for aGVHD, and prior to the development of cGVHD. Results: When comparing low (n = 39), intermediate (n = 11), and high (n = 8) AA risk, there was no difference in age ( p =0.254), primary disease ( p =0.10), DRI ( p =0.994), donor source ( p =0.193), conditioning regimen intent ( p =0.537), GVHD prophylaxis ( p =0.351) ATG use ( p =0.06). Low AA risk was associated with lower grades of aGVHD at onset (grade I = 15%, grade II = 80%, grade III = 5%, grade IV = 0%), whereas high AA risk was associated with higher grades of aGVHD at onset (grade I = 0%, grade II = 50%, grade III = 25%, grade IV = 25%) ( p =0.009). For low, intermediate, and high AA risk the day 28 ORR was 69%, 45% and 29% ( p = 0.083); the 6mFFTF was 82%, 82%, and 25% ( p = 0.0001); 6 month OS was 92%, 100%, and 50% ( p = 0.0006) respectively. Conclusions: Our study shows a high correlation between AA risk and outcomes. High risk AA risk was associated with inferior outcomes This study was limited by the retrospective single institutional experience with relatively small numbers. However, our findings using the commercial assay mirror that seen with the MAGIC studies. Our “real world data” can serve as a foundation and continued validation for institutional implementation of AA risk stratification for aGVHD.

7046 Background: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of JAKi naïve or previously JAKi treated intermediate/high risk MF patients as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 enrolled JAKi-naïve patients with MF (n = 432) double-blind randomized 1:1 to MMB or ruxolitinib (RUX). S2 enrolled patients with MF with hematological toxicity during prior RUX therapy (n = 156) randomized 2:1 to open-label MMB or best available therapy (BAT; consisting of RUX in 88% of patients). In both trials, following the 24-week randomized treatment (RT) period, patients could continue MMB (MMB→MMB) and those randomized to RUX/BAT could cross-over to MMB (RUX/BAT→MMB) for extended treatment (ET). Previously published data from the SIMPLIFY studies demonstrate robust overall survival (OS) for MMB-treated patients in S1 and S2 (median not reached and 34.3 months, respectively) with a maximum follow up of approximately 5 years and median of 2.9 years in S1 and 2.3 years in S2. Methods: OS data for patients receiving MMB in S1 and S2 are reported here for subgroups defined by Week 24 (W24) transfusion independence (TI) responders vs non-responders, and also other efficacy endpoints. Survival was estimated using KM analysis with descriptive log-rank tests for comparison applied (all p-values are descriptive). Results: As previously reported, W24 TI rates were higher in the MMB arms of S1 (67% vs 49%) and S2 (43% vs 21%). In S1, W24 TI responders in the MMB group show an OS advantage, with median OS not reached and 3-year survival of 80% (HR = 0.30; p = 0.0001) compared to MMB TI non-responders. Similarly in S2, W24 TI responders in the MMB group show a trend toward better OS compared to TI non-responders (HR = 0.57; p = 0.0652). The HRs in S1 for MMB responders vs non-responders for W24 SRR and TSS were 0.59 (p = 0.0904) and 0.65 (p = 0.1657), respectively. Alternative analyses using OS defined from W24 demonstrated consistent results. Conclusions: These new analyses suggest JAKi naïve patients receiving MMB who maintain or achieve TI at W24 have favorable OS compared to MMB TI non-responders, with a similar trend observed in S2. These findings are consistent with anemia and transfusion dependency being key predictors of shortened OS in MF and suggest that TI response at W24 may become a surrogate for clinical benefit, supporting the clinical relevance of MMB’s differentiated pro-erythropoietic ACVR1 inhibition. Clinical trial information: NCT01969838.

AbstractBackgroundBipolar disorder (BD) and borderline personality disorder (BPD) share overlapping phenomenology and are frequently misdiagnosed. This study investigated the diagnostic accuracy of the Mood Disorder Questionnaire (MDQ) and McLean Screening Instrument for Borderline Personality Disorder (MSI) in a clinical inpatient setting and whether individual screening items could differentiate BD from BPD.Methods757 sequential inpatients admitted to a Mood Disorder Unit completed both the MDQ and MSI. Screen positive for the MDQ was defined as ≥7/13 symptoms endorsed with concurrence and at least moderate impact. Screen positive for the MSI was defined as a score of ≥7. The clinical discharge summary diagnosis completed by a board‐certified psychiatrist was used as the reference standard to identify concordance rates of a positive screen with clinical diagnosis. Individual items predicting one disorder and simultaneously predicting absence of other disorder by odds ratio (OR>and <1) were identified.ResultsBoth screening instruments were more specific than sensitive (MDQ 83.7%/ 67.8%, MSI 73.2% / 63.3%). MDQ individual items (elevated mood, grandiosity, increased energy, pressured speech, decreased need for sleep, hyperactivity) were significant predictors of BD diagnosis and non‐predictors of BPD diagnosis. Whereas MSI subitem, self‐harm behaviors/suicidal attempts predicted BPD in the absence of BD; distrust and irritability were additional predictors of BPD.ConclusionWhile this study is limited by the lack of structured diagnostic interview, these data provide differential symptoms to discriminate BD and BPD. Further work with larger datasets and more rigorous bioinformatics machine learning methodology is encouraged to continue to identify distinguishing features of these two disorders to guide diagnostic precision and subsequent treatment recommendations.

Abstract Venetoclax (Ven) combined with a hypomethylating agent (HMA) has now emerged as an effective treatment regimen for acute myeloid leukemia, in both de novo and relapsed/refractory setting. The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast‐phase myeloproliferative neoplasm (MPN‐BP). Pre‐leukemic phenotype included essential thrombocythemia (ET)/post‐ET myelofibrosis (34%), polycythemia vera (PV)/post‐PV myelofibrosis (38%) and primary myelofibrosis (28%). Twenty‐nine study patients were fully annotated cytogenetically and molecularly (NGS): 69% harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%) and U2AF1 (7%). All patients received Ven combined with either azacitidine ( n = 12) or decitabine ( n = 20); either up front ( n = 23) or after failing another induction therapy ( n = 9). Complete remission with (CR) or without (CRi) count recovery was achieved in 14 (44%) patients and was more likely to occur in the absence of pre‐leukemic PV/post‐PV myelofibrosis phenotype ( p < .01), complex karyotype ( p < .01) or K/NRAS ( p = .03) mutations; seven of eight patients (88%) without vs four of 21 (19%) with complex karyotype or K/NRAS mutation achieved CR/CRi ( p < .01); all 11 informative patients with pre‐leukemic PV/post‐PV myelofibrosis phenotype displayed complex karyotype ( p < .01). In contrast, neither TP53 ( p = .45) nor IDH1/2 ( p = .63) mutations affected response. Compared to historical controls treated with HMA alone ( n = 26), the CR/CRi rate (44% vs 4%) and median survival (8 vs 5.5 months) were more favorable with Ven + HMA, but without significant difference in overall survival. Importantly, six patients with CR/CRi subsequently received allogeneic hematopoietic stem cell transplant (AHSCT). Note, Ven + HMA produces robust CR/CRi rates in MPN‐BP, especially in the absence of RAS mutations and complex karyotype, thus enabling AHSCT, in some patients.

Abstract Introduction: Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously described AREG as a circulating biomarker of late-onset aGVHD, but its relevance combined with clinical risk factors has not yet been tested in a large cohort of patients with aGVHD occurring prior to day 100 post-transplant. We therefore tested samples from two aGVHD first-line treatment trials, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0302 and 0802, and identified a clinically relevant threshold level of circulating AREG at aGVHD onset. We then investigated whether incorporating AREG into the refined Minnesota Risk Score could further risk-stratify patients. Patients and Methods: Blood samples were obtained at the onset of systemic aGVHD treatment within BMT CTN 0302 (serum) and BMT CTN 0802 (plasma). All patients with response data and samples for analysis from both trials were included (N=251). We determined the association of AREG with clinical outcomes, including risk stratification by the refined Minnesota criteria, day 28 complete/partial response (CR/PR) to first-line therapy, 2-year overall survival (OS) and 6-month and 2-year non-relapse mortality (NRM). We investigated the effect of AREG on clinical endpoints per a doubling in the value of AREG, defined a clinically relevant threshold level in the AREG values using two-fold cross-validation, and confirmed the clinical relevance of this cut-point in independent samples (N=92) from pooled from drawn from the Chronic GVHD Consortium and the Mount Sinai Acute GVHD International Consortium (MAGIC). Results: In patients enrolled in BMT CTN 0302/0802, AREG levels were 1.7-fold higher in patients with Minnesota high-risk (HR) compared to standard-risk (SR) aGVHD (HR median 53.4 vs SR 31 pg/ml, p&lt;0.01). Every 2-fold increase in AREG was associated with a 33% decrease in the likelihood of day 28 CR/PR (odds ratio [OR] 0.67, p&lt;0.01, table). Clinical factors alone, as determined by the refined Minnesota Risk Score, were associated with day 28 CR/PR (p=0.02, table). Adding AREG to the Minnesota Risk Score could further risk-stratify patients. Minnesota SR patients with elevated AREG ≥ 33 pg/mL showed a 59% lower odds of day 28 CR/PR than SR patients with low AREG (OR 0.41, p=0.02). Patients with Minnesota HR aGVHD with AREG ≥ 33 pg/mL had the worst outcomes, with an 82% lower odds of day 28 CR/PR in comparison to HR with low AREG (OR 0.18, p&lt;0.01). High AREG was associated with worse OS and NRM in both Minnesota SR (hazard ratios 2-year OS 2.3, p&lt;0.01 and 6 month NRM 2.95, p=0.01, respectively) and HR patients (hazard ratios 2-year OS 3.35, p&lt;0.01 and 6-month NRM 9.38, p&lt;0.01 respectively, figure). Finally, in independent samples from the Chronic GVHD Consortium/MAGIC we confirmed that high AREG was associated with worse day 28 CR/PR (55.2% vs. 79.4%, p=0.02) and significantly worse 6-month survival after the onset of aGVHD (57.1% vs. 82.5%, p=0.01). Conclusion: AREG is elevated in patients with poor aGVHD outcomes and adds to the accuracy of risk stratification when combined with the refined Minnesota Risk Score. AREG ≥33 pg/mL at aGVHD onset is associated with lower day 28 CR/PR and higher mortality in samples from 4 multicenter cohorts. The mechanism of elevated circulating AREG in severe aGVHD is not yet known, although we hypothesize the degree of AREG elevation reflects the intensity of immune-mediated tissue injury resulting in AREG release. With accumulating evidence of altered EGFR ligands in aGVHD, further investigation into epithelial repair pathways involving AREG may lead to new adjunctive therapies to overcome poor steroid response in high-risk aGVHD. Disclosures Holtan: Incyte: Other: One-time advisory board member. Khera: Novartis: Consultancy. Lee: Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Chen: Immudex: Research Funding. Arora: Takeda Oncology: Consultancy. Flowers: Pharmacyclics: Consultancy. Cutler: Pfizer: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy; Astellas: Consultancy. Jagasia: Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding; Mallinckrodt: Consultancy. Hexner: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Levine: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. MacMillan: Magenta Therapeutics: Research Funding.

Abstract Traditional Hardy–Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

Abstract Therapeutics that target cellular senescence, including novel “senolytic” compounds, hold significant promise for treating or preventing obesity-induced metabolic dysfunction, type 2 diabetes, and the multiple complications of diabetes and obesity. Senolytics selectively clear senescent cells, which accumulate with aging and obesity and represent a fundamental mechanism of aging that contributes to metabolic dysfunction and diabetes pathogenesis. In addition to improving metabolic function, targeting senescent cells holds promise as a preventive strategy to reduce the incidence and severity of diabetes complications. The intermittent administration schedule used for senolytic therapy may confer benefits in terms of improving adherence and limiting adverse effects. It is necessary to design effective clinical trials that will safely translate discoveries from preclinical models into human studies that may pave the way for a novel therapeutic class for treating obesity, diabetes, and their complications. In this review, we outline what is known regarding the role of cellular senescence in the pathogenesis of type 2 diabetes and its complications, present evidence from preclinical models that targeting cellular senescence is beneficial, review senolytic drugs, and outline the features of clinical trials investigating the role of targeting senescent cells for diabetes.

OBJECTIVE Posterior fossa decompression with duraplasty (PFDD) is commonly performed for Chiari I malformation (CM-I) with syringomyelia (SM). However, complication rates associated with various dural graft types are not well established. The objective of this study was to elucidate complication rates within 6 months of surgery among autograft and commonly used nonautologous grafts for pediatric patients who underwent PFDD for CM-I/SM. METHODS The Park-Reeves Syringomyelia Research Consortium database was queried for pediatric patients who had undergone PFDD for CM-I with SM. All patients had tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and ≥ 6 months of postoperative follow-up after PFDD. Complications (e.g., pseudomeningocele, CSF leak, meningitis, and hydrocephalus) and postoperative changes in syrinx size, headaches, and neck pain were compared for autograft versus nonautologous graft. RESULTS A total of 781 PFDD cases were analyzed (359 autograft, 422 nonautologous graft). Nonautologous grafts included bovine pericardium (n = 63), bovine collagen (n = 225), synthetic (n = 99), and human cadaveric allograft (n = 35). Autograft (103/359, 28.7%) had a similar overall complication rate compared to nonautologous graft (143/422, 33.9%) (p = 0.12). However, nonautologous graft was associated with significantly higher rates of pseudomeningocele (p = 0.04) and meningitis (p < 0.001). The higher rate of meningitis was influenced particularly by the higher rate of chemical meningitis (p = 0.002) versus infectious meningitis (p = 0.132). Among 4 types of nonautologous grafts, there were differences in complication rates (p = 0.02), including chemical meningitis (p = 0.01) and postoperative nausea/vomiting (p = 0.03). Allograft demonstrated the lowest complication rates overall (14.3%) and yielded significantly fewer complications compared to bovine collagen (p = 0.02) and synthetic (p = 0.003) grafts. Synthetic graft yielded higher complication rates than autograft (p = 0.01). Autograft and nonautologous graft resulted in equal improvements in syrinx size (p < 0.0001). No differences were found for postoperative changes in headaches or neck pain. CONCLUSIONS In the largest multicenter cohort to date, complication rates for dural autograft and nonautologous graft are similar after PFDD for CM-I/SM, although nonautologous graft results in higher rates of pseudomeningocele and meningitis. Rates of meningitis differ among nonautologous graft types. Autograft and nonautologous graft are equivalent for reducing syrinx size, headaches, and neck pain.