ALBERT

Description: Author(s): E. Parr et al. The α decay of Th 222 populating the low-lying J π = 3 − state, and also a proposed 1 − state, in Ra 218 has been observed. The observations suggest an excitation energy of 853 keV for the 1 − state, which is 60 keV above the 3 − state. The hindrance factors of these α decays give a possible boundary to the … [Phys. Rev. C 94, 014307] Published Tue Jul 12, 2016

Description: Author(s): Stefan Groot Nibbelink and Erik Parr Inspired by the tachyon-free nonsupersymmetric heterotic SO ( 16 ) × SO ( 16 ) string we consider a special class of nonsupersymmetric field theories: those that can be obtained from supersymmetric field theories by supersymmetry-breaking twists. We argue that such theories, like their supersymmetric counte… [Phys. Rev. D 94, 041704(R)] Published Tue Aug 23, 2016

Description: Author(s): E. Parr et al. Fine structure in the α decay of high-spin isomers in Lu 155 ( 25 / 2 − ) and Hf 156 ( 8 + ) has been studied for the first time using α γ -coincidence analysis. Three new α decays from Lu 155 ( 25 / 2 − ) and two from Hf 156 ( 8 + ) have been identified, populating seniority s 〉 1 states in the N = 82 nuclei Tm 151 and Yb 152 ,... [Phys. Rev. C 98, 024321] Published Wed Aug 29, 2018

Description: Author(s): S. V. Szwec, B. P. Kay, T. E. Cocolios, J. P. Entwisle, S. J. Freeman, L. P. Gaffney, V. Guimarães, F. Hammache, P. P. McKee, E. Parr, C. Portail, J. P. Schiffer, N. de Séréville, D. K. Sharp, J. F. Smith, and I. Stefan In neutrinoless double- β decay such as 136 Xe to 136 Ba, two neutrons become two protons, thus rearranging the occupancy of protons and neutrons in the ground states of the parent and daughter nuclei. From precision measurements of the cross sections of single-neutron adding and -removing reactions, the authors extract the change in ground-state neutron occupancies between 136 Xe and 136 Ba. Along with recent results on the proton occupancies, the new experimental neutron occupancies disagree with those used in existing theoretical calculations of the rate of this elusive β -decay mode, and provide a ​ ​basis for improved estimates of the uncertainties for new calculations. [Phys. Rev. C 94, 054314] Published Tue Nov 15, 2016

Description: Background Light-chain (AL) amyloidosis is a multi-organ amyloid deposition disease caused by misfolded protein aggregation. Current treatments have improved overall (OS) and progression-free survival (PFS) but challenges remain in improving therapy with newer agents and targeting amyloid protein deposits with novel immunotherapy. We review the literature regarding efficacy of existing chemotherapy in AL amyloidosis and summarize non-FDA approved novel drugs and monoclonal antibodies (mAbs) in early phase clinical development. Methods We searched databases including Cochrane library, PubMed and ClinicalTrials.gov for all prospective and retrospective studies (As of 4/15/2018) with measured hematologic response rate (HR) in patients with AL amyloidosis since 2000. Inclusion criteria included all prospective and retrospective studies with melphalan-based treatments, bortezomib combinations including bortezomib, cyclophosphamide and dexamethasone (VCD), bortezomib and dexamethasone (VD) and immunotherapies. We included all studies with at least 5 or more patients and reported HR. Results From 918 studies, we selected 57 studies (2640 patients) evaluating HR with melphalan-based stem cell transplant (SCT) treatments and non-stem cell transplant treatments including melphalan and bortezomib combinations. Other agents included daratumumab (anti-CD38 mAb), and ixazomib (proteasome inhibitor). Mean aggregate HR reported from studies with melphalan-based SCT treatment (17 studies, n=587) was 67%. Mean aggregate HR from all non-transplant treatments (40 studies, n=2053) was 64%. Of the non-transplant treatments, HR for melphalan-based treatments (21 studies, n=1148) was 59% and varied as follows: melphalan + lenalidomide + dexamethasone (57%) and melphalan + dexamethasone (52%). Mean aggregated HR for non-transplant bortezomib-based treatment (17 studies, n=859) was 72% consisting of VD (69%) and VCD (76%). HR with Ixazomib (1 study) and Daratumumab (1 study) was 52% and 76% respectively. Other novel drugs currently being studied include 11-1F4 (chimeric fibril-reactive mAb), GSK2398852 and GSK2315698 (anti-serum amyloid protein mAbs), and NEOD001 (anti-circulating soluble and deposited aggregated amyloid mAb). Conclusion For AL amyloidosis, melphalan-based SCT has shown effectiveness while VD and VCD demonstrate effectiveness in non-transplant patients. Further studies are warranted to evaluate novel proteasome inhibitors (Ixazomib) and emerging immunotherapy with daratumumab. Current trials including amyloid protein and fibril targeting (circulating and tissue-fixed) with novel immunotherapy are innovative and may have higher clinical efficacy, but need further testing. Disclosures No relevant conflicts of interest to declare.

Description: Key Points I-BET151 and I-BET-762 induce cell cycle arrest and apoptosis in myeloma cells associated with MYC downregulation and HEXIM1 upregulation. Preclinical functional and pharmacologic profiling of I-BET762 supports its use in phase 1 clinical studies.

Description: Background: Bispecific antibodies have been extensively studied in vitro and in vivo for their use in redirected tumor cell lysis. A particular challenge of bispecific antibody constructs recognizing the CD3 signaling complex is to achieve a controlled polyclonal activation of T-cells that, ideally, is entirely dependent on the presence of target cells. If this is not the case, systemic production of inflammatory cytokines and secondary endothelial reactions may occur as side effects, as are observed with the murine anti-human CD3e antibody OKT-3 (muromab, Orthoclone®). Here we present evidence that MT103 (or MEDI-538), a bispecific single chain antibody of the BiTE class that targets CD19 and CD3, induces T-cell activation exclusively in the presence of target cells. Material and methods: Peripheral blood mononuclear cells from healthy donors were prepared by Ficoll density centrifugation. PBMC were incubated for 24 hours with MT103 in presence or absence of specific target cells. Target cell lysis was determined by measurement of adenylate kinase activity released from lysed cells. De novo expression of activation markers CD69 and CD25 on T-cells was assessed by flow cytometry using directly conjugated monoclonal antibodies, and the concentration of cytokines in the supernatant was determined by a commercial FACS-based bead array. Results: MT103 was analyzed for conditional T-cell activation. In the presence of target-expressing cell lines, low picomolar concentrations of MT103 were sufficient to stimulate a high percentage of peripheral human T-cells to express cytokines and surface activation markers, to enter into the cell cycle and to induce redirected lysis of target cells. However, in the absence of target cells, the BiTE molecules no longer detectably activated human T-cells even at concentrations exceeding the ED50 for redirected lysis and conditional T-cell activation by more than five orders of magnitude. Conclusion: Our data show that T-cell activation by MT103 is highly conditional in that it is strictly dependent on the presence.

Description: Introduction Myelofibrosis (MF), a BCR-ABL negative myeloproliferative neoplasm (MPN), has an annual incidence of 1 in 100000 for the primary MF and 0.3-0.7 in 100000 for secondary MF in the USA. MF patients have a median survival of 6.5 years. The primary mutation, JAK2V617F, occurs in 40-60% of MF cases. Ruxolotinib, a JAK inhibitor, has been the mainstay in treating high risk, debilitating MF but largely clinical needs are unmet. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade ( Jan 2007 till Dec 2017) were screened for relevant studies. After screening by 2 independent reviewers, 212 articles were finalized for our final analyses. We have reviewed the mechanism of action, safety and efficacy of 2nd generation JAK inhibitors in this review. Results JAK1 inhibitor: Itacitinib reduced total symptom score (TSS) ≥ 50% in 15/42 (36%) patients. Mild gastrointestinal (GI) disturbances and some grade 3-4 myelosuppression (anemia: 33%, thrombocytopenia: 29%) were reported. JAK2 inhibitors: In PERSIST-1, pacritinib when compared to best available therapy (BAT) showed SVR ≥ 35% in 19.1% vs. 4.7% patients, with lower rates of myelosuppression (thrombocytopenia: 17%, anemia: 11%). In PERSIST-2, a phase III trial of pacritinb vs. BAT in patients with baseline cytopenias, similar efficacy was demonstrated (SVR ≥ 35%: 18% vs. 3%). Increasing rates of heart failure and intracranial hemorrhages led to a temporary hold which was lifted in August 2017. Lestaurtinib showed CI in 7 (44%) patients in a phase I trial (n=16) and 6 (27%) patients in a phase II trial (n=22). Most notable toxicities were G 1/2 GI disturbances, anemia occurred in 14% and thrombocytopenia in 23% of patients. In a phase III trial (n=193), fedratinib showed a SVR ≥ 35% and a TSS ≥ 50% in 40% and 36% patients, respectively. However, incidence of significant neurotoxicity and Wernicke's encephalopathy led to its suspension. Similarly, a trial of XL019 was terminated due to emergence of central and peripheral neurotoxicity. In a phase I trial (n=48), NS-018 exhibited a spleen length reduction (SLR) ≥ 50% in 20 (56%) patients along with prompt improvement in bone marrow fibrosis (37%). Anemia and thrombocytopenia were reported in 15% and 27% of patients, respectively. Dizziness (23%) and nausea (19%) were also reported. Gandotinib demonstrated SLR ≥50% in 62% patients, in a phase I trial (n=38). G1 diarrhea (55.3%) and nausea (42.1%) were the most common toxicities. JAK 1/2 inhibitors: SIMPLIFY-1 (S1), a phase III clinical trial (n=432) of momelotinib vs. ruxolotinib in JAK inhibitor-naïve patients, demonstrated non-inferiority for momelotinib, in spleen volume reduction (SVR) ≥ 35% (26.5% vs. 29%; p=0.01). However, SIMPLIFY-2 trial (S2), that compared these two drugs in JAK inhibitor exposed patients did not achieve similar responses with momelotinib (6.7% vs. 5.8%; p=0.90). Interestingly, momelotinib excelled at achieving transfusion independency in both trials (S1: 66.5% vs. 49.3%; p=0.001, S2: 43.3% vs 21.2%; p=0.001). Grade ≥ 3 infections and peripheral neuropathy were the major toxicities noted. These trials were suspended after 89% of patients failed to achieve the primary endpoint of SVR. AZD1480 demonstrated clinical improvement (CI) in four (11%) patients in a phase I trial (n=35). Most common adverse events included grade (G) 1-2 dizziness and anemia. Conclusion Novel JAK pathway inhibitors have shown promising efficacy in MF but safety concerns regarding the hematological (cytopenias) and non-hematological adverse effects needs to be addressed until their use in clinical practice is established. Momelotinib success in achieving anemia related endpoints is note-worthy and should be further explored in this regard. A phase II study [NCT03165734] evaluating pacritinib monotherapy as a second line treatment in patients with baseline thrombocytopenia is ongoing. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Multiple myeloma (MM) is an incurable malignancy of B-cell lineage. Introduction of immunomodulatory drugs such as lenalidomide has significantly improved overall survival of patients with MM. Lenalidomide maintenance is currently the standard of care for maintaining remission in MM. However, second primary malignancies are known to arise in patients on lenalidomide though their pathogenesis is not known. We report a patient who developed B-lymphoblastic leukemia (B-ALL) while on lenalidomide, which went into spontaneous remission after stopping lenalidomide. Whole exome sequencing (WES) was performed to examine the mutational landscape and clonal evolution of the different malignant clones. We also aimed to postulate a mechanism for lenalidomide-induced ALL. Case history and methods: A 59-year-old female with history of rheumatoid arthritis was diagnosed with IgG-κ MM and treated with 8 cycles of bortezomib, Lenalidomide and dexamethasone followed by lenalidomide-maintenance (10 mg/day). At 36 months after initiation of treatment for MM, she developed lymphopenia and her bone marrow (BM) biopsy showed 38% leukemic B lymphoblasts. Lenalidomide was discontinued and a follow-up BM biopsy done 2 months later showed spontaneous complete remission of ALL, which was confirmed at 8 months. She remains in complete remission of ALL and MM without any specific treatment at 12 months after the diagnosis of ALL. BM aspirate samples at diagnosis of MM, on lenalidomide-maintenance with MM in remission, at diagnosis of ALL, and after stopping lenalidomide with MM and ALL in remission were used to perform WES with 2x150 bp reads and 100x coverage utilizing the Illumina Hiseq. The raw reads were mapped to reference genome (hg19) and compared with peripheral blood T-lymphocytes as germ line control. Variants were annotated using dbSNP, CLINVAR and COSMIC through Mutect. Clonal evolution was analyzed by SciClone. The study was approved by Institutional Review Board. Results: The burden of somatic mutations was significantly higher at diagnosis of MM when compared to the three other time points. Analysis of clonal architecture revealed the distinct clustering of mutations at specific time points (Figure). Most mutations detected at diagnosis of MM (e.g. NOTCH2, BTG1, BCLAF1) disappeared after treatment for MM. Similarly, most mutations detected only at diagnosis of ALL (e.g.PIK3CD, CDK16) became undetectable at spontaneous remission. Interestingly, clones with mutations of IGSF3 (immunoglobulin superfamily) and CXXC4 (Wnt signaling pathway) were detectable while the patient was on lenalidomide and at diagnosis of ALL but disappeared after stopping lenalidomide, which suggests that these clones gained pro-survival advantage from lenalidomide. Only a few mutations (GSDMC, NBPF20, ANAPC1) persisted in both MM and ALL stages. GSDMC is a gasdermin family member which may modulate function of MYC. NBPF20 has been described in relapsed pediatric ALL. ANAPC1 is a cell cycle gene whose transcription is regulated by Ikaros. Loss of repressor function of Ikaros was recently reported to deregulate ANAPC1 expression and cause mitotic progression of ALL in vitro. As lenalidomide is known to induce degradation of Ikaros, we hypothesize that lenalidomide may create a favorable selection pressure for B-cell clones harboring mutations in Ikaros-dependent genes. Conclusions: Clonal evolution analysis suggests that MM and ALL arose from different B-cell sub-clones, which was consistent with previous observation. However, there are a few shared mutations between MM and pre-B ALL, which may be responsible for leukemogenesis in our case. Lenalidomide may affect intracellular protein interactions to induce selection of rare B-cell clones evolving into secondary ALL. Also, our case demonstrated that simply stopping lenalidomide may lead to spontaneous and durable regression of ALL. Transcriptomic and proteomic analysis including Ikaros expression is required to further understand the mechanism of appearance of ALL and its regression after stopping lenalidomide. Figure Disclosures Shlomchik: BlueSphere Bio: Other: Founder and Equity Interest.

Description: Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease: a homozygous deletion of approximately 11 kb of the fibrinogen α-chain gene (FGA). Subsequent studies revealed that the great majority of afibrinogenemia mutations are localized in FGA, but mutations were also found in FGG and FGB. Apart from 3 missense mutations identified in the C-terminal portion of FGB, all fibrinogen gene mutations responsible for afibrinogenemia are null. In this study, a young boy with afibrinogenemia was found to be a compound heterozygote for 2 mutations in FGB: an N-terminal nonsense mutation W47X (exon 2) and a missense mutation (G444S, exon 8). Coexpression of the FGB G444S mutant cDNA in combination with wild-type FGA and FGG cDNAs demonstrated that fibrinogen molecules containing the mutant β chain are able to assemble but are not secreted into the media, confirming the pathogenic nature of the identified mutation. (Blood. 2003;102:4413-4415)