Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma

Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton\u27s tyrosine kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib (IBR) has shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual reassessment method of 6 combinations of IBR (280 mg, 420 mg, and 560 mg by mouth daily) and VEN (max dose of 200 mg and 400 mg by mouth daily). Eligible participants were not previously exposed to BTKi and not high risk for tumor lysis syndrome (TLS). VEN, initiated first at 100 mg, then at 20 mg by mouth daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level assigned. Combination treatment continued for six 28-day cycles. Thirty-five participants were enrolled and treated. One TLS event occurred with starting dose of 100 mg VEN; no TLS was seen with 20 mg. The optimal dosing combination was considered to be VEN 200 mg and IBR 420 mg with an overall response rate (ORR) of 93.8% (95% CI: 73.6% to 99.7%) and DLT incidence of 6.2% (95% CI: 0.3% to 26.4%). ORR for all arms was 82.3% (28/34; 95% CI: 65.5% to 93.2%) with a complete response (CR) rate of 42.4% (14/33; 95% CI: 25.5% to 60.8%). A participant was not allocated to IBR 560 mg and VEN 400 mg. ORR benefit was not seen with higher dosing combinations and toxicity was higher; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560

Search for supersymmetry in events with large missing transverse momentum, jets, and at least one tau lepton in 20 fb−1 of √s=8 TeV proton-proton collision data with the ATLAS detector

A search for supersymmetry (SUSY) in events with large missing transverse momentum, jets, at least one hadronically decaying tau lepton and zero or one additional light leptons (electron/muon), has been performed using 20.3fb−1 of proton-proton collision data at √s= 8 TeV recorded with the ATLAS detector at the Large Hadron Collider. No excess above the Standard Model background expectation is observed in the various signal regions and 95% confidence level upper limits on the visible cross section for new phenomena are set. The results of the analysis are interpreted in several SUSY scenarios, significantly extending previous limits obtained in the same final states. In the framework of minimal gauge-mediated SUSY breaking models, values of the SUSY breaking scale Λ below 63 TeV are excluded, independently of tan β. Exclusion limits are also derived for an mSUGRA/CMSSM model, in both the R-parity-conserving and R-parity-violating case. A further interpretation is presented in a framework of natural gauge mediation, in which the gluino is assumed to be the only light coloured sparticle and gluino masses below 1090 GeV are excluded

Search for Eccentric Black Hole Coalescences during the Third Observing Run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass $M>70$ $M_\odot$) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities $0 < e \leq 0.3$ at $0.33$ Gpc$^{-3}$ yr$^{-1}$ at 90\% confidence level.Comment: 24 pages, 5 figure

Open data from the third observing run of LIGO, Virgo, KAGRA and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in April of 2019 and lasting six months, O3b starting in November of 2019 and lasting five months, and O3GK starting in April of 2020 and lasting 2 weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main dataset, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages.Comment: 27 pages, 3 figure

Open data from the third observing run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

Orbital mantle cell lymphoma presenting as myasthenia gravis

<p>A 69-year-old man, previously treated with pyridostigmine for myasthenia gravis (manifesting as ptosis and diplopia) was evaluated for several concomitant bilateral anterior orbital masses. Imaging revealed 3 discrete, solid masses within and around the orbits. An incisional biopsy demonstrated atypical lymphocytes positive for CD20 and Cyclin-D1, consistent with mantle cell lymphoma. The patient received induction chemotherapy with a rituximab-based regimen. He experienced resolution of his diplopia and ptosis after one cycle of chemotherapy and achieved complete remission of the orbital masses and myasthenia symptoms after 6 cycles. Myasthenia gravis is most commonly associated with thymoma, but may also be observed with other malignancies. Recognition that orbital lymphoma may coexist with myasthenia gravis will help in expediting the diagnosis of future cases and in guiding treatment decisions.</p

Patients with SF3B1 Mutation Have Good Prognosis Even in the Presence of Other Poor Prognostic MDS Features and Have Better Outcomes During Treatment with Low Intensity Chemotherapy

Abstract Abstract 3831 The discovery of mutations in components of the RNA splicing machinery has underlined the importance of this pathogenetic mechanism in MDS biology. We and others reported that mutations in SF3B1 are frequent in refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T). We recently reported good survival outcomes in a large cohort of SF3B1 mutant patients similar to the findings of Papaemmanuil et al, NEJM< 2011. Here, we aimed to evaluate the correlation between SF3B1 mutations in association with other poor prognostic clinical and pathologic factors in MDS. We focused on a large cohort of patients with several myeloid malignancies (n=340). Patients were grouped in MDS (n=176), MDS/MPN (n=88) and secondary AML (sAML) from a previous MDS (n=76). Diseases were classified according to the 2008 WHO classification. Survival outcomes (overall survival [OS], progression free survival [PFS] and event free survival [EFS]) were defined according to MDS IWG criteria. We studied a total of 340 patients with myeloid malignancies. median age, 69 years old (range 19–92), sex (Male, n=222; females, n=118). We performed direct sequencing for SF3B1 (exon 13–16) on a large cohort of MDS, MDS/MPN and sAML patients and found 11.8% SF3B1 mutants. The outcomes of SF3B1 mutant vs WT patients were compared based on the presence of poor clinicopathologic factors associated with MDS like RBC transfusion dependence, presence of SNP-A lesions, presence of acquired somatic uniparental disomy (AS-UPD), Age ≥ 60 years, presence of reticulin fibrosis in the bone marrow. We also assessed the effects of therapies in the prognostic effect of SF3B1 mutations. We previously reported that the presence of new SNP-A lesions in myeloid malignancies including MDS and AML are associated with poor prognostic outcomes. However, the good prognostic effects of SF3B1 mutation is still apparent even in the patients with new SNP-A abnormalities (OS: 40 vs 16 mos, p=.003; PFS: 40 vs 10 mos, p=.003, 40 vs 10 mos, p=.0007. However, when analysis is limited to acquired somatic uniparental disomy defects which we recently reported as the worst lesion among SNP-A abnormalities, the good prognostic effect of SF3B1 is lost (OS: 19 vs 9 mos, p=.29, PFS: 18 vs 7 mos, p=.20, EFS: 19 vs 8 mos, p=.17). Age is an important predictor of outcomes in MDS with higher age associated with worse outcomes. SF3B1 remained predictive of good outcomes in patients ≥ 60 years of age (OS: 40 vs 16, p=.002; PFS: 40 vs 11 mos, p=.003; EFS: 40 vs 10 mos, p=.0005). Persistent RBC transfusions are also associated with inferior survival in MDS, yet SF3B1 mutant patients continued to have good outcomes (OS 34 vs 13, p=.002; PFS: 27 vs 8 mos, p=.004; EFS: 14 vs 9 mos, p=.001). Reticulin fibrosis in the bone marrow is a characteristic feature of myeloproliferative neoplasms but their presence in MDS is associated with unfavorable results, SF3B1 mutant retain their good outcomes even in the presence of reticulin fibrosis in the BM (OS: 40 vs 15 mos, p=.09; PFS: 47 vs 12 mos, p=.04; EFS: 75 vs 13 mos, p=.008). Patients screened for SF3B1 were also further stratified according to treatments received. No patients with SF3B1 mutations underwent allogeneic hematopoietic stem cell transplantation and high intensity chemotherapy specifically induction chemotherapy or high dose cytarabine. However based on treatment with LIC, SF3B1 mutant patients have better survival outcomes compared to WT patients (OS: 61 vs 17 mos, p=.004; PFS: not reached [NR] vs 7 mos; p=.009; EFS: 61 vs 10 mos, p=.001). These observed survival outcomes remain significant when patients were stratified according to disease subtypes. MDS and MDS/MPN patients treated with LIC have better outcomes if they have SF3B1 mutation (OS: 61 vs 23 mos, p=.005; PFS: NR vs 16 mos, p=.01; EFS: 61 vs 16 mos, p=.001). A high number of TET2/DNMT3A mutations are found in SF3B1 mutants. TET2/DNMT3A mutations have been previously association with improved response to hypomethylating agents which is one of the possible reasons why SF3B1 mutants treated with LIC did better than their WT counterpart. In conclusion, SF3B1 retains its favorable prognostic effect even in the face of poor prognostic factors such as RBC transfusion dependence, presence of SNP-A lesions, Age ≥ 60 years, presence of reticulin fibrosis in the bone marrow except in the presence of AS-UPD. SF3B1 mutants treated with LIC also have better outcomes. Disclosures: No relevant conflicts of interest to declare