ALBERT

Description: © The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 7 (2017): 41095, doi:10.1038/srep41095.

Description: Adenosine-to-inosine RNA editing in transcripts encoding the voltage-gated potassium channel Kv1.1 converts an isoleucine to valine codon for amino acid 400, speeding channel recovery from inactivation. Numerous Kv1.1 mutations have been associated with the human disorder Episodic Ataxia Type-1 (EA1), characterized by stress-induced ataxia, myokymia, and increased prevalence of seizures. Three EA1 mutations, V404I, I407M, and V408A, are located within the RNA duplex structure required for RNA editing. Each mutation decreased RNA editing both in vitro and using an in vivo mouse model bearing the V408A allele. Editing of transcripts encoding mutant channels affects numerous biophysical properties including channel opening, closing, and inactivation. Thus EA1 symptoms could be influenced not only by the direct effects of the mutations on channel properties, but also by their influence on RNA editing. These studies provide the first evidence that mutations associated with human genetic disorders can affect cis-regulatory elements to alter RNA editing.

Description: This work was supported by the Vanderbilt Molecular Endocrinology Training Program (T32DK007563; E.A.F.K.), a Ruth L. Kirschstein National Research Service Award (F31NS087911; E.A.F.K), a Vanderbilt Dissertation Enhancement Grant (E.A.F.K.), and the Vanderbilt Joel G. Hardman Chair in Pharmacology (R.B.E). Additional support for J.J.C.R. included NINDS (R0111223855, R01NS64259) and the Cystic Fibrosis Foundation Therapeutics (Rosent14XXO). Infrastructural support for J.J.C.R. was provided by NIGMS (P20GM103642), NIMH (G12-MD007600), and NSF (DBI 0115825, DBI 1337284).

Description: After failure of DNA methyltransferase inhibition (DNMTi) there is no standard of care therapy for high-risk myelodysplastic syndromes (MDS), and median survival for higher risk disease is less than 6 months (Prebet et al, JCO 2011; Jabbour et al, Cancer 2015). Pevonedistat, a first in human small molecule inhibitor of the NEDD8 activating enzyme (NAE), downregulates Cullin ring ligases (CRL) which interferes with the shuttling and degradation of proteins in the proteasome and leads to accumulation of CRL substrates. Combining pevonedistat (Pev) with azacitidine (AZA) resulted in synergistic cell killing in in vitro and xenograft models of acute myeloid leukemia (AML) (Smith et al, Blood 2011), elicited favorable response rates in treatment naïve elderly or unfit AML patients (Swords et al Blood 2018), and is currently under study in treatment-naïve MDS. The study presented herein (NCT03238248) investigates the utility of adding pevonedistat to azacitidine (PevAz) after DNMTi failure in MDS and MDS/MPN overlap syndromes. Methods: In this on-going single-arm phase II study, MDS and MDS/MPN patients were eligible if they were refractory to DNMTi treatment, progressing after at least 2 cycles of therapy; had failed to achieve a complete remission (CR) after at least 4 cycles of DNMTi therapy; or had relapsed after an initial response to DNMTi therapy. Enrolled subjects received AZA 75mg/m2 sc/iv daily on days 1-5 and Pev 20mg/m2 iv on days 1, 3 and 5 of each 28-day cycle. Survival is the primary endpoint and is assessed at regularly scheduled study visits and every 3 months after ending protocol-directed therapy. Hematologic and bone marrow response rates are secondary endpoints. Responses to treatment are determined by the MDS International Working Group (IWG) response criteria (Cheson et al, Blood 2006) or for MDS/MPN, by the modified MDS/MPN IWG response criteria (Savona et al, Blood 2015). Results: As of the data cutoff on 15 MAR 2019, 23 subjects (21 with MDS, 2 with MDS/MPN) had enrolled and initiated treatment. Subjects had previously been treated with AZA (n=11/23), decitabine (n=11/23), and ASTX727 (n=4/23); some subjects had been treated with more than one DNMTi prior to enrollment. Median number of cycles of any prior DNMTi therapy was 7 (range 2-35). 65% of subjects were female. Median age at enrollment was 67 years (range 51 - 85). 65% had Intermediate-2 or High risk disease by IPSS at time of enrollment. Median number of PevAz cycles completed prior to the data cutoff was 4 (range 1-19). One subject had not reached the first response assessment at the time of the data cutoff and data was unavailable for one subject. The overall response rate including complete and partial remission, hematologic improvement and clinical benefit (CB) was 42.9% (9/21), and CR rate (including 1 CR + 4 marrow CR) was 23.8% (5/21) with a median duration of response (DOR) of 8.7m (range 2.8m-15.7m). An additional 38.1% (8/21) had stable disease as best response (Table 1). The most common Grade 〉2 adverse events (any attribution) include thrombocytopenia (39%), anemia (35%), leukopenia (26%), neutropenia (22%), infections (17%), and febrile neutropenia (13%). Six subjects experienced Grade ≤ 2 elevations in AST/ALT and 4 had Grade ≤ 2 elevation in bilirubin, whereas only one subject experienced Grade 〉 2 LFT abnormality (increase in ALT). There was one death on study due to intracerebral hemorrhage related to a previously undiagnosed metastatic carcinoma. PevAz treatment was discontinued in other subjects due to disease progression (n=7), adverse event (n=1), lack of response (n=1), or to pursue allogeneic stem cell transplant after achieving a satisfactory response to PevAz (n=3). Ten subjects were continuing PevAz therapy on study as of the data cutoff. Summary: PevAz was well-tolerated in MDS and MDS/MPN patients who had previously failed DNMTi, with the most common adverse events of cytopenias, which are a common feature of these diseases. 5/21 subjects achieved CR/mCR with meaningful DOR, and the ORR of 42.9% exceeded expectations for MDS patients with previous failure of DNMTi therapy; both MDS/MPN patients responded with CR and CB. For these patients whose treatment options are limited and prognosis very poor, these preliminary data are especially encouraging and warrant further investigation. This therapy combination is being tested in a phase 3 study in treatment naïve high risk MDS, CMML and low-blast AML. Disclosures Watts: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Byrne:Karyopharm: Research Funding. Bradley:AbbVie: Other: Advisory Board. Savona:Sunesis: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties.

Description: Abstract 4358 Objective Warfarin is an oral vitamin K antagonist commonly used in pediatric patients who require anticoagulation. Studies in adults receiving warfarin demonstrate that polymorphisms in 2 genes involved in warfarin disposition and response, cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1), explain 30–40% of the variation in stable dose. Recent evidence suggests a role for a cytochrome P450 4F2 (CYP4F2) variant in altered warfarin disposition. These associations have not been well-studied in the pediatric population. We hypothesized that polymorphic variants in CYP2C9, VKORC1, and CYP4F2 are associated with interindividual variability in stable warfarin dose in pediatric patients. Methods We designed a cross-sectional study examining the relationship between stable warfarin dose and commonly occurring polymorphisms in CYP2C9 (*2 and *3), VKORC1 (haplotype A, comprised of 5 promoter and intronic variants), and CYP4F2 (variant allele T) in children. Patients

Description: Background: Therapies for myelofibrosis (MF) are limited and most are palliative. The JAK1/2 inhibitor ruxolitinib reduces spleen size and MF-related symptoms and improves survival, but can be limited by dose-dependent anemia and thrombocytopenia. Moreover, nearly half of ruxolitinib responders relapse within 5 years. PI3Kd is highly expressed in MF patient samples, independent of ruxolitinib pre-exposure. In JAK2-mutated cell lines, inhibition of PI3K/AKT signaling reduced proliferation and clonogenic potential. The once daily, next generation PI3Kd inhibitor TGR-1202 inhibited PI3K/AKT signaling and led to apoptosis in leukemia and lymphoma cell lines and was well-tolerated in clinical studies, with a toxicity profile distinct from that of ruxolitinib and other PI3Kd inhibitors. We hypothesized that adding TGR-1202 to ruxolitinib could resensitize or augment the response of MF patients with lost or suboptimal response to single-agent ruxolitinib. Objective: To assess safety of TGR-1202 in combination with ruxolitinib in MF patients Secondary Objectives: Hematologic response, symptom assessment Methods: MF patients who had sub-optimal responses to ruxolitinib continued their highest tolerated dose of ruxolitinib without change for ≥ 8 weeks, and were assigned to escalating doses of TGR-1202 in a standard 3+3 algorithm. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Efficacy was assessed according to IWG-MRT consensus response criteria. Symptoms were assessed by the MPN symptom assessment form total symptom score (TSS). All patients received Pneumocystis pneumonia prophylaxis after cycle 1. Results: Eleven MF patients were enrolled and received 400 mg (n=3), 800 mg (n=6), or 600 mg TGR-1202 (n=2) daily. Nine were evaluable for response. Median age was 66y, 73% were male. All had ECOG PS 0-1. Five patients had mutations in JAK2, 4 in CALR, and 3 in MPL; these were mutually exclusive with exception of 1 patient with CALR and MPL mutations (Table 1). Median number of cycles of TGR-1202 + ruxolitinib treatment was 5 (1-13). Grade 2 anemia was the most common AE (Table 2). Two patients had asymptomatic Grade 3 elevations in amylase and lipase that persisted after drug was held, meeting criteria for dose limiting toxicities (DLTs) in 2 separate cohorts (TGR-1202 800mg+ruxolitinib 15mg BID and TGR-1202 800mg+ruxolitinib 10mg BID). Both patients had peak plasma TGR-1202 concentrations 1.5-2x higher than the other patients receiving 800mg TGR-1202, although steady-state levels were equivalent. The maximum tolerated dose (MTD) of TGR-1202 in combination with ruxolitinib was not established. Two patients went off-study due to AEs, and 3 due to progressive disease. One of 9 evaluable patients achieved complete remission and 7 had stable disease. Seven of the 9 evaluable patients had improvement in hematologic parameters and 8 had reduced MF symptoms with a median 33% decrease in TSS (Fig. 1). Conclusions: TGR-1202 + ruxolitinib was well-tolerated. Pharmacokinetic data were consistent with single-agent TGR-1202 (unpublished data), indicating that ruxolitinib does not alter absorption or metabolism of TGR-1202. Grade 3 elevations in amylase and lipase were considered DLTs, per protocol. Although the clinical significance of these asymptomatic laboratory findings is not clear, the protocol was amended to further assay these labs and to exclude concomitant medications with the potential to increase amylase/lipase. Importantly, no grade ≥3 hepatotoxicity, colitis, or thrombocytopenia was seen and no MTD was found. Although only one patient achieved CR, 89% demonstrated clinical benefit with the addition of TGR-1202 to ruxolitinib, supporting further exploration of this combination. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Cavers:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Sunesis: Research Funding; Incyte: 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; Gilead: Membership on an entity's Board of Directors or advisory committees.

Description: Background: AML is an aggressive malignancy with a median age of 67 yrs at diagnosis and an age-adjusted 5-yr survival of less than 25%. Most older patients (pts) with AML have poor risk cytogenetic/genetic features associated with suboptimal complete remission (CR) rates and overall survival (OS). Until recently, the anthracycline and cytarabine based induction remained unchanged for over 4 decades. Vosaroxin (Vos) is a first-in-class anticancer quinolone derivative which is thought to induce less cardiac toxicity than standard anthracycline therapy. Vos was previously administered in combination with intermediate dose cytarabine (IDAC) in relapsed/refractory (r/r) AML pts in a large randomized phase 3 trial (VALOR) and demonstrated significantly improved CR rates compared to IDAC alone but without improvement in OS. In the VITAL study, we investigated the combination of infusional cytarabine (iAC) with Vos ("7 + V") in newly diagnosed AML. Methods: VITAL (NCT02658487) is a single-arm, open-label, two-stage phase II study of 90 mg/m2, Vos on days 1 and 4 (reduced to 70 mg/m2, days 1 and 4 in the event of re-induction) and 100 mg/m2 continuous iAC on days 1-7. Oral cryotherapy was administered during Vos administration as prophylaxis for oral mucositis seen in prior studies. Enrollment in stage 1 was limited to 17 evaluable pts 〉55 yrs of any risk classification or pts 18-54 years with high-risk disease. The two-stage design required CR in more than 7 of the first 17 pts in order to proceed to stage 2. The operating characteristics of the study design provided a 64% probability of early termination if CR occurred in 7 or fewer pts suggesting that the true CR rate would be ≤ 40%. Stage 2 included an additional 24 pts (age 18-54 yrs with intermediate or high-risk disease, or 55 years or older with any risk disease). Response was assessed using the modified IWG-2003 criteria. Results: In total, 42 pts were enrolled and assessed for toxicity. One patient who achieved an aplastic marrow biopsy at day 14, succumbed to an AML-related sepsis event prior to formal response assessment was initially deemed unevaluable for response and replaced but was ultimately included in the response assessment. Baseline demographics of the 42 enrolled pts are seen in Table 1a. Median age was 63 yrs (range, 43-74) and 86% (36/42) were ≥ 55yrs at time of enrollment. Almost all, 40/42 (95%), had intermediate (11/40) or poor (29/40) risk AML. Adverse events (AEs) of special interest of any Grade (Gr) and Gr 3-5 AEs occurring in 〉 10% of pts are listed in Table 1b. Oral mucositis was observed in 16/42 (38%) pts with 12/42 (29%) having Gr 1-2 and only 4/42 (10%) having Gr 3 severity. Three Gr 5 events occurred (2-Infection/Sepsis; 1-neutropenic colitis). No acute cardiac toxicity was seen. CR was achieved in 20/42 (48%) pts, while 3 additional pts achieved CR with incomplete count recovery (CRi) for a CR/CRi rate of 55% (23/42). CR was observed in 100% (2/2) with favorable risk (both 〉65 yrs old). CR/CRi was seen in 73% (8/11) intermediate and 45% (13/29) poor risk pts. One poor risk pt with CRi converted to CR in the absence of additional therapy but did so outside of the protocol defined time period for response assessment (Day 57 +/- 3 days) and was recorded as CRi for this analysis. CR/CRi was noted in 40% (4/10) pts whose AML had TP53 mutations. Allogeneic hematopoietic stem cell transplant was performed in 45% (19/42) of pts. Progression-free survival was 43% and OS was 48% for all pts at 1-year of follow-up (Figure 1). Conclusion: The combination of Vos and iAC in newly diagnosed AML pts appears safe. Mucocutaneous complications were observed as noted in previous studies with Vos. Administration of oral cryotherapy during Vos administration appeared to reduce occurrence of oral mucositis during induction, but 〉 Gr 3 neutropenic enterocolitis occurred in 7/42 (17%) pts. Still, the combination appears to be tolerable with an adverse event profile analogous to conventional induction regimens. While the VALOR trial observed Gr 3-5 cardiac AEs in 〈 1% of the 705 r/r AML pts with prior anthracycline exposure, no attributable cardiac events were seen within the VITAL trial population. Vosaroxin and infusional cytarabine is a clinically active induction regimen which warrants further investigation based on response rates and toxicity profile at least similar to current anthracycline based induction strategies with an apparent absence of cardiac toxicity. Disclosures Strickland: Astellas: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Sunesis: Research Funding; AbbVie: Consultancy. Podoltsev:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Kartos Therapeutics: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding. Zeidan:Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria. Byrne:Karyopharm: Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Savona:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: 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, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: BACKGROUND: Lymphoma treatment with alkylating agents and steroids can cause premature osteoporosis, increasing the risk of vertebral and hip fracture. Mechanisms of bone loss may include local microenvironment lymphoma-related cytokine activity, steroid-mediated bone loss, and hypogonadism from chemotherapy. The bisphosphonate pamidronate every three months has been found to reduce bone loss and the risk of new vertebral fractures in lymphoma patients receiving chemotherapy; however, the more potent bisphosphonate, zoledronic acid, has not been evaluated in this patient population. We are conducting a randomized study of zoledronic acid in untreated non-Hodgkin’s lymphoma (NHL) patients to study chemotherapy induced bone loss and improve NHL survivorship. While this trial is still accruing patients, we report the abnormal baseline bone mineral density (BMD) and endocrine characteristics found in patients screened for this study. METHODS: We report the preliminary baseline endocrine characteristics for this ongoing bone health research study. Untreated NHL patients were screened for BMD and endocrine studies including vitamin D levels, testosterone, and bone turnover markers. Patients on the study were stratified as male, female (pre-menopausal), and female (post-menopausal). Exclusion criteria included bone fractures, BMD T-scores worse than −2.0, creatinine clearance less than 60 mL/min, dental problems, and prior steroid or bisphosphonate use. Patients accrued to the study are randomized to receive either: 1) oral calcium and vitamin D (Ca+D) or 2) Ca+D and 4 mg zoledronic acid IV at baseline and at 6 months. RESULTS: Patient characteristics included: 49 male, 35 female (10 pre-menopausal), median age 61 (range: 18–87). Of 84 patients screened for BMD to date, patients had the following abnormalities: 12/84 (14%) had osteoporosis and 47/84 (56%) had osteopenia or osteoporosis. Of 20 patients who consented to the trial and who were evaluated with additional studies, 10 were excluded due to the following: 3/20 hypovitaminosis D, 1/20 with prior steroid use, 1/20 low testosterone, 1/20 prior HRT, 1/20 with bone disease, 2/20 required dental extractions, and 1/20 treatment changed to chemotherapy without steroids. Patients with osteoporosis or T score worse than −2.0 were evaluated by their primary oncologist for treatment with bisphosphonates. Patients with other abnormal studies were further evaluated and treated by specialists in endocrinology and dentistry. CONCLUSIONS: Baseline testing of BMD and endocrine studies revealed osteopenia or osteoporosis in 56% of untreated NHL patients. Hypovitaminosis D or low testosterone was found in a smaller number of tested patients. While these patients were excluded from the remainder of the study and referred for further evaluation, patients should benefit from having these underlying problems addressed. Our ongoing clinical trial will address the potential role of zoledronic acid in preserving bone density for survivors of NHL. This trial was funded by Novartis. ClinicalTrials.gov Identifier: NCT00352846.