Citations

Abstract Background: A major cause of mortality in patients receiving hematopoietic stem cell transplantation (HCT) is acute graft-versus-host disease (GVHD), a multiorgan disorder that includes the skin, liver and gastrointestinal tract. We have previously identified elafin, a protease inhibitor overexpressed in inflamed epidermis, as a diagnostic biomarker of GVHD in the skin, the most commonly involved GVHD organ. However, our initial study was limited to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT patients is GI GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have since been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker of acute GVHD in the general population of previously unstudied acute GVHD patients, and to compare it to ST2 and REG3α. Study Design: 526 patients who received systemic corticosteroid treatment for skin GVHD were analyzed from the Mount Sinai Acute GVHD International Consortium (MAGIC), which includes patients from 25 HCT centers. We used ELISA to measure serum concentrations of elafin, ST2 and REG3α. Patients were divided randomly into equal training and validation sets; and we developed a competing risk regression model for 6-month NRM using elafin concentration in the training set. We developed additional models for 6-month NRM using concentrations of ST2 and REG3α, or the combination of all three biomarkers as predictors. We then constructed ROC curves to evaluate the predictive accuracy of each model and to analyze the ability of each model to stratify patients into high- and low-risk groups. We analyzed the cumulative incidence of 6-month NRM and overall survival in each model and compared the accuracy of each model in the validation set. Results: The area under the receiver operating curve (AUROC) for elafin alone was 0.55 whereas it was 0.75 and statistically superior (P = 0.02) for the combination of ST2 and REG3α. The combination of 3 biomarkers produced an AUROC of 0.76 that was not significantly better than the two biomarker model (P = 0.10). Elafin concentrations, either alone or in combination with ST2 and REG3α, did not produce higher hazard ratios of NRM (data not shown). Patients in the low-risk elafin group paradoxically demonstrated a higher incidence of 6-month NRM, although this difference was not statistically significant (17% vs. 11%, P=0.19), and both overall survival at 6 months (68% vs. 68%, P>0.99) and four-week response (78% vs. 78%, P=0.98) were similar in the low- and high-risk elafin groups (Figure 1). As demonstrated in previous data sets, the combination of ST2 and REG3α divided patients into two groups with a nearly five-fold difference in NRM (6.7% vs. 31%, P <0.001). Conclusion: We demonstrated that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD in a multicenter population of patients treated systemically for acute GVHD do not predict 6-month NRM, overall survival, or treatment response. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD. Figure 1. Cumulative incidence of nonrelapse mortality and overall survival in high and low risk groups Six-month cumulative incidences of nonrelapse mortality (NRM) in high (solid line) and low (dotted line) risk groups defined by optimized biomarker thresholds (upper panels) and six-month overall survival estimated using the Kaplan-Meier method (lower panels). (A) Cumulative incidence of NRM (14%) and overall survival (75%) in the total validation set (N=263). (B) Cumulative incidence of NRM in the low (N=150) and high (N=113) elafin group (17% vs. 11%, P=0.19). Overall survival in the low and high elafin group (68% vs. 68%, P > 0.99). (C) Cumulative incidence of NRM in the low (N=175) and high (N=88) ST2 + REG3a group (6.7 vs. 31%, P < 0.001). Overall survival in the low and high ST2 + REG3a group (77% vs. 51%, P < 0.001). (D) Cumulative incidence of NRM in the low (N=180) and high (N=83) elafin + ST2 + REG3a group (7.0 vs. 30%, P < 0.001). Overall survival in the low and high elafin + ST2 + REG3a group (79% vs. 64%, P < 0.001). Figure 1 Figure 1. Disclosures Ozbek: Viracor: Patents & Royalties: GVHD biomarker patent with royalties from Viracor. DeFilipp: Omeros, Corp.: Consultancy; Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Syndax Pharmaceuticals, Inc: Consultancy. Grupp: Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding; Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards. Hexner: Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tmunity Therapeutics: Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Kitko: Co-investigator on two NIH grants as part of the cGVHD consortium: Research Funding; Vanderbilt University Medical Center: Current Employment; PER: Other: PER - CME educational talks about GVHD; Horizon: Membership on an entity's Board of Directors or advisory committees. Qayed: Novartis: Honoraria; Mesoblast: Honoraria; Medexus: Honoraria. Reshef: ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Bayer: Consultancy; Gilead and Novartis: Honoraria; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy. Levine: Incyte: Consultancy, Research Funding; Viracor: Patents & Royalties: GVHD biomarker patent with royalties from Viracor; Mesoblast: Consultancy, Research Funding; Equillium Bio: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Talaris Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees; Symbio: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Kamada: Research Funding. Ferrara: Eurofins Viracor: Consultancy, Other: Royalties. Chen: Incyte: Consultancy; Gamida: Consultancy.

Abstract Background Prognosis is poor for patients (pts) with relapsed/refractory multiple myeloma (RRMM; median overall survival: <1 year), indicating a clear need to identify agents with novel mechanisms of action. B-cell maturation antigen (BCMA) has recently emerged as a novel treatment target for MM due to its highly selective expression in plasma cells. TNB-383B, a BCMA x CD3 T-cell engaging bispecific antibody, was designed to overcome the toxicity limitations of existing BCMA therapies and has demonstrated promising results in an ongoing first-in-human phase 1 study in pts with RRMM (Rodriguez C, et al. Blood 2020;136[suppl 1]:43-44). Herein, we report the updated efficacy and safety outcomes of this phase 1 study. Methods This multicenter, phase 1, open-label, dose-escalation/expansion study (NCT03933735) enrolled pts with RRMM (≥3 prior lines of therapy that included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody), estimated glomerular filtration rate ≥30 mL/min as calculated by the Modification of Diet in Renal Disease formula, and ECOG performance status ≤2. Prior BCMA-targeted therapy is prohibited. Primary objectives include safety/tolerability, pharmacokinetics (PK), and determination of recommended phase 2 dose (RP2D); secondary objectives include assessment of clinical activity (per IMWG criteria 2016). TNB-383B is administered intravenously over 1-2 hours every 3 weeks (Q3W) with the first dose administered inpatient. The study uses a 3+3 design with backfilling for dose and permits intrapatient dose escalation to highest safe dose. Dose expansion was initiated on selection of RP2D. Pts are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. The efficacy-evaluable population includes all pts who received at least 1 dose of TNB-383B and have at least 1 postdose assessment. The safety population includes all pts who received at least 1 dose of study drug; adverse events (AEs) are graded according to NCI CTCAE v5.0. Results As of 10 May 2021, 103 pts (dose escalation, n=73; dose expansion, n=30) have been treated with TNB-383B (0.025-120 mg). The RP2D of 60 mg Q3W was selected on the basis of tolerability, safety, PK, and clinical activity. Pt demographics and baseline characteristics are summarized in Table 1. Three dose-limiting toxicities were reported in dose escalation (platelet count decreased: grade [Gr] 4, 60 mg; cytokine release syndrome [CRS]: Gr 3, 90 mg and 120 mg); none were reported as serious. Treatment-related AEs (TRAEs) were reported in 79 (77%) pts, with Gr ≥3 and serious AEs occurring in 33 (32%) and 23 (22%) pts, respectively. The most common TRAEs (Table 2) include CRS (n=54, 52%), neutropenia (n=18, 17%), and fatigue (n=14, 14%). At the RP2D (n=39), the Gr ≥3 CRS rate was 3% (n=1). Onset of CRS typically occurred on the same or next day following the first dose and all pts recovered using tocilizumab or standard supportive care measures. Treatment-emergent AEs (TEAEs) of infusion-related reactions were reported in 8 (8%) pts and infections occurred in 29 (28%) pts; pneumonia (n=5, 5%) and upper respiratory tract infection (n=4, 4%) were the most common. Five deaths from TEAEs were reported; all were unrelated to study drug. Forty-two (40%) pts discontinued treatment due to disease progression. In the dose-escalation cohorts of ≥40 mg Q3W (n=24), the objective response rate (ORR) was 79% (19/24), with a very good partial response or better (≥VGPR) rate of 63% (15/24), and a complete response (CR) rate of 29% (7/24) at the data cutoff date; these pts have the longest follow-up (ie, mature data) with median time on study of 6.1 months (Figure 1). At doses ≥40 mg in the combined dose-escalation and -expansion cohorts (n=44), the observed ORR, ≥VGPR, and CR rates were 64% (28/44), 43% (19/44), and 16% (7/44), respectively; these pts have shorter follow-up (ie, immature data) with median time on study of 3.1 months. Twenty-nine (66%) of the 44 pts administered ≥40 mg were triple-class refractory and reported an ORR of 55% (16/29). Conclusions TNB-383B in pts with RRMM is well tolerated with an ORR of 79% observed at doses ≥40 mg in the dose-escalation cohorts. Despite having a shorter follow-up period, this trend was also observed at doses ≥40 mg in the combined dose-escalation/expansion cohorts (ORR: 64%). Enrollment into the dose-expansion arm is ongoing; updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Kumar: Novartis: Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. D'Souza: Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Janssen, Prothena: Consultancy. Shah: Oncopeptides: Consultancy; Nektar: Research Funding; Poseida: Research Funding; Janssen: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; CSL Behring: Consultancy; Teneobio: Research Funding; Kite: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy; Precision Biosciences: Research Funding; Sanofi: Consultancy. Rodriguez: Takeda: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau. Voorhees: AbbVie Inc, Bristol-Myers Squibb Company; Consulting Agreement: GlaxoSmithKline, Novartis, Oncopeptides: Other: Advisory Committee; Bristol-Myers Squibb Company.: Other: Data Safety & Monitoring. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Buelow: Teneobio, Inc.: Current Employment, Current holder of stock options in a privately-held company. Freise: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Yue: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Pothacamury: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Polepally: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria.

Abstract Background: IVO is an oral potent inhibitor of mutated IDH1 (IDH1m) enzyme, recently approved for the treatment (Tx) of ND adult patients (pts) with IDH1m AML ≥75 years old or with comorbidities precluding use of intensive induction chemotherapy, and adult pts with relapsed or refractory AML. In this Phase 2 sub-study of the Beat AML Master Trial, we evaluated the efficacy of IVO + AZA combination Tx in ND pts aged ≥60 years with IDH1m AML (ClinicalTrials.gov: NCT03013998) Methods: This open-label multicenter (16 sites / 9 enrolling) combination Tx study enrolled ND pts with R132 mIDH1 AML, utilizing the modified minimax Simon's 2-stage Phase 2 design. Pts received IVO + AZA for 6 cycles in the absence of disease progression (PD), unacceptable toxicity or stem cell transplant. Pts who achieved complete remission (CR)/complete remission with hematologic improvement (CRh)/complete remission with incomplete hematologic recovery (CRi) continued IVO + AZA for a total of 12 cycles, then IVO monotherapy until PD. Pts without CR/CRh/CRi after 6 cycles continued IVO + AZA if they demonstrated Tx benefit, as defined in Figure 1. Key eligibility included ND IDH1 R132 mutated AML pts aged ≥60 years and ECOG performance status 0 - 2 (Karnofsky ≥60). All pts received IVO 500 mg/day orally in continuous 28-day cycles + AZA 75 mg/m2 IV or SC on days 1-7 every 28 days. The primary endpoint was CR+CRh+CRi rate after 6 cycles of Tx. Response was assessed using modified 2017 ELN AML criteria. The modified minimax Simon's 2-stage design required 40 pts and tested the null hypothesis that the CR/CRh/CRi rate equaled 25% vs the alternative of 50% (one-sided alpha = 0.025, power 90%). Stage 1 required >5/16 responses for continued enrollment. Even though these criteria were met, the sponsor decided to discontinue the trial on 12/12/2019. Here we report the final primary endpoint results. Data were frozen 02/03/2021. Results: Between 07/2018 and 11/2019, 19 patients were enrolled with IDH1m AML; 18 started IVO + AZA Tx and are included in the analyses. At data freeze, 5 pts had died and 7 pts still on Tx were offered standard of care IVO. Median age of the pts was 75 years, 50% were ≥75 years, 61% were female and 89% were White (Table 1). The most common reasons for Tx discontinuation were trial discontinued by sponsor (7 or 39%), stem cell transplant (4 or 22%), and PD (3 or 17%). A total of 13 pts achieved CR/CRh/CRi (72%) by up to 6 cycles of Tx (Table 2 & Figure 2). Over the entire study period, 14 pts achieved CR/CRh/CRi (78%) with 8 CR (44%), 3 CRh (17%) and 3 CRi (17%). No deaths occurred within the first 60 days of Tx. After a median follow up of 19.8 months (mos), Page 2 median response duration was not reached, with 12-mos disease-free survival rate of 69%; also, median OS was not reached, with 12- and 18-mos OS rates of 100% and 73%, respectively. The median (range) time on Tx was 12 mos (<1 - 26.6); 2 pts (11%) discontinued Tx due to an adverse event (AE) - 2 Grade 3 serious AEs (SAEs), differentiation syndrome and skin infection. Overall, 5 pts had 7 Tx-related SAEs; most common Tx-related SAE was differentiation syndrome in 4 pts (22%), of which 3 (17%) were considered Grade ≥3 (Table 3). The most common AEs of any grade (in ≥25% of pts) were diarrhea (61%), constipation (50%), nausea and hypokalemia (each 44%); and most common Grade ≥3 Tx-related AEs were differentiation syndrome and QTc prolongation (each 17%). The most common Tx-related laboratory abnormalities of any grade were decreased platelet count (22%) and decreased WBC count (17%). Conclusions: In ND pts with IDH1m AML and ≥60 years of age, IVO + AZA Tx was associated with a high CR/CRh/CRi rate, no early deaths (60 days) and a 1-year OS of 100%. IVO + AZA was acceptably tolerated and no unexpected toxicities occurred. Most common unique toxicities of IVO observed during the study were differentiation syndrome and QTc prolongation; these led to Tx discontinuation in only 1 pt. CR/CRh/CRi rate obtained with IVO +AZA is higher than that previously reported in studies with the individual agents or intensive chemotherapy approaches, suggesting a synergistic effect. Our overall response rate is similar to that reported recently for IVO + AZA in older ND IDH1 mutant AML pts, despite not including pts with morphologic leukemia-free state and partial remission. Based on these results, a global Phase 3 evaluation of IVO or placebo plus AZA is ongoing (NCT03173248). Figure 1 Figure 1. Disclosures Patel: BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Peerview: Honoraria. Ruppert: Telios Pharma: Consultancy. Borate: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Stein: Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; PinotBio: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Novartis: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria. Blum: Leukemia and Lymphoma Society: Research Funding; Nkarta: Research Funding; Celyad Oncology: Research Funding; Syndax: Honoraria; Xencor: Research Funding; Abbvie: Honoraria; Forma Therapeutics: Research Funding; AmerisourceBergen: Honoraria. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Schiller: Sangamo: Research Funding; Takeda: Research Funding; Ono-UK: Consultancy, Research Funding; Gamida Cell Ltd.: Research Funding; Tolero: Research Funding; Samus: Research Funding; Karyopharm: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Mateon: Research Funding; Genentech-Roche: Research Funding; FujiFilm: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Actinium Pharmaceuticals, Inc: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Arog: Research Funding; Delta-Fly: Research Funding; Celator: Research Funding; Forma: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; PrECOG: Research Funding; Constellation Pharmaceuticals: Research Funding; Trovagene: Research Funding; Elevate: Research Funding; Deciphera: Research Funding; Actuate: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding; Onconova: Research Funding; Geron: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Actinium: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Cellectis: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Daiichi Sankyo: Research Funding; Astellas: Honoraria, Research Funding. Foran: pfizer: Honoraria; gamida: Honoraria; servier: Honoraria; kura: Research Funding; abbvie: Research Funding; takeda: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; novartis: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; bms: Honoraria; syros: Honoraria; taiho: Honoraria; OncLive: Honoraria; actinium: Research Funding; aptose: Research Funding; boehringer ingelheim: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: Pluristem: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Foster: Agios: Consultancy; Daiichi Sankyo: Consultancy; Macrogenics: Consultancy; Rafael Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Bellicum Pharmaceuticals: Research Funding. Cogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding. Vergilio: Roche: Current equity holder in publicly-traded company; Foundation Medicine: Current Employment. Gana: Bausch: Current holder of individual stocks in a privately-held company; The Leukemia & Lymphoma Society: Consultancy. Druker: The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; EnLiven: Consultancy, Research Funding; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Nemucore Medical Innovations, Inc.: Consultancy; Merck & Co: Patents & Royalties; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bristol-Myers Squibb: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; Recludix Pharma, Inc.: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: QIAGEN: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Celgene: Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Incyte: Consultancy; Janssen: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; Gilead: Honoraria; Amgen: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees. Mims: Leukemia and Lymphoma Society: Consultancy; Kura Oncology: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Aptevo: Research Funding; Xencor: Research Funding; Glycomemetics: Research Funding; Jazz Pharmaceuticals: Consultancy; Daiichi-Saynko: Consultancy. OffLabel Disclosure: IVO is an oral potent inhibitor of mutated IDH1 enzyme, recently approved for the treatment of ND adult patients with IDH1m AML âââ,¬Â°Ã,Â¥75 years old or with comorbidities precluding use of intensive induction chemotherapy, and adult pts with relapsed or refractory AML. The combination of AZA, a hypomethylating agent, and venetoclax, an oral BCL-2 inhibitor, is also FDA approved for newly diagnosed AML in adults 75 years or older, or who have comorbidities precluding intensive chemotherapy. This presentation will discuss the combination of IVO and AZA.

AbstractObjectiveDrug‐resistant epilepsy (DRE) occurs at higher rates in children <3 years old. Epilepsy surgery is effective, but rarely utilized in young children despite developmental benefits of early seizure freedom. The present study aims to identify unique patient characteristics and evaluation strategies in children <3 years old who undergo epilepsy surgery evaluation as a means to assess contributors and potential solutions to health care disparities in this group.MethodsThe Pediatric Epilepsy Research Consortium Epilepsy Surgery Database, a multicentered, cross‐sectional collaboration of 21 US pediatric epilepsy centers, collects prospective data on children <18 years of age referred for epilepsy surgery evaluation. We compared patient characteristics, diagnostic utilization, and surgical treatment between children <3 years old and those older undergoing initial presurgical evaluation. We evaluated patient characteristics leading to delayed referral (>1 year) after DRE diagnosis in the very young.ResultsThe cohort included 437 children, of whom 71 (16%) were <3 years of age at referral. Children evaluated before the age of 3 years more commonly had abnormal neurological examinations (p = .002) and daily seizures (p = .001). At least one ancillary test was used in 44% of evaluations. Fifty‐nine percent were seizure‐free following surgery (n = 34), with 35% undergoing limited focal resections. Children with delayed referrals more often had focal aware (p < .001) seizures and recommendation for palliative surgeries (p < .001).SignificanceThere are relatively few studies of epilepsy surgery in the very young. Surgery is effective, but may be disproportionally offered to those with severe presentations. Relatively low utilization of ancillary testing may contribute to reduced surgical therapy for those without evident lesions on magnetic resonance imaging. Despite this, a sizeable portion of patients have favorable outcome after focal epilepsy surgery resections.

Abstract Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ∼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1−/− accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1−/− (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.

Background Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. Methods Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. Results For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). Conclusions Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. Trial registration number NCT01546571.

Key Points A computable phenotype combines routinely collected data elements from the EHR with logic elements to identify a condition of interest. This validated computable phenotype has strong classification characteristics to identify individuals with primary nephrotic syndrome. This computable phenotype for primary nephrotic syndrome can facilitate future research of these rare diseases. Background Primary nephrotic syndromes are rare diseases which can impede adequate sample size for observational patient-oriented research and clinical trial enrollment. A computable phenotype may be powerful in identifying patients with these diseases for research across multiple institutions. Methods A comprehensive algorithm of inclusion and exclusion ICD-9 and ICD-10 codes to identify patients with primary nephrotic syndrome was developed. The algorithm was executed against the PCORnet CDM at three institutions from January 1, 2009 to January 1, 2018, where a random selection of 50 cases and 50 noncases (individuals not meeting case criteria seen within the same calendar year and within 5 years of age of a case) were reviewed by a nephrologist, for a total of 150 cases and 150 noncases reviewed. The classification accuracy (sensitivity, specificity, positive and negative predictive value, F1 score) of the computable phenotype was determined. Results The algorithm identified a total of 2708 patients with nephrotic syndrome from 4,305,092 distinct patients in the CDM at all sites from 2009 to 2018. For all sites, the sensitivity, specificity, and area under the curve of the algorithm were 99% (95% CI, 97% to 99%), 79% (95% CI, 74% to 85%), and 0.9 (0.84 to 0.97), respectively. The most common causes of false positive classification were secondary FSGS (nine out of 39) and lupus nephritis (nine out of 39). Conclusion This computable phenotype had good classification in identifying both children and adults with primary nephrotic syndrome utilizing only ICD-9 and ICD-10 codes, which are available across institutions in the United States. This may facilitate future screening and enrollment for research studies and enable comparative effectiveness research. Further refinements to the algorithm including use of laboratory data or addition of natural language processing may help better distinguish primary and secondary causes of nephrotic syndrome.

Abstract Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P &lt; .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P &lt; .001), as was overall survival (HR, 1.32; P &lt; .001, and HR, 1.45; P &lt; .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Abstract The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P &lt; .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P &lt; .001) and grade 3 to 4 aGVHD (HR, 1.97; P &lt; .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.