tbuckley/cabot-search huggingface dataset:
Real-world (RW) treatment (tx) patterns and outcomes of 3,455 previously untreated mantle cell lymphoma (MCL) patients (pts) in U.S. routine clinical practice.
Authors: Peter Martin, Michael Wang, Anita Kumar, Keqin Qi, Katherine Daly, Lori Parisi, Angeline Zhu, Gilles A. Salles
Journal: Journal of Clinical Oncology (2021)

7504 Background: MCL is a non-Hodgkin lymphoma with heterogeneous biology and outcomes. We characterized RW tx patterns and outcomes of MCL pts to identify factors associated with outcomes in the US. Methods: This retrospective study included adult MCL pts diagnosed Jan 2011-Nov 2020 in the nationwide Flatiron Health EHR-derived deidentified database. Pt characteristics, tx patterns, time to next tx (rwTTNT, defined as start of first-line [1L] tx to subsequent tx or death) and rwOS were evaluated. Results: 3455 pts were included, 85.3% from a community oncology setting. In 2946 (85.2%) pts with documented 1L MCL tx, median age was 69.5 y (range 27.7-85.3); 9.5% had blastoid/pleomorphic MCL. 262 (39.6%) and 235 (35.6%) of 661 pts with available MCL international prognostic index (MIPI) had intermediate and high risk, respectively. 150/1253 pts (12.0%) with available ECOG PS had PS ≥ 2. Chemoimmunotherapy was the most common 1L tx, including BR in 1223 (41.5%), R-CHOP in 512 (17.4%) and cytarabine (ara-C)-containing tx in 414 (14.1%). 667 pts received R maintenance (MR). In 1036 pts &lt; 65 y, 243 pts received 1L stem cell transplant (SCT), mainly autologous. In 1L-treated pts, with median follow-up of survivors of 45.3 mos (range 0.03-117.2), median rwTTNT was 24 mos; 36-mo rwOS was 67%. The Table shows tx received and outcomes by age and SCT status. MVA analyses showed age ≥ 65 y, ECOG PS ≥ 2, LDH/ULN ≥ 1, WBC ≥ 10 × 10 9 /L, bulky disease (≥ 5 cm) and blastoid/pleomorphic morphology were associated with shorter rwTTNT and rwOS; MR was independently associated with longer rwTTNT and rwOS. In pts &lt; 65 y who were alive and did not initiate subsequent tx within 6 mos of 1L tx (“SCT-eligible”), 36-mo rwTTNT and rwOS were similar between pts treated with vs without SCT: 65% vs 59% and 86% vs 85%, respectively. Conclusions: In this large RW cohort of primarily community-based US practices, median 1L rwTTNT for MCL pts was ̃ 2 y. BR was the most commonly used 1L tx. SCT was uncommon even in pts &lt; 65 y, suggesting RW considerations may influence SCT eligibility and availability. Also, SCT was not clearly associated with rwOS. As with other reports, older age and high-risk disease features were predictive of worse outcome in RW, while MR appeared to be associated with better outcomes. Outcomes across the board appear worse than prospective trials, suggesting a need to focus on developing tx that can be delivered effectively in the community setting.[Table: see text]
Dual role of EZH2 in megakaryocyte differentiation
Authors: Stefania Mazzi, Philippe Dessen, Mathieu Vieira, Virginie Dufour, Marie Cambot, Mira El Khoury, Iléana Antony-Debré, Brahim Arkoun, Francesca Basso-Valentina, Salwa BenAbdoulahab, Valerie Edmond, Philippe Rameau, Rachel Petermann, Monika Wittner, Bruno Cassinat, Isabelle Plo, Najet Debili, Hana Raslova, William Vainchenker
Journal: Blood (2021)
Modeling the cost-effectiveness of adjuvant osimertinib in resected EGFR-mutant non-small cell lung cancer patients.
Authors: Christopher Lemmon, Emily Craig Zabor, Nathan A. Pennell
Journal: Journal of Clinical Oncology (2021)

8527 Background: Adjuvant Osimertinib (Osi) was recently approved for resected EGFR-mutant non-small cell lung cancer (NSCLC) based on disease free survival (DFS) benefits from the ADAURA trial. Prior studies of adjuvant EGFR inhibitors yielding DFS benefits have lacked an overall survival (OS) benefit, leading to debate over early clinical implementation given the associated drug costs. This study aims to evaluate the cost-effectiveness (CE) of Osi in this setting. Methods: We constructed Markov models using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of the use of 3 years of adjuvant Osi versus placebo in the ADAURA patient population of stage IB to IIIA NSCLC patients over a 10-year time horizon. All patients entering the progressive disease (PD) state were assigned for re-treatment with Osi. Cost and utility values were derived from Medicare reimbursement data and literature (Table). A CE threshold of 3 times the GDP per capita was used. Deterministic sensitivity analyses were performed to assess the impact of a range of OS benefit, as the impact of adjuvant Osi on OS has not yet been reported. Results: The incremental cost-effectiveness ratio (ICER) for adjuvant Osi was $317,119.90 per QALY gained. Initial costs of Osi are higher in the first 3 years, but become lower than the placebo group in year 4 onward, with similar costs after year 7. Costs due to PD are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2,388, $379,047, and $502,937, respectively in the placebo group, compared to $505,775, $255,638, and $800,697, respectively in the Osi group. QALYs were higher in the Osi arm throughout. Sensitivity analysis using incremental OS gains reaches the CE threshold of $195,000 between 25-30% OS benefit of Osi over placebo. A 50% discount to the Osi annual cost yielded an ICER of $115,419. Conclusions: 3 years of adjuvant Osi is more cost-effective than placebo if one is willing to pay $317,119 more per QALY gained, with most costs accruing in the first 3 years as drug cost. This strategy became cost-effective with an OS benefit between 25-30% over placebo. Discount to Osi annual costs improves the ICER significantly. True cost-effectiveness of adjuvant Osi will require further study due to immaturity of ADAURA OS data and model limitations.[Table: see text]
Unintended Consequences From the 2016 US Centers for Disease Control and Prevention Guideline for Prescribing Opioids—Accelerating Change in Postoperative Prescribing
Authors: Mark C. Bicket, Jennifer Waljee, Anne C. Fernandez
Journal: JAMA Network Open (2021)

Tori N. Sutherland, MD, MPH; Hannah Wunsch, MD, MSc; Ruxandra Pinto, PhD; Craig Newcomb, MS; Colleen Brensinger, MS; Lakisha Gaskins, MHS; Brian T. Bateman, MD, MSc; Mark D. Neuman, MD, MSc
Clinical Features and Early Effect in EVI1 Positive Acute Myeloid Lleukemia
Authors: Wenbing Duan, Lizhong Gong, Jinsong Jia, Honghu Zhu, Xiaosu Zhao, Qian Jiang, Ting Zhao, Ya-Zhen Qin, Xiaojun Huang, Hao Jiang
Journal: Blood (2017)
Safety of subcutaneous daratumumab in the treatment of plasma-cell disorders: A single-center experience.
Authors: Jung Kye, Magdalena Seyer, Samit Patel, Eun-Jeong Kim, Rhonda Hewitt, Michaela Liedtke, David Joseph Iberri
Journal: Journal of Clinical Oncology (2021)

e20007 Background: Daratumumab (Dara) is a CD38-directed monoclonal antibody approved for the treatment of patients with multiple myeloma (MM) and light-chain amyloidosis (AL). Infusion-related reactions (IRRs) have been reported in 28-56% of individuals receiving the conventional intravenous (IV) formulation, necessitating slow infusions and frequent use of rescue medications to mitigate complications. Recently subcutaneous (SC) Dara received approval in MM, and randomized data suggests a lower rate of IRRs compared to IV Dara. Guidelines regarding post-injection monitoring with SC Dara are not well established. This retrospective study aims to evaluate the safety of SC Dara in patients with MM and AL, and to suggest guidelines for monitoring following SC Dara administration. Methods: This single-center retrospective study included patients treated with MM or AL receiving SC Dara between June 2020 and December 2020. The primary outcome of the study was incidence of IRRs. Secondary outcomes include timing and severity of IRRs based on CTCAE version 4.0. Results: A total of 82 patients received SC Dara during the study period. Of these 82, forty-nine (60%) had previously received Dara (Dara-exposed), and 33 patients (40%) were Dara-naïve. Eight of the 82 patients (9.8%) experienced an IRR. All were grade 1 (n=5, 63%) or grade 2 (n=3, 38%) in severity. Seven patients in the Dara-naïve group experienced an IRR (21%), and one patient in the Dara-exposed group (2%) experienced injection-site erythema with the second SC dose after transitioning from IV. Three patients experienced reactions immediately after SC Dara administration, and four patients experienced delayed reactions &gt;4 hours after SC Dara administration (median 11.9 hours; range 5-24). Among those with delayed reactions, three experienced reactions after being discharged from the treatment area but symptoms resolved without any intervention. Conclusions: In this single-center study of patients receiving SC Dara, IRRs occurred in about 10% of patients, and were more likely with a patient’s first dose of SC Dara. All reactions were mild to moderate in severity and could be managed in the outpatient setting. We suggest that Dara-naïve patients receiving their 1 st SC Dara dose be monitored for one hour after SC Dara administration. Monitoring does not appear necessary for patients transitioning from IV to SC Dara or receiving subsequent doses of SC Dara. [Table: see text]
Outcomes of patients (pts) with advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs): Associations with age, race, sex and smoking history.
Authors: Dimitrios Makrakis, Rafee Talukder, Lucia Carril, Ivan de Kouchkovsky, Joseph J Park, Mehmet Asim Bilen, Rana R. McKay, Neeraj Agarwal, Yousef Zakharia, Michael E. Devitt, David James Pinato, Christopher J. Hoimes, Benjamin Adam Gartrell, Abhishek Tripathi, Aristotelis Bamias, Alexandra Drakaki, Jure Murgic, Giuseppe Di Lorenzo, Petros Grivas, Ali Raza Khaki
Journal: Journal of Clinical Oncology (2021)

e16526 Background: ICIs have altered the therapeutic landscape in pts with aUC and new biomarkers are needed to better predict response and outcomes with ICIs. It is unclear whether demographics, such as race, age, sex and history of smoking, are associated with outcomes with ICIs. We hypothesized that specific demographic groups (sex, age, race, smoking history) would be associated with outcomes with ICIs in aUC. Methods: We performed a retrospective cohort study across 25 institutions. Data collected included demographic and clinicopathologic factors, response and outcomes. We calculated observed response rate (ORR), Progression-Free Survival (PFS) and overall survival (OS) for specific demographic groups. We built multivariable models (logistic regression for ORR; Cox regression for PFS and OS) with all demographic groups to assess outcomes. Analysis was done for the overall population and stratified by treatment line (first line [1L]; salvage [2+L]). The stratified analysis was also adjusted for known prognostic risk scores (internally developed for 1L; Bellmunt for 2+L); p-value &lt; 0.05 was significant. Results: We identified 1026 pts; 754, 744 and 780 were included in OS, ORR and PFS analysis. Overall, median age at ICI initiation was 70; 26% female; 75% White, 11% Hispanic, 5% Black, 8% other; 69% had smoking history; 28% with mixed histology; 17% with upper tract UC. In the unstratified analysis, age 65-74 (vs &lt; 65) was significantly associated with higher ORR (32% vs 22%) and median PFS (5 vs 3 mo HR 0.8); otherwise no significant difference was noted among groups for ORR, PFS, OS in both the stratified and unstratified analyses (Table). Conclusions: We did not identify significant associations between age, sex, race or smoking history and ORR, PFS, OS with ICIs in pts with aUC. Limitations include retrospective nature, lack of randomization, possible selection and confounding factors. Further research is required to identify prognostic and predictive biomarkers for ICI therapy in aUC.[Table: see text]
The clinical study of anti-BCMA CAR-T with single-domain antibody as antigen binding domain.
Authors: Lu Han, Quanli Gao, Keshu Zhou, Jian Zhou, Qing-Song Yin, Baijun Fang, Xing-Hu Zhu, Jishuai Zhang, Chaolemeng Bao, Yongping Song
Journal: Journal of Clinical Oncology (2021)

8025 Background: Relapsed/refractory (RR) multiple myeloma (MM), RRMM, remains as an incurable disease and has a 5-year survival rate of nearly 50%. To address the unmet medical need, an autologous CAR-T cell therapy was developed previously with a humanized single-domain antibody (sdAb) targeting BCMA as the antigen binding domain, 4-1BB and CD3ζ as cytoplasmic domain. Methods: An investigator-initiated clinical trial (IIT) was conducted in China to assess the safety and efficacy of the sdAb-based CAR-T. The trail was started in June 2018 and the last patient infused in June 2019. As of 1 February 2021, 34 were treated and followed up. The patients had received multiple lines of prior treatment (including bortezomib, lenalidomide, and others). Following a lymphodepleting regimen of cyclophosphamide (300-600 mg/m 2 , d-5, -4) and fludarabine (25-30 mg/m 2 , d-5 to d-3), patients were infused with 2.5-10.0 × 10 6 CAR + cells/kg body weight. CAR-T was infused immediately after preparation and quality control performed in all patients except one, who was infused a 10.0 × 10 6 CAR + cells/kg dose of frozen cells. Efficacy was assessed based on the IMWG criteria, toxicity was graded by CTCAE 4.02, and CRS grading was based on the grading system by CARTOX working group. Results: All 34 patients had the tumor burden of plasma cells in bone marrow, or M protein or free light chains (FLCs) in serum, 7 patients were accompanied with extramedullary diseases. The efficacy shows the best ORR is 88.2% (30/34), sCR rate is 55.9% (19/34). The mPFS was 12.1 months, several patients shows continuous sCR after 2 years. No obvious correlation between efficacy and dosage were found in three dose groups of 2.5×10 6 CAR + cells/kg (6 pts), 5.0×10 6 CAR + cells/kg (23 pts) or 10.0×10 6 CAR + cells/kg (5 pts). The observed adverse events include thrombocytopenia (≥grade 3, 38.2%), neutropenia (≥grade 3, 44.1%), leukopenia (≥grade 3, 32.4%), lymphopeniPa (≥grade 3, 26.5%), and anemia (≥grade 3, 20.6%). CRS was monitored occurring in 29 patients (any grade, 85.3%, ≥grade 3, 2.9%). Conclusions: Our result demonstrates that the CART employing one humanized sdAb targeting BCMA is safe and efficacious for clinical application. The phase I clinical trial has been initiated in China for searching the RP2D using the cryopreserved CAR-T cells. Clinical trial information: NCT03661554.
All-oral longer regimens are effective for the management of multidrug-resistant tuberculosis in high-burden settings
Authors: Palwasha Y. Khan, Molly F. Franke, Catherine Hewison, Kwonjune J. Seung, Helena Huerga, Sidney Atwood, Saman Ahmed, Munira Khan, Tanha Sultana, Mohammad Manzur-ul-Alam, Luan N.Q. Vo, Leonid Lecca, Kalkidan Yae, Serik Kozhabekov, Meseret Tamirat, Alain Gelin, Stalz C. Vilbrun, Marina Kikvidze, Jamil Faqirzai, Abdullaat Kadyrov, Alena Skrahina, Anita Mesic, Nana Avagyan, Mathieu Bastard, Michael L. Rich, Uzma Khan, Carole D. Mitnick
Journal: European Respiratory Journal (2021)

Recent World Health Organization guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline and/or delamanid as part of their multidrug regimen.Patients with a positive baseline culture were included. 6-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods.Culture conversion was observed in 83.8% (526 out of 628) of patients receiving an all-oral regimen and 85.5% (425 out of 497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95% CI 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients.Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.
COVID-19 in immunocompromised populations: implications for prognosis and repurposing of immunotherapies
Authors: Jason D Goldman, Philip C Robinson, Thomas S Uldrick, Per Ljungman
Journal: Journal for ImmunoTherapy of Cancer (2021)

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. COVID-19 has highly variable disease severity and a bimodal course characterized by acute respiratory viral infection followed by hyperinflammation in a subset of patients with severe disease. This immune dysregulation is characterized by lymphocytopenia, elevated levels of plasma cytokines and proliferative and exhausted T cells, among other dysfunctional cell types. Immunocompromised persons often fare worse in the context of acute respiratory infections, but preliminary data suggest this may not hold true for COVID-19. In this review, we explore the effect of SARS-CoV-2 infection on mortality in four populations with distinct forms of immunocompromise: (1) persons with hematological malignancies (HM) and hematopoietic stem cell transplant (HCT) recipients; (2) solid organ transplant recipients (SOTRs); (3) persons with rheumatological diseases; and (4) persons living with HIV (PLWH). For each population, key immunological defects are described and how these relate to the immune dysregulation in COVID-19. Next, outcomes including mortality after SARS-CoV-2 infection are described for each population, giving comparisons to the general population of age-matched and comorbidity-matched controls. In these four populations, iatrogenic or disease-related immunosuppression is not clearly associated with poor prognosis in HM, HCT, SOTR, rheumatological diseases, or HIV. However, certain individual immunosuppressants or disease states may be associated with harmful or beneficial effects, including harm from severe CD4 lymphocytopenia in PLWH and possible benefit to the calcineurin inhibitor ciclosporin in SOTRs, or tumor necrosis factor-α inhibitors in persons with rheumatic diseases. Lastly, insights gained from clinical and translational studies are explored as to the relevance for repurposing of immunosuppressive host-directed therapies for the treatment of hyperinflammation in COVID-19 in the general population.
National surveillance of bacterial and fungal coinfection and secondary infection in COVID-19 patients in England: lessons from the first wave
Authors: Sarah M. Gerver, Rebecca Guy, Kate Wilson, Simon Thelwall, Olisaeloka Nsonwu, Graeme Rooney, Colin S. Brown, Berit Muller-Pebody, Russell Hope, Victoria Hall
Journal: Clinical Microbiology and Infection (2021)
Pharmacologic characterization of TACH101, a first-in-class KDM4 inhibitor for development as a cancer therapeutic.
Authors: Sanghee Yoo, Chandtip Chandhasin, Joselyn Del Rosario, Young K Chen, Jeffrey Stafford, Frank Perabo, Michael F. Clarke
Journal: Journal of Clinical Oncology (2021)

e15067 Background: The histone Lysine (K) Demethylase 4 family, KDM4 family, is involved in nuclear functions such as programming development, activation or repression of transcription, timing and control of the cell cycle, and initiating DNA replication and repair through chromatin remodeling. Overexpression of KDM4 leading to mistakes in post-translational histone modification has been associated with many cancer types and is being investigated as a potential therapeutic drug target. TACH101 is a novel potent and small molecule inhibitor of the KDM4 family. It demonstrated strong efficacy in multiple cancer types in vitro and in vivo and favorable pharmacokinetics (PK) and safety profiles in preclinical models. Methods: The target interaction properties of TACH101 were evaluated using purified enzymes for biochemical, biophysical, and inhibition mechanism studies. For PK parameter measurements, Sprague-Dawley rats and Beagle dogs were used for intravenous or oral administration of TACH101. Hepatocytes or liver microsomes were used to measure cytochrome P450 (CYP) inhibition and induction studies. Cell lines expressing cardiac channels were used for radioligand displacement assays and patch clamping. Results: Biochemical, biophysical, and inhibition mechanism studies using purified enzymes showed TACH101 is a reversible, alpha-KG (co-factor) competitive, and slow-binding inhibitor with IC50 values less than 100 nM. Pharmacologic studies showed plasma protein binding of TACH101 to be ≥99% bound in mouse, rat, dog, and human. TACH101 appeared to be selective in off-target panel assays of receptors, ion channels and transporters. TACH101 did not show any significant binding displacement activity against cardiac ion channels or any effect on hERG in CHO cells using manual patch clamp techniques. In rats and dogs, TACH101 exhibited low systemic clearance, a moderate volume of distribution in rats and dogs, linear exposure profiles with a terminal half-life (̃ 6-hour) and high bioavailability (46-100%). In repeated dose studies in rats and dogs, mean Cmax and AUC values increased in a dose-related manner over the dose range evaluated. There was no significant impact of food on systemic exposure in dogs. TACH101 did not show inhibition or induction of CYP enzymes tested. Conclusions: TACH101 is a potent KDM4 specific inhibitor without significant off-target activity in in vitro and in vivo studies. It did not show inhibition or induction of CYP enzymes suggesting low probability of CYP mediated drug-drug interaction. The exposure from oral administration in rats and dogs was dose proportional and was not significantly affected by food intake in dogs. Given the favorable target activity, PK properties and safety profile, a Phase 1 study is being planned to advance TACH101 for patients with advanced cancer.
Effects of UGT1A1 Polymorphism, Glucose-6-Phosphate Dehydrogenase Deficiency and Deletional (-3.7кb) α-Thalassemia Among Young Nigerians with Sickle Cell Anemia
Authors: Oladele Olatunya, Dulcinéia Martins de Albuquerque, Daniela Pinheiro Leonardo, Kleber Yotsumoto Fertrin, Adekunle Adekile, Fernando Ferreira Costa
Journal: Blood (2017)