Expression and role of RIP140/NRIP1 in chronic lymphocytic leukemia

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Quantum-Classical Computation of Schwinger Model Dynamics using Quantum Computers

We present a quantum-classical algorithm to study the dynamics of the two-spatial-site Schwinger model on IBM's quantum computers. Using rotational symmetries, total charge, and parity, the number of qubits needed to perform computation is reduced by a factor of $\sim 5$, removing exponentially-large unphysical sectors from the Hilbert space. Our work opens an avenue for exploration of other lattice quantum field theories, such as quantum chromodynamics, where classical computation is used to find symmetry sectors in which the quantum computer evaluates the dynamics of quantum fluctuations.Comment: 5 pages, 4 figures, 23 pages supplemental, 8 figures supplementa

Obinutuzumab in hematologic malignancies: Lessons learned to date

AbstractThe routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing.Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil.Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies

Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma

Abstract Background In the absence of randomized studies directly comparing chimeric antigen receptor T cell therapies, this study used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory large B cell lymphoma (LBCL). Methods Primary data sources included individual patient data from the TRANSCEND NHL 001 study (TRANSCEND [NCT02631044]; N = 256 for efficacy set, N = 269 for safety set) for liso-cel and summary-level data from the ZUMA-1 study (NCT02348216; N = 101 for efficacy set, N = 108 for safety set) for axi-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order. Since bridging therapy was allowed in TRANSCEND but not ZUMA-1, the initial efficacy and safety analyses included bridging therapy use as a matching factor (TRANSCEND patients who received bridging therapy were removed). Subsequent sensitivity analyses excluded this matching factor. Results The initial analysis showed similar MAIC-weighted efficacy outcomes between TRANSCEND and ZUMA-1 for overall and complete response rates (odds ratio [95% confidence interval (CI)], 1.40 [0.56–3.49] and 1.21 [0.56–2.64], respectively) and for overall survival and progression-free survival (hazard ratio [95% CI], 0.81 [0.44–1.49] and 0.95 [0.58–1.57], respectively). MAIC-weighted safety outcomes favored liso-cel, with significantly lower odds of all-grade and grade ≥ 3 cytokine release syndrome (odds ratio [95% CI], 0.03 [0.01–0.07] and 0.08 [0.01–0.67], respectively) and study-specific neurological events (0.16 [0.08–0.33] and 0.05 [0.02–0.15], respectively). Efficacy and safety outcomes remained similar in sensitivity analyses, which did not include use of bridging therapy as a matching factor. Conclusions After matching and adjusting for clinically relevant prognostic factors, liso-cel demonstrated comparable efficacy and a more favorable safety profile compared with axi-cel in patients with third- or later-line relapsed or refractory LBCL. Trial registration: NCT02631044 and NCT0234821

Combined inhibition of Wee1 and Chk1 as a therapeutic strategy in multiple myeloma

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress. In response to replicative and DNA damage stress, MM cells activate various DNA damage signaling pathways. In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Combined targeting of Chk1 and Wee1 demonstrates synergistic toxicities on MM cells and was associated with higher DNA double-strand break induction, as evidenced by an increased percentage of γH2AX positive cells subsequently leading to apoptosis. The therapeutic interest of Chk1/Wee1 inhibitors’ combination was validated on primary MM cells of patients. The toxicity was specific of MM cells since normal bone marrow cells were not significantly affected. Using deconvolution approach, MM patients with high CHK1 expression exhibited a significant lower percentage of NK cells whereas patients with high WEE1 expression displayed a significant higher percentage of regulatory T cells in the bone marrow. These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression

Comparative analysis of CAR T-cell therapy access for DLBCL patients: associated challenges and solutions in the four largest EU countries

IntroductionCAR T-cell therapy has emerged as a promising new immuno-oncology treatment that engages the patient’s immune system to fight certain hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). In the European Union (EU), CAR T-cell therapies have been approved for relapsed/refractory (R/R) DLBCL patients since 2018, but patient access is often still limited or delayed. This paper is aimed at discussing challenges to access and possible solutions in the largest four EU countries.MethodsThe analysis relied on literature review, market data collection, since homogeneous data coming from registries were not available, and discussion with experts coming from all four countries.ResultsWe calculated that in 2020, between 58% and 83% of R/R DLBCL patients (EMA approved label population) or between 29% and 71% of the estimated medically eligible R/R DLBCL patients, were not treated with a licensed CAR T-cell therapy. Common challenges along the patient journey that may result in limited access or delays to CAR T-cell therapy were identified. These include timely identification and referral of eligible patients, pre-treatment funding approval by authorities and payers, and resource needs at CAR T-cell centers.DiscussionThese challenges, existing best practices and recommended focus areas for health systems are discussed here, with the aim to inform necessary actions for overcoming patient access challenges for current CAR T-cell therapies as well as for future cell and gene therapies

Deep-Learning Assessed Muscular Hypodensity Independently Predicts Mortality in DLBCL Patients Younger Than 60 Years.

[en] BACKGROUND: Muscle depletion (MD) assessed by computed tomography (CT) has been shown to be a predictive marker in solid tumors, but has not been assessed in non-Hodgkin's lymphomas. Despite software improvements, MD measurement remains highly time-consuming and cannot be used in clinical practice. METHODS: This study reports the development of a Deep-Learning automatic segmentation algorithm (DLASA) to measure MD, and investigate its predictive value in a cohort of 656 diffuse large B cell lymphoma (DLBCL) patients included in the GAINED phase III prospective trial (NCT01659099). RESULTS: After training on a series of 190 patients, the DLASA achieved a Dice coefficient of 0.97 ± 0.03. In the cohort, the median skeletal muscle index was 50.2 cm2/m2 and median muscle attenuation (MA) was 36.1 Hounsfield units (HU). No impact of sarcopenia was found on either progression free survival (PFS) or overall survival (OS). Muscular hypodensity, defined as MA below the tenth percentile according to sex, was associated with a lower OS and PFS, respectively (HR = 2.80 (95% CI 1.58-4.95), p < 0.001, and HR = 2.22 (95% CI 1.43-3.45), p < 0.001). Muscular hypodensity appears to be an independent risk factor for mortality in DLBCL and because of DLASA can be estimated in routine practice

Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia

Background: Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. Methods: In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax–rituximab group) or bendamustine plus rituximab for 6 months (bendamustine–rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine–rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. Results: After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax–rituximab group (32 events of progression or death in 194 patients) than in the bendamustine–rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax–rituximab group versus 27.8% in the bendamustine–rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax–rituximab group than in the bendamustine–rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax–rituximab group was 3.1% (6 of 194 patients). Conclusions: Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471.

Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe

Étude de l'influence du volume tumoral sur la pharmacocinétique du rituximab dans le traitement des lymphomes diffus à grandes cellules B

Introduction : La pharmacocinétique du rituximab présente une variabilité inter-individuelle importante, ce qui pourrait expliquer en partie les différences en termes d'efficacité. Parmi les facteurs pouvant influencer l'exposition au rituximab, les données sur l'influence du volume tumoral sont contradictoires. Objectif: Etudier l'influence du volume tumoral sur la pharmacocinétique du rituximab dans le lymphome diffus à grandes cellules (LDGCB). Patients et méthodes : Les patients étaient au diagnostic d'un LDGCB au stade localisé sans masse bulky > 7cm. Les concentrations sériques de rituximab ont été mesurées par ELISA avant et à la fin de chaque perfusion de la 1ère à la 4ème cure de R-CHOPI4. Les paramètres pharmacocinétiques ont été estimés à l'aide d'un modèle à deux compartiments, avec une approche de population. Le volume tumoral a été mesuré à l'aide du logiciel Myrian, Intrasense®. Le volume tumoral a été testé comme une covariable sur le modèle final. Résultats : 42 patients ont été inclus; 257 échantillons étaient disponibles pour la mesure du rituximab sérique. L'étude pharmacocinétique n'a pas mis en évidence d'influence de la surface corporelle, du sexe et du volume tumoral sur les paramètres pharmacocinétiques estimés. Conclusion: Nous n'avons pas retrouvé d'influence significative du volume tumoral sur la pharmacocinétique du rituximab. Ce résultat est certainement lié au faible volume tumoral présenté par les patients inclus dans cet essai.MONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF