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Cytotherapy ; 25(6 Supplement):S245-S246, 2023.
Artigo em Inglês | EMBASE | ID: covidwho-20245241


Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

International Journal of Radiation Oncology, Biology, Physics ; 114(3):S2-S3, 2022.
Artigo em Inglês | Academic Search Complete | ID: covidwho-2036131


Radiation therapy (RT) to doses of 24-30 Gy is used for the treatment of indolent B-cell lymphoma (BCL);however, significant acute and late ocular effects are common. We aimed to develop a response adapted (RA) strategy that maintains excellent disease outcomes but reduces orbital morbidity. We performed a phase II prospective study of a RA strategy in 50 patients (pts) with stage I-IV orbital indolent BCL. Pts were treated with ultra-low dose (ULD) RT to 4 Gy in 2 fractions and assessed in 3-month intervals for response. Pts with persistent orbital lymphoma were offered an additional 20 Gy in 10 fractions. Pts that had a complete response (CR) to ULD RT were observed. We also evaluated this treatment strategy in a separate 55 pt retrospective cohort. From July 2015-January 2021 51 pts were enrolled. Fifty evaluable pts had follow-up for study inclusion. The median age was 63 years (29-88);62% were female (n=31). Pts had MALT lymphoma (n=32, 64%), follicular lymphoma (FL, n=16, 32%) and low grade BCL (n=6, 12%). Most pts (62%, n=31) had stage I disease limited to one (n=28) or both (n=3) orbits. Pts had newly diagnosed (n=36, 72%);relapsed (n=9, 18%) and refractory lymphoma (n=5, 10%). At a median follow up of 35 months [95% CI 22.2 – 37.4], 90% of pts (n=45) experienced a CR to RA RT, including 44 pts that had a CR to ULD RT (median time to CR 3.4 months) and 1 pt that had a CR after an additional 20 Gy. No local recurrences were observed. Treatment was well tolerated with no grade ≥3 toxicity. Five pts did not have a CR to planned RA therapy including 1 pt that refused additional RT, one pt treated with rituximab, one pt that had a PR on initial evaluation but has not returned for subsequent in person evaluations due to COVID, one pt being observed with stable disease and a final pt that received an additional 20 Gy to the orbit that has a persistent stable mass after the 20 Gy. In a planned subset analysis of 26 pts with newly diagnosed stage 1 disease (MALT, n=22;FL, n=3;low grade BCL, n=1);92.3% (n=24) had a CR to RA RT, with one pt requiring an additional 20 Gy. For all 26 pts with newly diagnosed stage 1 disease, the 3-year freedom from distant relapse rate was 90.4% with 3 distant relapses (contralateral orbit, n=2;paratracheal nodes, n=1). The median follow-up among the 55 pts (MALT, n=38;FL, n=13;low grade B-cell lymphoma, n=4) treated in the retrospective cohort between March 2013 and October 2021 was 28.7 months (95% CI 21.2 - 36.1);98% (n=54) of pts had a CR with RA RT, including 2 pts with a CR after an additional 20 Gy. The remaining pt went on to receive systemic therapy in lieu of additional RT for persistent disease. Among the 54 pts that had a CR with RA RT there was one local relapse in a pt with conjunctival FL 27.8 months after experiencing a CR to ULD RT. This pt received 20 Gy with resolution of the locally relapsed disease. We observed excellent disease control with negligible toxicity in the first prospective study assessing this novel approach of RA ULD RT for pts with indolent B-cell lymphoma. [ FROM AUTHOR] Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Journal of Clinical Oncology ; 40(16), 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2009556


Background: Burnout is a psychological syndrome defined by the Maslach Burnout Inventory (MBI) as emotional exhaustion, depersonalization, and a low sense of personal accomplishment. Risk of job-related burnout for early-career medical oncologists can significantly impact career longevity and health outcomes for providers and patients alike. Because little is known about burnout specific to early-career academic oncologists, we sought to characterize the prevalence of burnout and associated factors among Assistant Professors at MD Anderson Cancer Center (MDACC). Methods: For this IRB-approved retrospective study, an electronic survey was developed for Assistant Professors in medical oncology at MDACC. Participants were all involved directly in patient care with at least some clinical effort. Our survey included nine questions validated in the MBI addressing equally the 3 aforementioned domains of burnout. An additional 31 questions were formulated to assess personal and professional factors that may contribute to burnout at our institution (clinical workload, research expectations, communication, COVID, and home-life). Each question was scored on a scale of 1 to 5, with higher scores correlating to higher levels of burnout. Descriptive statistics were used to describe the prevalence of burnout, and logistic regression analyses were performed to identify characteristics associated with burnout. Results: Among 70 (of 86 total) Assistant Professors who responded, mean duration on faculty was 3.1 years (standard deviation +/-1.8). Mean clinical effort was 67% (range, 19-95). Gender identifications were 44% female, 54% male, and 2% non-binary. 54% of respondents reported symptoms of burnout already, including 21% endorsing severe burnout. Severe burnout was more common for solid tumor providers than liquid tumor providers (55% vs 13%, p =.03). Using the MBI, severe emotional exhaustion (25%) was more prevalent (p <.0001) than depersonalization (6%) or lack of personal accomplishment (17%). Sentiments of being “emotionally drained” (20%), fatigue to face another day on the job” (37%), and “becoming more callous” (30%) were especially concerning among early-career faculty. Emotional exhaustion was associated with a feeling of less autonomy over personal decision making (p =.03) and female gender (p =.04). Conclusions: Burnout exists with high prevalence among early-career medical oncologists in this single-institution analysis. Emotional exhaustion was the specific manifestation of burnout in this population. Further validation of these data nationwide is anticipated. Interventions focusing on reducing emotional exhaustion are under development to reduce medical oncology-specific burnout in an academic setting for faculty retention and for deliverance of optimal care to patients with cancer.

Journal of Clinical Oncology ; 40(16), 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2009531


Background: Many hospitals have established goals-of-care (GOC) programs in response to the COVID- 19 pandemic;however, few have reported their outcomes. MD Anderson Cancer Center launched a multicomponent interdisciplinary GOC (myGOC) program in March 2020 that involved risk stratification, team huddles to discuss care planning, oncologist-initiated GOC discussions, communication training, palliative care involvement, rapid-response GOC team deployment, and daily monitoring with immediate feedback. We examined the impact of this myGOC program among medical inpatients. Methods: This single-center study with a quasi-experimental design included consecutive adult patients with cancer admitted to medical units at MD Anderson Cancer Center, Texas during an 8-month pre-implementation (May 1, 2019 to December 31, 2019) and post-implementation period (May 1, 2020 to December 31, 2020). The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included ICU length of stay, hospital mortality, and proportion/timing of patients with inhospital do-not-resuscitate (DNR) orders, medical power of attorney (MPOA), living will (LW) and outof- hospital DNR (OOHDNR). Propensity score weighting was used to adjust for differences in potential covariates, including age, sex, cancer diagnosis, race/ethnicity, and Sequential Organ Failure Assessment (SOFA) Score. With a sample size of 600 ICU patients over each time period and a baseline ICU mortality of 28%, we had 80% power to detect a 5% reduction in mortality using a two-tailed test at 5% significance level. Results: This study involved 12,941 hospitalized patients with cancer (Pre n = 6,977;Post n = 5,964) including 1365 ICU admissions (Pre n = 727;Post n = 638). After myGOC initiation, we observed a significant reduction in ICU mortality (28.2% vs. 21.9%;change -6.3%, 95% CI -9.6, -3.1;P = 0.0001). We also observed significant decreases in length of ICU stay (mean change -1.4 days, 95% CI -2.0, -0.7 days;P < 0.0001) and in-hospital mortality (7% vs. 6.1%, mean change -0.9%, 95% CI -1.5%, -0.3%;P = 0.004). The proportion of hospitalized patients with an inhospital DNR order increased significantly from 14.7% to 19.6% after implementation (odds ratio [OR] 1.4, 95% CI 1.3, 1.5;P < 0.0001) and DNR was established earlier (mean difference -3.0 d, 95% CI -3.9 d, -2.1 d;P < 0.0001). OOHDNR (OR 1.3, 95% CI 1.1, 1.6, P < 0.0007) also increased post-implementation but not MPOA and LW. MPOA, LW and OOHDNR were documented significantly earlier relative to the index hospitalization in the post-implementation period (P < 0.005 for all). Conclusions: This study showed improvement in hospital outcomes and care plan documentation after implementation of a system-wide, multicomponent GOC intervention. Our findings may have implications for GOC programs during the pandemic and beyond.

Blood ; 138(SUPPL 1):3525, 2021.
Artigo em Inglês | EMBASE | ID: covidwho-1770434


Background - The WINDOW-1 regimen introduced first-line ibrutinib with rituximab (IR) followed by 4 cycles of R-HCVAD for younger mantle cell lymphoma (MCL) patients (pts) demonstrating 90% CR on IR alone and we aimed to improve the CR rate with the addition of venetoclax. We therefore investigated the efficacy and safety of IR and venetoclax (IRV) followed by risk-stratified observation or short course R-HCVAD/MTX-ARA-C as consolidation in previously untreated young patients with mantle cell lymphoma (MCL). Our aim was to use a triplet chemotherapy-free induction to reduce the toxicity, complications and minimize chemotherapy exposure in MCL pts. Methods - We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT03710772. Pts received IR induction (Part-1) for initial 4 cycles. Pts were restaged at cycle 4 and received IRV for up to eight cycles (Cycle 5 to Cycle 12) starting with ramp up venetoclax dosing in Cycle 5. All pts who achieved CR prior to cycle 12 continued to receive IRV for 4 cycles (maximum 12 cycles) and then moved to part 2. Pts were stratified into three disease risk groups: high, moderate and low risk categories from the baseline data for assignment to R-HCVAD/MTX-ARA-C as consolidation in part 2 (4 cycles, 2 cycles, or no chemotherapy for high, medium and low risk pts respectively). Briefly, low risk pts were those with Ki-67 ≤30%, largest tumor mass <3 cm, low MIPI score and no features of high risk disease (Ki-67 ≥50%, mutations in the TP53, NSD2 or in NOTCH genes, complex karyotype or del17p, MYC positive, or largest tumor diameter >5 cm or blastoid/pleomorphic histology or if they remain in PR after 12 cycles of part 1. Medium risk are pts which did not belong to low or high-risk category. Those who experienced progression on part 1 went to part 2 and get 4 cycles of part 2. Patient were taken off protocol but not off study, if they remained in PR after 4 cycles of chemotherapy, these patients were followed up for time to next treatment and progression free survival on subsequent therapies. After part 2 consolidation, all pts received 2 years of IRV maintenance. The primary objective was to assess CR rates after IRV induction. Adverse events were coded as per CTCAE version 4. Molecular studies are being performed. Results - Among the 50 pts, the median age was 57 years (range - 35-65). There were 20 pts in high-risk group, 20 pts in intermediate-risk group and 10 pts in low-risk group. High Ki-67 (≥30%) in 18/50 (36%) pts. Eighteen (36%) had high and intermediate risk simplified MIPI scores. Six (12%) pts had aggressive MCL (blastoid/pleomorphic). Among the 24 TP53 evaluable pts, eight pts (33%) had TP53 aberrations (mutated and/or TP53 deletion by FISH). Forty-eight pts received IRV. Best response to IRV was 96% and CR of 92%. After part 2, the best ORR remained unaltered, 96% (92% CR and 4% PR). The median number of cycles of triplet IRV to reach best response was 8 cycles (range 2-12). Fifteen pts (30%) did not receive part 2 chemotherapy, two pts (4%) received 1 cycle, 16 pts (32%) 2 cycles and 13 pts (26%) got 4 cycles of chemotherapy. With a median follow up of 24 months, the median PFS and OS were not reached (2 year 92% and 90% respectively). The median PFS and OS was not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. The median PFS and OS was inferior in blastoid/pleomorphic MCL pts compared to classic MCL pts (p=0.01 and 0.03 respectively). Thirteen pts (26%) came off study - 5 for adverse events, 3 for on study deaths, and 2 for patient choice, 2 patients lost to follow up and one for disease progression. Overall, 5 pts died (3 on trial and 2 pts died off study, one due to progressive disease and another due to COVID pneumonia). Grade 3-4 toxicities on part 1 were 10% myelosuppression and 10% each with fatigue, myalgia and rashes and 3% mucositis. One pt developed grade 3 atrial flutter on part 1. None had grade 3-4 bleeding/bruising. Conclusions - Chemotherapy-free induction with IRV induced durable and deep responses in young MCL pts in the frontline setting. WINDOW-2 approach suggests that pts with low risk MCL do not need chemotherapy but further follow up is warranted. This combined modality treatment approach significantly improves outcomes of young MCL pts across all risk groups. Detailed molecular analyses will be reported. (Figure Presented).

Blood ; 138:1460, 2021.
Artigo em Inglês | EMBASE | ID: covidwho-1582437


Introduction: Non-Hodgkin lymphoma (NHL) constitutes ~40% of hematologic malignancies and, in 2020, resulted in 19,940 deaths in the USA. The most common NHL subtypes are diffuse large B-cell lymphoma (DLBCL), including primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma (FL). Although a majority of patients respond to standard-of-care therapy, many patients with NHL eventually relapse, highlighting the need for additional treatments. Real-world data regarding the safety and efficacy of emerging therapies in the relapsed/refractory (R/R) population, and the association between treatment patterns and patient outcomes, are limited. These data could provide unique insights to clinical and health-related quality of life (HRQoL) outcomes in patients with DLBCL, FL, or PMBCL treated with emerging therapies, especially novel options such as chimeric antigen receptor (CAR) T cell therapies. Methods: The Connect ® Lymphoma Disease Registry (NCT04982471) is a US-based, multicenter, prospective observational cohort study of patients with R/R NHL (DLBCL, FL, and PMBCL). Approximately 2100 patients ≥ 18 years of age from ~200 community oncology (~80%) or academic (~20%) sites will be enrolled over a ~3-year period. Patients with histologically confirmed NHL subtypes will be enrolled into 1 of 4 cohorts: first R/R DLBCL, second R/R DLBCL, first R/R FL, or first R/R PMBCL (Figure). Patients will be required to have begun second- (first R/R) or third- (second R/R) line systemic treatment within 60 days prior to enrollment. Patients receiving treatment for any active malignancy other than DLBCL, FL, or PMBCL at the time of enrollment, or who are diagnosed with any other malignancy in the 6 months prior to enrollment, will be excluded. All treatment and management decisions will be determined by the practicing clinicians. Patients may undergo hematopoietic stem cell transplantation, CAR T cell therapy, or other treatments at other sites while participating in this study. Patients will be followed from enrollment for up to 5 years or until death, withdrawal of consent, loss to follow-up, or study termination, whichever occurs first. Data collection will occur at enrollment (baseline) and then every ~3 months. The main objectives of the Connect ® Registry are to describe patient characteristics, practice patterns, and factors associated with treatment choice, sequencing, and effectiveness in NHL subtypes. Secondary objectives include describing treatment regimen safety, patient-reported outcomes (PROs) including HRQoL, and healthcare resource utilization outcomes. Exploratory objectives include tumor and blood biomarker evaluation and understanding the availability of social support and its impact on long-term treatment decision-making. Case report forms will be used to collect clinical and treatment data, including baseline demographics, clinical characteristics, treatment details and response, and socioeconomic factors. Outcome measures for efficacy will be progression-free survival, event-free survival, objective response rate, time to next treatment, and overall survival. The availability of social support will be assessed via a specific questionnaire administered at baseline. General (EQ-5D-5L) and disease-specific (FACT-Lym) questionnaires will also be administered. Patients may also optionally agree to release tumor biopsies and blood samples for biomarker analysis. Clinicians will be required to report serious adverse events (AEs), secondary primary malignancies, and confirmed COVID-19 infections within 24 hours. Non-serious AEs of interest include grade 1-3 cytokine release syndrome, grade 1-3 neurotoxicity, grade 3 colitis, grade 3 arrhythmia, grade 3 hemorrhage. Other AEs of interest to be collected include grade 3 hypogammaglobulinemia, prolonged grade 3 cytopenia, and grade 3 infections. Data collected in the Connect ® Registry will increase understanding of the association between emerging therapies and patient outcomes for R/R DLBCL, FL, and PMBCL. Study support: Bristol Myers Squibb [Formula presented] Disclosures: Flowers: Amgen: Research Funding;Janssen: Research Funding;Biopharma: Consultancy;Ziopharm: Research Funding;Burroughs Wellcome Fund: Research Funding;Nektar: Research Funding;Karyopharm: Consultancy;Iovance: Research Funding;Allogene: Research Funding;AbbVie: Consultancy, Research Funding;Cellectis: Research Funding;Pfizer: Research Funding;Sanofi: Research Funding;BeiGene: Consultancy;Kite: Research Funding;EMD: Research Funding;Genentech/Roche: Consultancy, Research Funding;Morphosys: Research Funding;Adaptimmune: Research Funding;Novartis: Research Funding;Epizyme, Inc.: Consultancy;Spectrum: Consultancy;Pharmacyclics/Janssen: Consultancy;Acerta: Research Funding;4D: Research Funding;Denovo: Consultancy;Celgene: Consultancy, Research Funding;Guardant: Research Funding;Genmab: Consultancy;Gilead: Consultancy, Research Funding;Bayer: Consultancy, Research Funding;SeaGen: Consultancy;Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding;Takeda: Research Funding;National Cancer Institute: Research Funding;TG Therapeutics: Research Funding;Eastern Cooperative Oncology Group: Research Funding;Xencor: Research Funding;Pharmacyclics: Research Funding. Andorsky: Celgene/Bristol Myers Squibb: Research Funding;AbbVie: Consultancy;Celgene/Bristol Myers Squibb: Consultancy;AstraZeneca: Other: served on steering committees;Epizyme: Research Funding;AbbVie: Research Funding. Burke: SeaGen: Consultancy, Speakers Bureau;X4 Pharmaceuticals: Consultancy;Bristol Myers Squibb: Consultancy;Verastem: Consultancy;AstraZeneca: Consultancy;MorphoSys: Consultancy;Adaptive Biotechnologies: Consultancy;Roche/Genentech: Consultancy;Epizyme: Consultancy;Kura: Consultancy;AbbVie: Consultancy;Beigene: Consultancy, Speakers Bureau;Kymera: Consultancy. Cerhan: Genentech: Research Funding;NanoString: Research Funding;Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding;Regeneron Genetics Center: Other: Research Collaboration. Grinblatt: Astellas Pharma, Inc.: Consultancy;Bristol Myers Squibb: Consultancy;Astra Zeneca: Consultancy;AbbVie: Consultancy. Toomey: Bristol Myers Squibb: Consultancy. Zelenetz: Gilead: Honoraria, Research Funding;Verastem: Honoraria;Novartis: Honoraria;MEI Pharma: Honoraria, Research Funding;SecuraBio: Honoraria;Abbvie: Honoraria, Research Funding;MorphoSys: Honoraria;Pharmacyclics: Honoraria;AstraZeneca: Honoraria;LFR: Other;Genentech/Roche: Honoraria, Research Funding;NCCN: Other;MethylGene: Research Funding;Beigene: Honoraria, Other, Research Funding;BMS/Celgene/JUNO: Honoraria, Other;Amgen: Honoraria;Gilead: Honoraria;Janssen: Honoraria. Sullivan: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Flick: Bristol Myers Squibb: Current Employment. Kiselev: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kaplan: Bristol Myers Squibb: Current Employment. Ahn: Bristol Myers Squibb: Current Employment.