Abstract: Spin-transfer torque magnetic tunnel junction (STT-MTJ) based on double-barrier magnetic tunnel junction (DMTJ) has shown promising characteristics to define low-power non-volatile memories. This, along with the combination of tunnel FET (TFET) technology, could enable the design of ultralow-power/ultralow-energy STT magnetic RAMs (STT-MRAMs) for future Internet of Things (IoT) applications. This paper presents the comparison between FinFET- and TFET-based STT-MRAM bitcells operating at ultralow voltages. Our study is performed at the bitcell level by considering a DMTJ with two reference layers and exploiting either FinFET or TFET devices as cell selectors. Although ultralow-voltage operation occurs at the expense of reduced reading voltage sensing margins, simulations results show that TFET-based solutions are more resilient to process variations and can operate at ultralow voltages ( 〈 0.5 V), while showing energy savings of 50% and faster write switching of 60%.

Abstract: The hypomethylating agent decitabine inhibits DNA methyltransferase (DNMT) enzymatic activity and is approved by the FDA for treatment of myelodysplastic syndromes. We previously performed a phase I trial in AML of decitabine (with or without the histone deacetylase inhibitor valproic acid); the trial was designed to establish a biologically effective dose (BED) of decitabine based on drug-induced re-expression of methylated and silenced genes. With the derived BED of 20mg/m2/day given for 10 days, every 4 weeks, clinical activity was observed in previously untreated older AML patients (pts, CR in 4/12); clinical response correlated with gene re-expression (Blum, JCO 2007). The addition of tolerable doses of valproic acid did not appear to improve clinical results or increase gene re-expression compared to decitabine alone. Therefore, we designed a phase II study of single agent decitabine for previously untreated AML pts of age≥60 who were not candidates for intensive chemotherapy (or who refused it). Performance status was ECOG & lt;3. All pts received induction with decitabine at 20mg/m2 IV over 1 hour on days 1–10 of a 28 day cycle. The schedule for subsequent cycles was customized for each patient based on clinical response and/or toxicity (e.g., myelosuppression). Pts with persistent AML at the end of a cycle received a repeat of the 10 day treatment. In contrast, pts with & lt;5% blasts received decitabine as consolidation for only 5 days/cycle (every 4 weeks for 1 year). For CR/CRi patients, the decitabine schedule could be reduced further to 4 or 3 days/cycle for Grade 4 neutropenia lasting more than 2 weeks, if applicable. 33 pts were enrolled; accrual was completed in 13 months. Pts had a median age of 74 years (range, 60–83); 24 pts were age≥70. 18 pts had de novo AML; 15 had secondary or t-AML. Pts had a median presenting white blood cell count of 2,400/uL (range, 400–58,800/uL) with median marrow blasts of 44% (range, 21–92%). 13 pts had complex karyotype (≥3 abnormalities); 12 had normal karyotype; one patient had t(8;21), and the rest had other abnormalities (with one unknown). This was a high risk group by any comorbidity measure. Scoring was as follows on four high-risk factors of age ≥70, antecedent hematologic disorder, unfavorable karyotype, and ECOG 2: 16 pts had 3+ risk factors; 15 had two, and the other 2 pts had one risk factor. Using the transplant comorbidity index for older AML pts (HCT-CI; Giles, BJH 2007), pts had scores of 3+ (N=18), 1–2 (N=10), or 0 (N=5). The median number of cycles received to date is 3 (range, 1–10); 17 pts continue to receive study therapy. 10 pts have received 4+ cycles. Of the first 22 consecutive pts enrolled, 11 achieved CR (50%); 4 more have achieved CRi by IWG criteria for response (Cheson, JCO 2003). 11 pts are & lt;3 months since entry onto the study, with response evaluations ongoing. The response rate was similar between cytogenetic risk subgroups and in both de novo and secondary AML. 4 pts who achieved CR subsequently relapsed, with CR duration of 9, 6, 6, or 2 months, respectively. The other CR pts have maintained ongoing responses for 2–11+ months. 9/11 pts who achieved CR required only 1 cycle of induction therapy (10 day course) before initial response was achieved (CR, N=2; CRi, N=7). For pts who had CRi as initial response, the median number of additional cycles to achievement of full CR was 1 (range, 1–3). In this high risk group, death within 8 weeks of any cause occurred in 4 pts and was related to infection in each case. Though therapy was often administered in the outpatient clinic, febrile neutropenia and infections in the setting of drug and/or disease-related myelosuppression requiring hospitalization during the induction courses were frequent, occurring in nearly all pts. Post-CR therapy, however, was very well tolerated with no hospitalizations for complications during consolidation courses. In conclusion, decitabine in this novel schedule of induction with outcome-adapted modification of consolidation therapy was highly active and well tolerated by most in this poor risk cohort of older AML pts. Clinical results compare favorably to those seen in this population with low dose clofarabine (Erba, ASCO 2008a) or decitabine-5 day schedule (Cashen, ASH 2006a). Correlative studies including re-expression of epigenetically silenced genes, target gene promoter methylation, and global DNA methylation are ongoing.

Abstract: Acute myeloid leukemia (AML) is the most commonly diagnosed acute leukemia in adults. Despite newly approved treatment, AML still results in poor outcomes especially in older patients (pts). Cytogenetic abnormalities, gene mutations, and their combinations contribute to the pathogenesis and pt outcomes in AML. The PTPN11 gene encodes the phosphatase Shp2, which activates the RAS-MAPK pathway. Despite the relatively high frequency of PTPN11 mutations in AML, little is known about associations of PTPN11 mutations with other genomic features and their influence on outcomes of pts with standard 7+3 chemotherapy. In addition, primary resistance to targeted therapy, such as venetoclax and enasidenib, has been preliminarily noted in PTPN11+ pts. This study sought to determine the type and frequency of PTPN11 mutations as well as associations with clinical, cytogenetic, and genomic features and outcome in adult AML pts treated with 7+3 induction chemotherapy followed by consolidation chemotherapy on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. 1,725 newly diagnosed AML pts, defined by the European LeukemiaNet 2017 recommendations (excluding acute promyelocytic leukemia), were examined using targeted next generation sequencing analysis and centrally reviewed metaphase cytogenetics. Missense, nonsense, or frameshift variants not reported in the 1000 Genomes database, dbSNP137 or dbSNP142, were considered mutations. Fisher's exact test was used to determine mutation association and complete remission (CR) rates while continuous variables are from Wilcoxon rank sum test. The median follow-up was 9 years. We identified 140 pts (8.1%) with PTPN11 mutations with the majority (61%) located in the N-terminal SH2 domain (Figure 1). 98 younger ( & lt;60 years of age) and 42 older (≥60 years of age) pts were PTPN11+. Variant allele frequency (VAF) varied from 0.05 to 0.54, with 59 (42%) mutations having a VAF & gt; 0.3. NPM1 (61% vs 31%, P & lt; .001) and DNMT3A (R882 or other) mutations (39% vs 22%, P & lt; .001) were more likely to co-occur with PTPN11 mutations than wild-type (WT) PTPN11 (Figure 2). PTPN11 mutations were less common in FLT3-ITD pts than in those without (17% vs 25%, P = .07). PTPN11 mutations were more common in inv(3)(q21q26)/t(3;3)(q21;q26) pts (26%, P = .004) and were rare in pts with core-binding factor AML, inv(16)/t(16;16) (3%, P = .03) and t(8;21) (0%, P =.005). Clinical features of PTPN11+ pts were similar to those of WT pts except for elevated platelet counts (P & lt; .001) and more extramedullary involvement (P = .03). For all pts, there was no difference in CR rate, disease-free (DFS), overall (OS), and event-free (EFS) survival between PTPN11+ and PTPN11- pts. DFS of older PTPN11+ pts was shorter (3-y rates: 5% vs 15%, P = .04). Given that PTPN11 mutations often co-occur with NPM1 mutations, which are typically associated with favorable outcome (in the absence of a high FLT3-ITD ratio), we focused on the contribution of PTPN11 mutations to outcomes in the NPM1+/FLT3-WT subset. Compared with PTPN11-/NPM1+/FLT3-WT, PTPN11+ pts had a lower CR rate (38% vs 64%, P = .001) and shorter EFS (3-y rates: 10% vs 21%, P = .01), whereas there was no significant differences in OS (3-y rates: 23% vs 32%, P = .13) or DFS (3-y rates: 27% vs 33%, P = .75). When considering the role of PTPN11 mutations with WT NPM1, there was a reduction in survival in PTPN11+/NPM1- pts compared with PTPN11-/NPM1- pts. Younger PTPN11+/NPM1- pts had a lower CR rate (45% vs 71%, P = .002) and shorter OS (3-y rates: 30% vs 41%, P = .04), and EFS (3-y rates: 13% vs 27%, P = .008). Compared to older PTPN11-/NPM1-, older PTPN11+/NPM1- pts had a lower CR rate (18% vs 43%, P = .04) and shorter DFS (3-y rates: 0% vs 10%, P = .02) and EFS (3-y rates: 0% vs 4%, P = .02), whereas OS (3-y rates: 12% vs 10%, P = .58) had no significant difference. To our knowledge, this study is the largest cohort of PTPN11+ pts in adult AML and demonstrates specific mutational and cytogenetic associations. When considering PTPN11+ pts based on NPM1 mutation status, we showed that PTPN11 mutations associated with worse outcome in both NPM1+ and NPM1- AML pts when treated with intensive chemotherapy. Developing targeted treatments to this genomic group in AML represents a research priority. Support: U10CA180821, U10CA180882, U24CA196171, R35CA198183; https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifier: NCT00048958, NCT00899223, NCT00900224 Disclosures Mims: Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. Stone:Takeda: Consultancy; Trovagene: Consultancy; Pfizer: Consultancy; Gemoab: Consultancy; Janssen: Consultancy; AbbVie: Consultancy, Research Funding; Actinium: Consultancy; Agios: Consultancy, Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Arog: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Biolinerx: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Syntrix: Consultancy; Syros: Consultancy; Elevate: Consultancy; Syndax: Consultancy; Daiichi-Sankyo: Consultancy; Stemline: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy. Wang:Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy. Kolitz:Pfizer: Membership on an entity's Board of Directors or advisory committees; Magellan: Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding. Eisfeld:Vigeo Therapeutics: Consultancy; Karyopharm: Current Employment, Current equity holder in publicly-traded company. Byrd:Syndax: Research Funding; Vincera: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Acerta Pharma: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other.

Abstract: Background:The expression and prognostic significance of long non-coding RNAs (lncRNAs) in older (≥60 years) patients with cytogenetically normal acute myeloid leukemia (CN-AML) has recently been reported (Garzon et al, 2014). Among the top up-regulated lncRNAs in NPM1-mutated (NPM1mut) CN-AML, the lncRNA HOXB-AS3 wasidentified. As aberrant expression of HOX genes is associated with NPM1mut AML and HOX-related lncRNAs have been reported to regulate HOX genes (e.g. HOTAIR), we hypothesized that HOXB-AS3 could have a functional role in this disease setting. Methods:HOXB-AS3 expression profiling was performed by qRT-PCR in AML cell lines (Kasumi-1, KG1a, MOLM-13, MV-4-11, OCI-AML3 and THP-1), 12 primary CN-AML patient samples (NPM1mut=6, NPM1-wild-type (WT)=6) and mononuclear cells from healthy donors (n=6). Correlation analysis of mRNA/lncRNA expression was performed using Spearman analysis in 71 older CN-AML patients, profiled by RNA-sequencing. Knock-down (KD) of HOXB-AS3 was performed in vitro (Amaxa-nucleoporation) and in vivo (in a patient-derived xenograft (PDX) model) using LNA-modified gapmers. Comparative proteomic analysis was conducted by applying a modified version of the RNA antisense purification (RAP) protocol (McHugh et al, 2015). Results:Of the cell lines tested, only OCI-AML3, which harborsmutated NPM1, showed high levels of HOXB-AS3 expression. Five- and 3-prime RACE assays identified 3 previously annotated (NR_033201/NR_033203/ENST000491264) and 1 novel variant of HOXB-AS3 in OCI-AML3 cells. NPM1 mutated patient samples exhibited higher expression of HOXB-AS3 in comparison to those with WT NPM1 (P 〈 .01) and healthy donors (P 〈 .01). To gain insights into the function of HOXB-AS3, we derived a HOXB-AS3-related mRNA expression signature; 154 mRNA transcripts correlated positively and 122 correlated negatively with high HOXB-AS3 expression. Gene ontology analysis revealed enrichment of genes involved in the pathway of DNA repair (P 〈 .01) in patients with high HOXB-AS3 expression. To assess the functional impact of HOXB-AS3, HOXB-AS3 KD studies using LNA gapmers were performed. In vitro KD of HOXB-AS3 led to decreased proliferation of OCI-AML3 cells, as measured by BrdU-based cell cycle analysis (S-phase average % in control v KD: 24% v 16%, P=.02). HOXB-AS3 KD also led to a reduction in the number of formed colonies by OCI-AML3 cells (P 〈 .01), whereas it had no significant effect on apoptosis. HOXB-AS3 KD in primary NPM1mut AML samples (n=3) led to a decrease in colony formation (P 〈 .01). Gene set enrichment analysisperformed in HOXB-AS3 silenced OCI-AML3 cells (profiled by RNAseq) revealed activation of the DNA damage response pathway in the HOXB-AS3 expressing cells. To assess the in vivo effects of HOXB-AS3 KD,we treated 10 NSG mice transplanted with the blasts of a NPM1mut AML patient with nanoparticle-formulated anti-HOXB-AS3 gapmers or control gapmers. We obtained RNA after 7 days of treatment and confirmed HOXB-AS3 KD in human cells (P 〈 .01). Survival analysis is currently ongoing but when we compared the leukemia burden at 3- and 6-weeks post-transplant in mice with adequate leukemia engraftment ( 〉 30% human CD45+ cells) the percentage of circulating blasts decreased in HOXB-AS3-KD (from 43% to 30%), while it increased in controls (from 36.5% to 62.8%). Last, to identify potential HOXB-AS3-binding proteins we performed RAP experiments in OCI-AML3 cells. HOXB-AS3- and U1-specificRNA-protein complexes were isolated by hybridization with biotinylated probes. Mass spectrometry and comparative analysis of theeluates yielded 22 candidate HOXB-AS3-interacting RNA-binding proteins. These included the core components of the DSHB complex (SFPQ and NONO). RNA-immunoprecipitation experiments validated the interaction of HOXB-AS3 with NONO. The DSHB complex is a major mediator of the DNA damage response and experiments that will elucidate the importance of HOXB-AS3 interaction with NONO in this context are underway. Conclusions: HOXB-AS3 is highly expressed in NPM1mut CN-AML and regulates cell cycle progression of AML blasts. HOXB-AS3 KD decreases cell proliferation and colony formation capacity of leukemia cells in vitro. HOXB-AS3 KD also decreases leukemia burden in an in vivo PDX model. Comparative proteomic analyses identified several binding partners of HOXB-AS3, such as the DSHB complex, which is a key mediator of the DNA repair process. Disclosures No relevant conflicts of interest to declare.