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Abstract Background: CML is managed by life-long TKI therapy in most pts which can be associated with chronic toxicities and substantial costs. Discontinuation of TKI in some pts can result in sustained therapy-free remission (TFR); however only a minority are candidates for discontinuation approaches; of those most still relapse and must restart TKI. High expression of programmed death receptor-1 (PD-1) and its ligand PD-L1 on CML-specific cytotoxic T-cells and CML cells, respectively, suggests that PD-1/PD-L1-mediated immune escape contribute to CML persistence and relapse after TKI discontinuation. We designed the BLAST MRD CML trial (NCT#03516279) to study whether adding anti-PD-1 antibody pembrolizumab to TKI therapy is safe and tolerable and increases rate of conversion to undetectable minimal residual disease (UMRD). We present data from the early safety cohort from this ongoing trial with a data cut-off date June 15th, 2021. Methods: BLAST MRD CML-1 is an ongoing national, ECOG-sponsored, single-arm pilot phase II clinical trial that enrolls adults with chronic phase CML who achieved a major molecular response (MR 3) but not UMRD while on a stable dose of up to three lines of TKI therapy. UMRD was defined as an undetectable BCR-ABL by central RQ-PCR (assay sensitivity of 4.5 [MR 4.5]) on 2 consecutive samples separated by ≥4 weeks. Once enrolled, pts continue on TKI and concurrently receive pembrolizumab 200mg IV on day (D)1 of each 21-D cycle with central MRD assessment every 4 cycles for 17 cycles. Pts who achieve UMRD at or prior to C17 discontinue pembrolizumab, while those with persistent MRD continue TKI + pembrolizumab for another 18 cycles. TKI is discontinued one year following first documentation of UMRD. After TKI discontinuation, BCR-ABL is monitored at defined intervals for 24 months. Primary endpoint is proportion of CML pts on stable-dose TKI who convert to UMRD within 2 years (yrs) of combined TKI + pembrolizumab therapy. Secondary endpoints include rates of TKI discontinuation and proportion of pts achieving 2-year TFR, MRD kinetics, and safety. Immune related and other adverse events (AE) were assessed and graded according to CTCAE v 5.0. Results: As of cut-off date, 6 pts enrolled in safety cohort. Median age was 43 yrs (range 32-65). TKIs received on trial included imatinib (N=2), dasatinib (N=3), and nilotinib (N=1). All 6 pts were on 2 nd line TKI. Median exposure to pembrolizumab was 20 doses (range, 5-36). Five pts were still on combined pembrolizumab + TKI treatment, while the 6 th pt has completed combined therapy for 2 yrs and then continued TKI monotherapy on trial after achievement of UMRD (pt has to be in UMRD for 1 yr before TKI can be discontinued). The combination of TKI and pembrolizumab was safe and well tolerated (Table 1). Only 3 pts experienced grade (G) 1/2 AEs as the worst non-hematologic AE while on trial. Hematologic toxicity reported was also generally minimal with only one G 1/2 anemia AE. The only reported G3 AE was a lipase elevation (283 U/L, normal range 11 - 55 U/L) noted on routine laboratory assessment in a pt receiving nilotinib at 400mg BID dose after 48 weeks of starting on trial combined therapy. Amylase was also elevated at G2. No baseline lipase levels were available as protocol at that time did not require baseline assessments. The pt had no symptoms and CT imaging showed no radiologic evidence of pancreatitis. The lipase and amylase levels normalized with holding of both nilotinib and pembrolizumab for 7 weeks, and the AE did not recur with resumption of combined therapy at same dose of pembrolizumab but with nilotinib reduced to 400mg daily. No G4 or 5 AEs occurred. No other dose-adjustments or treatment discontinuation/interruptions due to AEs occurred. No immune-related AEs (IRAEs) have been reported. Discussion: Data from the early safety cohort suggest that the combination of TKI and pembrolizumab is safe and well tolerated. The AEs observed were mild and generally G1/2. No pt discontinued trial therapy due to AEs. Only one G3 AE (asymptomatic lipase elevation) was reported, which could have been related to nilotinib therapy and could have predated trial entry as no baseline lipase value was available and was fully reversible with a temporary hold of therapy. No IRAEs have been reported to date. Work is ongoing on an amendment to study protocol to enhance accrual. Efficacy results will be reported as they mature. Figure 1 Figure 1. Disclosures Zeidan: Boehringer Ingelheim: Consultancy, Research Funding; Ionis: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Astex: Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BeyondSpring: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BioCryst: Other: Clinical Trial Committees; Janssen: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Geron: Other: Clinical Trial Committees; Astellas: Consultancy; ADC Therapeutics: Research Funding; Agios: Consultancy; Jazz: Consultancy; Pfizer: Other: Travel support, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bhatt: National Marrow Donor Program: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Research Funding; Jazz: Research Funding; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Litzow: Omeros: Other: Advisory Board; Astellas: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Pluristem: Research Funding; Biosight: Other: Data monitoring committee; Actinium: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Pembrolizumab has not been approved for the treatment of CML

Abstract Introduction: Patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) who cannot tolerate or who are not eligible for autologous or chimeric antigen receptor T cell (CAR-T) therapy have limited therapeutic options and suboptimal long-term outcomes. In patients who were not eligible for HSCT, the rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) regimen (and variations using methylprednisolone or carboplatin/oxaliplatin) have shown an overall response rates (ORR) of ~50%, a complete response (CR) rate of ~25% (Gopal, Leuk Lymphoma, 2010), and a median progression-free survival (PFS) and an overall survival (OS) of 3 and 9 months, respectively (Crump, Hematol Oncol Clin N Am. 2016; Gopal Leuk Lymphoma, 2010; Ng, Br J Cancer, 2005; Sirohi, Hematology, 2007; Barton, Eur J Haematol. 2015; Moccia Leuk Lymphoma, 2017). Selinexor is an oral small molecule selective inhibitor of exportin-1 (XPO1) mediated nuclear export (SINE) compound leading to activation of tumor suppressor proteins and reduction in oncoprotein levels. It also reduces the expression of deoxyribonucleic acid (DNA) damage repair proteins and therefore potentiates DNA damage-based therapies leading to an increased death of cancer cells. Selinexor has synergistic effects with gemcitabine and cisplatin, and enhanced anti-lymphoma effects with dexamethasone. In the SADAL study (n=134), single-agent oral selinexor 60 mg twice weekly induced an ORR of 29% and a CR rate of 13% in patients with RR DLBCL. The response rates were consistent across various subgroups including patients <70 vs ≥70 years old, those with de novo and transformed DLBCL, and GCB and non-GCB subtypes of DLBCL. The median duration of response (DOR) was 9.3 months, and 23 months for patients who achieved CR. OS was 9.0 months. In June 2020, selinexor monotherapy was approved in the US for the treatment of adult patients with RR DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor in combination with R-GDP was evaluated in a Phase 1 clinical trial (SELINDA), in which patients with DLBCL received either 40 or 60 mg selinexor once or twice weekly in combination with standard dose R-GDP. The recommended phase 2 dose for further exploration was 40 or 60 mg once weekly with an ORR of 60-80%. Therefore, combining selinexor with R-GDP is expected to improve response rates, and continuation of treatment with single-agent selinexor is expected to prolong the duration of responses, improve PFS (and potentially OS) in patients with RR DLBCL. Materials and methods: XPORT-DLBCL-030 is a Phase 2/3, multicenter study. The Phase 2 portion of the study is an open-label randomized study to identify the optimal dose of selinexor (40 or 60 mg) in combination with R-GDP in patients (n=120) with RR DLBCL. Patients ≥18 years with 1-3 prior lines of therapy and ECOG performance status ≤2 who are not intended for HSCT or CAR-T therapy are randomized 1:1:1 to one of 3 treatment arms: Arm 1: selinexor 40 mg+R-GDP (S40+R-GDP); Arm 2: selinexor 60 mg+R-GDP (S60 + R-GDP); Arm 3: R-GDP. Combination treatment will be given for up to 6 cycles (21 days/cycle). After completing the SR-GDP combination therapy (EoC), patients in Arms 1 and 2 who reach at least partial response (PR), will receive weekly single-agent selinexor 60 mg (28 days/cycle) as "continuous therapy" until disease progression (PD) or unacceptable toxicity. After PD, patients will be followed up for survival. Patients in the R-GDP arm will be followed up for PD and survival. Patients who are ineligible for HSCT due to an active disease, or those who have primary refractory DLBCL, defined as no response or relapse within 6 months after ending first-line treatment, will be allowed to enroll in the study (up to 15% and 25%, respectively of all patients enrolled). The primary endpoint of the study is ORR according to the Lugano 2014 criteria. Secondary endpoints include PFS, OS, ORR-EoC, DOR and incidence and severity of adverse events. Figure 1 Figure 1. Disclosures Pinto: Takeda: Consultancy; MSD: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau; Bristol Myers Squibb-CELGENE: Honoraria. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Canales: Sanofi: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Honoraria; Sandoz: Honoraria, Speakers Bureau; iQone: Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; Jagiellonian University: Ended employment in the past 24 months; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees. Sureda: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Ma: Karyopharm Therapeutics Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Li: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Ingalls: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arriola: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arazy: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. The recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated in adult and pediatric populations. Radiographic regressions with single agent ONC201 have been reported in recurrent H3 K27M-mutant glioma patients. In another study, twice/week dosing was explored in adult patients and deemed to be safe (no DLTs observed). This warranted exploration of twice/week dosing in pediatric patients and will be discussed in this presentation. This multi-arm, dose-escalation and dose-expansion trial (ONC014; NCT03416530) determined the pediatric RP2D of ONC201 administered once per week and twice per week on two consecutive days. ONC201 was orally administered and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with two 125mg capsules less than the adult RP2D equivalent. Twelve children (8 females; 4 males) with H3 K27M-mutant gliomas (pons: 8; thalamus: 2; spinal cord: 2) aged 4-19 years have been treated post-radiation: 3 at dose level -1; 3 at dose level 1; 6 as part of the dose expansion cohort on dose level 2. Median KPS was 90 (range 70-100). One treatment cycle was 21 days (6 doses), which also defined the DLT window. Patients were on-treatment for a median length of 4 cycles (range: 2-11). Twice weekly dosing of ONC201 was tolerated well, as observed with weekly dosing, with no instance of DLT. A total of 4 SAEs were reported, none of which were related to the study drug. The most common AEs (regardless of relatedness) included headache, facial nerve disorder, abducens nerve disorder, nausea, fatigue and ataxia. Additional safety data, PK, and clinical outcomes from this arm will be reported.

Abstract Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer’s disease based on inferred underlying histopathology. Parkinson’s disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington’s disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers—we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

Abstract We studied the performance of an algorithm combining multiplex polymerase chain reaction with phenotypic detection of extended-spectrum β-lactamases and carbapenemases directly from positive blood culture bottles in patients with gram-negative bacteremia and found good concordance with routine cultures. Such an algorithm may be a tool to improve time to optimal therapy in patients with gram-negative bacteremia.

Invasive infections with emerging yeasts such asGeotrichum,Saprochaete/Magnusiomyces, Trichosporon, and other species are associated with high morbidity and mortality rates. Due to the rarity and heterogeneity of these yeasts, medical mycology has lacked guidance in critical areas affecting patient management.