Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma

Bruton tyrosine kinase (BTK) inhibitors have greatly improved the spectrum of treatment options in mantle cell lymphoma (MCL) [1–4]. Acalabrutinib is a highly selective, orally administered, and potent BTK inhibitor with limited off-target activity [5]. Acalabrutinib was approved in 2017 by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data from the open-label, multicenter, phase 2 ACE-LY-004 study of acalabrutinib 100 mg twice daily [1]. Here, we present updated results from the ACE-LY-004 study after a median 26-month follow-up. Eligibility criteria and study design were published previously (Supplementary methods) [1]. Analysis of minimal residual disease (MRD) was conducted after complete response (CR) or partial response (PR) was achieved using the quantitative ClonoSEQ next-generation sequencing (5 × 10−6 ) assay (Adpative Biotechnologies, Seattle, WA, USA) in consenting patients with available paired archival tumor and whole blood samples. Data are updated as of February 12, 2018

Paths Explored, Paths Omitted, Paths Obscured: Decision Points & Selective Reporting in End-to-End Data Analysis

Drawing reliable inferences from data involves many, sometimes arbitrary, decisions across phases of data collection, wrangling, and modeling. As different choices can lead to diverging conclusions, understanding how researchers make analytic decisions is important for supporting robust and replicable analysis. In this study, we pore over nine published research studies and conduct semi-structured interviews with their authors. We observe that researchers often base their decisions on methodological or theoretical concerns, but subject to constraints arising from the data, expertise, or perceived interpretability. We confirm that researchers may experiment with choices in search of desirable results, but also identify other reasons why researchers explore alternatives yet omit findings. In concert with our interviews, we also contribute visualizations for communicating decision processes throughout an analysis. Based on our results, we identify design opportunities for strengthening end-to-end analysis, for instance via tracking and meta-analysis of multiple decision paths

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit