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

Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or r-chop consolidation in an international, prospective, multicenter Phase II trial

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective

<i>Mei long</i> (DNHM D2514) in dorsal view.

<p><b>A</b>, interpretive line drawing; <b>B</b>, photograph. <b>Abbreviations</b>: <b>aofe</b>, antorbital fenestra; <b>c</b>, cervical vertebra(e), unnumbered; <b>c6</b>, sixth cervical vertebra; <b>c7</b>, seventh cervical vertebra; <b>ca1–ca18</b>, caudal vertebrae (one through eighteen); <b>co</b>, coracoid; <b>d</b>, dentary; <b>dv</b>, dorsal vertebra(e); <b>f</b>, frontal; <b>fm</b>, femur; <b>fl</b>, fibula; <b>h</b>, humerus; <b>il</b>, ilium; <b>l</b>, lacrimal; <b>mt-II</b>, <b>mt-III</b>, second metatarsal, third metatarsal etc.; <b>mx</b>, maxilla; <b>mxfl?</b>, maxillary fenestra; <b>n?</b>, nasal; <b>nc</b>, neural canal; <b>ns</b>, neural spine; <b>o</b>, orbit; <b>p</b>, parietal; <b>pu</b>, pubis; <b>pmx</b>, premaxilla; <b>q</b>, quadrate; <b>r</b>, radius; <b>s1</b>, <b>s2</b>, etc., first sacral vertebra, second sacral vertebra etc.; <b>sa</b>, surangular; <b>sc</b>,scapula; <b>sp</b>, fused neural spine of sacrum; <b>t</b>, tibia; <b>u?</b>, possible manual ungual; <b>ul</b>, ulna; <b>II-2</b>, second phalanx of digit II of pes; <b>II-3</b>, third phalanx of digit II of pes; <b>III-1</b>, first phalanx of digit III of pes; <b>IV-1</b>–<b>IV-4</b>, first through fourth phalanges of digit IV. Note: Abbreviations follow the convention of Weishampel et al., 2004. Scale bar equals 1 cm.</p

Details of the right manus in lateral view and skull in left lateroventral view.

<p>Manus shows the unusual features of reduced divergence in digit I and metacarpal III longer than metacarpal II. <b>Abbreviations: I-1</b>, <b>II-1</b>, and <b>II-2</b>, corresponding manus digit and phalanx; <b>mcI</b>, <b>mcII</b>, and <b>mcIII</b>, metacarpals for digits I–III; and other abbreviations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045203#pone-0045203-g001" target="_blank">Figure 1</a>. Scale bar equals 0.5 cm.</p

Hindlimb details of <i>Mei long</i> DNHM D2514.

<p><b>A</b>, articulated left hindlimb in lateral view; <b>B</b>, distal tibia and metatarsals IV and V of left hindlimb. Arrow and dashed line indicate caudodorsal edge of articular surface; <b>C</b>, distal end of tibia in caudodistal view. Dashed line as in <b>B</b>. Abbreviations as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045203#pone-0045203-g001" target="_blank">Figure 1</a>. Scale bars equal 0.5 cm.</p

Character changes to the coding for <i>Mei long</i> from Xu et al. (2011).

<p>Character changes to the coding for <i>Mei long</i> from Xu et al. (2011).</p

Detail of left forelimb of <i>Mei long</i> DNHM D2514 in articulation.

<p>Photograph showing scapula and coracoid (caudolateral view), humerus (mediolateral view), and partial ulna and radius (lateral view), as well as a portion of the right scapula (dorsal view). Lines on the left scapula demarcate border with the coracoid. <b>Abbreviations</b>: <b>co</b>, coracoid; <b>h</b>, humerus; <b>lsc</b>, left scapula; <b>r</b>, radius; <b>rsc</b>, right scapula; <b>ul</b>, ulna. Scale bar equals 0.5 cm. [planned for 2/3 page width].</p

A Second Soundly Sleeping Dragon: New Anatomical Details of the Chinese Troodontid <i>Mei long</i> with Implications for Phylogeny and Taphonomy

<div><p>A second nearly complete, articulated specimen of the basal troodontid <i>Mei long</i> (DNHM D2154) is reported from the Early Cretaceous (Hauterivian-Valanginian) lower Yixian Formation, Liaoning Province, China. New diagnostic features of <i>Mei long</i> are identified, including: a uniquely shaped maxilla, low with small, low maxillary fenestra; sacrum with an extremely wide caudal portion and elongate 4^th and 5^th sacral processes; and a large distal articular surface on the tibiotarsus which continues caudally on the tibia. A phylogenetic analysis including new data from the second specimen recovered <i>Mei</i> as a basal troodontid, in keeping with previous analyses. Although the skeleton exhibits several juvenile-like features including free cervical ribs, unfused frontals and nasals, and a short snouted skull, other attributes, full fusion of all neurocentral synostoses and the sacrum, and dense exteriors to cortical bone, suggest a small, mature individual. Microscopic examination of tibia and fibula histology confirms maturity and suggests an individual greater than two years old with slowed growth. Despite being one of the smallest dinosaurs, <i>Mei long</i> exhibits multi-year growth and cortical bone consisting largely of fibro-lamellar tissue marked by lines of arrested growth as in much larger and more basal theropods. This <i>Mei long</i> specimen lies in a similar but mirrored sleeping position to that of the holotype, strengthening the hypothesis that both specimens were preserved in a stereotypical life position. Like many Liaoning specimens, the new specimen also lacks extensive taphonomic and stratigraphic data, making further behavioral inference problematic.</p></div

Histology of the right tibia and fibula of <i>Mei long</i>, DNHM D2514.

<p><b>A</b>, cross-section of tibia and fibula in articulation. <b>B</b>, partial cross-section of fibula. <b>C</b>, partial cross-section of tibia. Note two zones of fibro-lamellar bone separated by a LAG in the tibia and the largely avascular lamellar bone that marks the periphery of both elements. The latter can be interpreted as an external fundamental system. Abbrevaitions: <b>el</b>, endosteal lamellar bone; <b>fl</b>, fibro-lamellar bone; <b>fl1</b>, first and interior zone of fibro-lamellar bone; <b>fl2</b>, second and more exterior zone of fibro-lamellar bone; <b>LAG</b>, line of arrested growth; <b>mc</b>, medullary cavity; <b>pl</b>, peripheral lamellar bone. Scale bars equal 0.5 mm in <b>A</b> and 0.2 mm in <b>B</b> and <b>C</b>.</p