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Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32–0·58]; median progression-free survival 14·6 months [95% CI 10·4–not estimable] vs 6·2 months [4·2–7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit–risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. Janssen Research & Development, LLC.

CHFR , a novel checkpoint gene inactivated in human cancer, delays chromosome condensation in cells treated with microtubule poisons. To understand the molecular mechanism for this delay, we characterized cells with inactivated CHFR and stably transfected derivatives expressing the wild-type gene. After exposure to microtubule poisons, the CHFR -expressing cells arrested transiently in early prophase with a characteristic ruffled morphology of the nuclear envelope and no signs of chromosome condensation. Several markers suggested that Cyclin A/Cdc2 had been activated, whereas Aurora-A and -B and Cyclin B1/Cdc2 were inactive. Further, Cyclin B1 was excluded from the nucleus. Ectopic expression of Cyclin B1 with a mutant nuclear export sequence induced chromosome condensation, and thus overcame the CHFR checkpoint. We conclude that the mechanism by which CHFR delays chromosome condensation involves inhibition of accumulation of Cyclin B1 in the nucleus.

Upregulation of programmed death ligand-1 (PD-L1) has been observed in patients with MDS, and its expression on myeloblasts is associated with progression to AML. This open-label, phase 1 study evaluated the safety and tolerability of the PD-L1 antibody durvalumab as monotherapy (part 1) and in combination with tremelimumab, with or without azacitidine (part 2), in patients with MDS who progressed following hypomethylating agent treatment. Sixty-seven adults with MDS were enrolled (part 1, 40 with low/intermediate-1 or intermediate-2/high IPSS risk status; part 2, 27 with intermediate-2/high IPSS risk status). Primary safety endpoints included dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). Secondary endpoints included evaluation of clinical outcomes, survival, and pharmacokinetics. Dose-limiting toxicities were experienced by no patients in part 1 and 3 patients (11%) in part 2. The most common treatment-emergent adverse events were diarrhea and fatigue (40% each) in part 1 and fatigue (44%) and anemia (37%) in part 2. In parts 1 and 2, 15% of patients experienced marrow complete response as their best overall response, according to IWG criteria. Hematologic improvement was observed in 35% and 30% of patients respectively in part 1 and part 2. The study was terminated early due to limited efficacy.

BackgroundMEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer.ObjectiveThis first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies.Patients and methodsAdults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity.ResultsAs of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUCinf geometric CV%: 62.3–134.2, and 74.8–126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%.ConclusionsThrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD.The study was registered with ClinicalTrials.gov (NCT03106428).

We recently described a novel checkpoint pathway that functions early in mitosis to delay chromosome condensation in response to microtubule poisons. The only gene implicated so far in this checkpoint pathway is chfr , whose protein product contains a RING domain and has ubiquitin ligase activity in vitro . The significance of this activity in vivo is unclear. A recent report suggested that the Chfr protein targets itself for proteasome-dependent degradation in mitotic cells through autoubiquitination. However, we observe that in mitosis Chfr exhibits a phosphorylation-dependent electrophoretic mobility shift with no change in overall protein levels. Further analysis of its ubiquitin ligase activity revealed that Chfr can catalyse the formation of noncanonical Lys63-linked polyubiquitin chains with Ubc13-Mms2 acting as the ubiquitin-conjugating enzyme. Ubc13-Mms2 and Lys63-polyubiquitin chains are not associated with targeting proteins to the proteasome, but rather with signaling cellular stress. We propose that Chfr may have a role in signaling the presence of mitotic stress induced by microtubule poisons.

Checkpoints are vital for the cell because they provide dependency throughout the cell cycle and are directly involved in monitoring the integrity of the genome. Inactivation of checkpoints is the underlying cause of many cancers. Therefore, understanding their regulation could potentially lead to new cancer treatments by taking advantage of the differences between normal and cancerous cells. This work focuses on two mitotic checkpoint pathways, the prophase checkpoint and the mitotic exit network, and more specifically, on two important proteins of those pathways, chfr and LATS1. The chfr gene is a member of a newly discovered checkpoint pathway that monitors centrosome separation in early prophase and inhibits chromosome condensation in the event that centrosomes fail to separate. This works shows that chfr has ubiquitin ligase activity and is capable of catalyzing the formation of noncanonical Lys63-linked polyubiquitin chains with Ube13-Mms2 acting as the ubiquitin-conjugating enzyme. Therefore, I propose that chfr may have a role in signaling mitotic stress. I also looked for inactivation of chfr in human cancer patients and I found that chfr is indeed inactivated by multiple mechanisms in human cancer, thus signifying the importance of studying this gene. The LATS1 gene is the mammalian homologue of the Drosophila LATS/WARTS tumor suppressor. It is an evolutionarily conserved serine/threonine kinase of the NDR kinase family. In both Drosophila and mice it has been shown that inactivation of WARTS/LATS leads to spontaneously developed tumors. This work shows that LATS1 functions late in the cell cycle, during the end of mitosis, by monitoring mitotic exit. I show that ectopic expression of LATS1 overrides the spindle checkpoint and drives cells out of mitosis; in doing so, LATS1 requires the help of hMob1. Even though chfr and LATS1 themselves are not similar, they belong to pathways that monitor similar events. The investigation of one pathway might provide insights that can be applied for the understanding of the other pathway. This work provides the basis for the study of both checkpoint pathways.