122 results on '"Barta SK"'
Search Results
2. Retrospective Cohort Study of Novel Oral Agents Lenalidomide and Duvelisib For Relapsed or Refractory Mycosis Fungoides and Sézary Syndrome.
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Elghawy O, Yang AG, Sussman JH, Thomas CJ, Carter JS, Landsburg DJ, Svoboda J, Kim E, Rook AH, Chung J, Villasenor-Park J, Plastaras JP, LaRiviere M, Hubbeling H, Chelius M, Nasta SD, Chong EA, Schuster SJ, and Barta SK
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- 2024
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3. Evaluation of prognostic factors in patients with high-risk classical Hodgkin lymphoma undergoing autologous transplantation.
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Epperla N, Huang Y, Cashen AF, Vaughn JL, Hanel W, Badar T, Barta SK, Caimi PF, Sethi TK, Reddy N, Karmali R, Bello C, Chavez JC, Kothari SK, Hernandez-Ilizaliturri FJ, Svoboda J, Lansigan F, Glenn MJ, Cohen JB, Sorge C, Christian B, Herrera AF, Hamadani M, Costa LJ, and Xavier AC
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- Humans, Adult, Middle Aged, Male, Female, Prognosis, Retrospective Studies, Young Adult, Adolescent, Aged, Risk Factors, Hodgkin Disease therapy, Hodgkin Disease mortality, Hodgkin Disease diagnosis, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation methods
- Abstract
Abstract: There are limited data assessing the risk scores for primary treatment failure (PTF) in patients with classical Hodgkin lymphoma (cHL; PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs) is a multicenter retrospective cohort of patients with PTF-cHL (aged ≥15 years) diagnosed on or after 1 January 2005, at 15 US medical centers. PTF was defined as 1 of the following patterns of failure: (1) progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); (2) partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); (3) progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR; early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of nonrelapse mortality after auto-HCT were 0.9% and 1.1%, respectively. The median progression-free survival (PFS) and overall survival (OS) after auto-HCT were 4.33 and 10.09 years, respectively. Although those not in CR at the time of auto-HCT were associated with inferior PFS and OS, advanced age and diagnosis before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high-risk disease who are traditionally considered chemotherapy refractory, and will serve as a benchmark for the ongoing transplant vs no transplant trials., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2024
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4. Genomic Features of Newly Diagnosed Large B-cell Lymphoma with or without Subsequent Disease Progression.
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Landsburg DJ, Morrissette JJD, Nasta SD, Barta SK, Schuster SJ, Chong EA, Svoboda J, Barlev A, Bagg A, and Priore SF
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- Humans, Male, Female, Middle Aged, Aged, Adult, Aged, 80 and over, Biomarkers, Tumor genetics, Disease Progression, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Large B-Cell, Diffuse diagnosis, Genomics
- Abstract
Significance: Genomic features of LBCL that can be detected by clinical laboratory assays may predict for resistance to first-line immunochemotherapy, as well as support the exploration of genomic features as biomarkers of response to therapies which could be offered to patients who experience disease progression., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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5. ASTCT and USCLC Clinical Practice Recommendations for Allogeneic Stem Cell Transplant in Mycosis Fungoides and Sézary Syndrome.
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Goyal A, O'Leary D, Dabaja B, Weng WK, Zain J, Cutler C, Guitart J, Kim YH, Geskin LJ, Hoppe RT, Wilson LD, Beaven AW, Horwitz S, Allen PB, Barta SK, Bohjanen K, Brammer JE, Carter JB, Comfere N, DeSimone JA, Dusenbery K, Duvic M, Huen A, Jagadeesh D, Kelsey CR, Khodadoust MS, Lechowicz MJ, Mehta-Shah N, Moskowitz AJ, Olsen EA, Poh C, Pro B, Querfeld C, Sauter C, Sokol L, Sokumbi O, Wilcox RA, Zic JA, Hamadani M, and Foss F
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- Humans, Skin Neoplasms therapy, Skin Neoplasms pathology, United States epidemiology, Consensus, Practice Guidelines as Topic, Mycosis Fungoides therapy, Sezary Syndrome therapy, Hematopoietic Stem Cell Transplantation, Transplantation, Homologous
- Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease; Sézary syndrome is an aggressive lymphoma associated with high morbidity and mortality. Although allogeneic hematopoietic cell transplant (allo-HCT) is the only currently available potentially curative treatment modality for MF/SS there is no published guidance on referral criteria, transplant timing orallo-HCT approach. To develop consensus clinical practice recommendations, we performed a Delphi survey of 32 specialists in dermatology (n = 9), transplant hematology/oncology (n = 10), non-transplant hematology/oncology (n = 8), and radiation oncology (n = 5) from across the United States. Consensus required agreement of ≥75% of participants. Sixteen consensus statements were generated on four topics: (1) criteria for referral for consideration for allo-HCT, (2) allo-HCT preparative regimens and procedures (3) disease status at the time of allo-HCT, and (4) multidisciplinary management in the pre- and post-transplant settings. These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2024
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6. Valemetostat for patients with relapsed or refractory peripheral T-cell lymphoma (VALENTINE-PTCL01): a multicentre, open-label, single-arm, phase 2 study.
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Zinzani PL, Izutsu K, Mehta-Shah N, Barta SK, Ishitsuka K, Córdoba R, Kusumoto S, Bachy E, Cwynarski K, Gritti G, Prica A, Jacobsen E, Feldman T, Guillermin Y, Ennishi D, Yoon DH, Domenech ED, Zain J, Wang J, Kim JS, Poel MV, Jin J, Wu S, Chen Y, Moriyama T, Inoue A, Nakajima K, and Horwitz SM
- Abstract
Background: Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma., Methods: VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment., Findings: Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0-74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0-73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8-13·8). 52 (44%; 95% CI 35-53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3-4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported., Interpretation: These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile., Funding: Daiichi Sankyo., Competing Interests: Declaration of interests PLZ has received consulting fees from lncyte, Novartis, BeiGene, and SOBI, and honoraria from Takeda, AstraZeneca, MSD, Bristol Myers Squibb (BMS), lncyte, Roche, Gilead, Recordati, Kyowa Kirin, Novartis, BeiGene, Janssen, and SOBI, unrelated to this study. KIz has received manuscript support from Daiichi Sankyo to their institution, related to this work; research funding Chugai, BMS, Incyte, Genmab, LOXO Oncology, Daiichi Sankyo, BeiGene, AbbVie, AstraZeneca, Regeneron, Yakult, Chugai, Otsuka, Novartis, Pfizer, MSD, Bayer, Kyowa Kirin, Eisai, Janssen, Ono Pharmaceutical, Gilead, Astellas, and Amgen to their institution, unrelated to this work; consulting fees from AstraZeneca, Ono Pharmaceutical, Mitsubishi Tanabe, Eisai, Chugai, BMS, AbbVie, Takeda, Zenyaku, Genmab, Kyowa Kirin, MSD, Carna Biosicences, Novartis, Yakult, Nihon Shinyaku, Novartis, and BeiGene, unrelated to this work; and honoraria from AstraZeneca, Ono Pharmaceutical, Eisai, Chugai, Janssen, Symbio, BMS, Daiichi Sankyo, Otsuka, AbbVie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, Meiji Seika Pharma, Novartis, Nihon Kayaku, and Gilead, unrelated to this work. NM-S has received research funding from AstraZeneca, BMS, C4 Therapeutics, Celgene, Corvus Pharmaceuticals, Daiichi Sankyo, Dizal Pharmaceuticals, Genetech/Roche, Incyte, Innate Pharmaceuticals, Secura Bio, Verastem, and Yingli Pharmaceuticals, to their institutions, unrelated to this work; consulting fees from AstraZeneca, Kyowa Hakka Kirin, Karyopharm, Ono Pharmaceuticals, Secura Bios, Daiichi Sankyo, Genentech, and Janssen, unrelated to this work; and participated on a data safety monitoring board and an advisory board for Daiichi Sankyo, unrelated to this work. SKB received manuscript support from Daiichi Sankyo, related to this work; consulting fees and honoraria from Acrotech, Kyowa Kirin, and Seagen, unrelated to this work; and participated on a data safety monitoring board or advisory board for Janssen, unrelated to this work. KIs has received manuscript support from Daiichi Sankyo, related to this work; research funding from Ono Pharmaceutical and Kyowa Kirin to their institutions, unrelated to this work; honoraria from Kyowa Kirin, Takeda, Chugai Pharmaceutical, Celgene, BMS, Daiichi Sankyo, Ono Pharmaceutical, Astellas, Eisai, Pfizer, Otsuka, Sanofi, CSL Behring, AbbVie, Yakult, Janssen Pharmaceutical, and Nippon Shinyaku, unrelated to this work; participated on data safety monitoring board or advisory board for Meiji Seika Pharma and Daiichi Sankyo, unrelated to this work; and received materials from Ono Pharmaceutical to their institution, unrelated to this work. SK has received support from Daiichi Sankyo, related to this work; research funding from Chugai, Kyowa Kirin, and Janssen, unrelated to this work; and honoraria from Daiichi Sankyo, Chugai, Kyowa Kirin, and Janssen, unrelated to this work. EB has received research funding from Amgen and BMS, to their institution, unrelated to this work; honoraria from Novartis, Kite/Gilead, Roche, Takeda, Janssen, and AbbVie, unrelated to this work; support for attending meetings or travel from Roche and Kite/Gilead, unrelated to this work; and participated on data safety monitoring board or advisory board from Novartis, Kite/Gilead, Roche, Incyte, ADC Therapeutics, and AbbVie, unrelated to this work. KC received consulting fees from Roche, Takeda, Celgene, and AbbVie, unrelated to this work; honoraria from Roche and Takeda, unrelated to this work; support for attending meetings or travel from Roche, Takeda, and BMS, to their institution; and participated on data safety monitoring board or advisory board for Daiichi Sankyo, unrelated to this work. GG received honoraria from Ideogen and Takeda, unrelated to this work; support for attending meetings or travel from Roche, Kite-Gilead, Sandoz, BeiGene, and Janssen, unrelated to this work; and participated on data safety monitoring board or advisory board for AbbVie, Roche, Takeda, Kite-Gilead, Italfarmaco, Ideogen, and Genmab, unrelated to this work. EJ received research funding from Celgene, Merck, Pharmacyclics, and F Hoffman-LaRoche, unrelated to this work; honoraria from Merck, Daiichi, BMS, and Bayer, unrelated to this work; and has patents planned, issued, or pending with UpToDate, unrelated to this work. TF has received research funding from ADCT, AstraZeneca, BMS, Corvus, Daiichi, Genmab, Kymera, Merck, Seagen, TESSA, Trillium, Alexion, and Portola, unrelated to this work; consulting fees from ADCT, AstraZeneca, BMS, Epizyme, Genmab, Seagen, Pharmacyclics, and Celgene, unrelated to this work; honoraria from Takeda, Seagen, Genmab, Epizyme, ADCT, AstraZeneca, BMS, Pharmacyclics, AbbVie, and Pfizer, unrelated to this work; and owns stock in OMI and Genomic Testing Cooperative, unrelated to this work. DE received research funding from Nippon Shinyaku Pharmaceutical, Chugai Pharmaceutical, and Eisai Pharmaceutical, to their institution, unrelated to this work; and honoraria from Eisai Pharmaceutical, Chugai Pharmaceutical, SymBio Pharmaceuticals, BMS, Kyowa Kirin Pharmaceutical, and Nippon Shinyaku Pharmaceutical, unrelated to this work. EDD received consulting fees from Takeda, unrelated to this work; honoraria from Takeda and BeiGene, unrelated to this work; and funding for attending meetings or travel from Takeda, unrelated to this work. JZ received research funding from Secura Bio, Astex, CRSPR, Myeloid Therapeutics, and Daichi Sankyo, unrelated to this work; consulting fees from Seattle genetics, Secura Bio, Kyowa Kirin, and Myeloid Therapeutics, unrelated to this work; and honoraria from Kyowa Kirin, unrelated to this work. JJ, SW, TM, AI, and KN are employed by Daiichi Sankyo. TM has received support for attending meetings or travel from Daiichi Sankyo, unrelated to this work. AI, TM, and YC own stock options in Daiichi Sankyo, unrelated to this work. KN owns stock in Daiichi Sankyo, unrelated to this work. SH received research funding from the US National Institutes of Health/National Cancer Institute Cancer Center, (support grant P30 CA008748); research funding from ADC Therapeutics, Affimed, Aileron, Celgene, Crispr Therapeutics, Daiichi Sankyo, Forty Seven, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio; and honoraria from Abcuro, Autolus, Auxilius Pharma, Corvus, Cimeio Therapeutics, Daiichi Sankyo, Dren Bio, Kyowa Hakko Kirin, March, Bio, Ono Pharmaceuticals, SecuraBio, Shore line, Biosciences, Takeda, Tubulis and Yingli Pharma. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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7. Evaluation of Ki-67 expression and large cell content as prognostic markers in MZL: a multicenter cohort study.
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Grover NS, Annunzio K, Watkins M, Torka P, Karmali R, Anampa-Guzmán A, Oh TS, Reves H, Tavakkoli M, Hansinger E, Christian B, Thomas C, Barta SK, Geethakumari PR, Bartlett NL, Shouse G, Olszewski AJ, and Epperla N
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- Humans, Female, Male, Middle Aged, Aged, Prognosis, Adult, Retrospective Studies, Aged, 80 and over, Biomarkers, Tumor, Young Adult, Ki-67 Antigen metabolism, Ki-67 Antigen analysis, Lymphoma, B-Cell, Marginal Zone pathology, Lymphoma, B-Cell, Marginal Zone mortality, Lymphoma, B-Cell, Marginal Zone metabolism
- Abstract
Marginal zone lymphoma (MZL) can have varied presentations and pathologic features, including high Ki-67 expression ( > 20%) as well as increased numbers of large B cells (LC). However, there are limited data available demonstrating the prognostic significance of these variables in patients with MZL. In this multi-institutional retrospective cohort study of patients with MZL treated at 10 centers, we evaluated the association between the presence of Ki-67 expression and increased LCs on survival and risk of histologic transformation (HT). A total of 785 patients were included (60% with extranodal MZL, 20% with nodal MZL, and 20% with splenic MZL). Among the 440 patients with Ki-67 staining, 22% had high Ki-67 (Ki-67 >20%). The median progression-free survival (PFS) for patients with high Ki-67 was 5.4 years compared to 7.0 years for patients with low Ki-67 (HR = 1.45, 95%CI = 1.03-2.05). Ki-67 > 20% strongly correlated with high LDH level. The risk of HT was higher in patients with increased Ki-67 than those without (5-year risk, 9.8% vs 3.87%, p = 0.01). Twelve percent of patients had LC reported on biopsy with 6% having >10% LC. The presence of LC was associated with high Ki-67 (p < 0.001), but not associated with shorter PFS or overall survival (OS). The cumulative risk for HT was higher in patients with LC compared to those without LC (5-year risk, 9.4% vs 2.9%, p = 0.04). Receipt of anthracycline-based therapy did not impact PFS or OS in either group. Ki-67 staining >20% was a prognostic factor for worse survival and strongly correlated with elevated LDH. Novel therapies should be investigated for their potential ability to overcome the high-risk features in MZL. Our data reinforce the importance of obtaining biopsies at relapse or progression, particularly in patients with baseline high Ki-67 and increased LCs, given their increased risk for HT., (© 2024. The Author(s).)
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- 2024
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8. Prevalence and Prognostication of CD5+ Mature T-Cell Lymphomas.
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Elghawy O, Cao M, Xu J, Landsburg DJ, Svoboda J, Nasta SD, Chong EA, Schuster SJ, Thomas CJ, Carter JS, Tavakkoli M, Ruella M, and Barta SK
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Background: T-cell lymphomas (TCLs) are a group of heterogenous cancers with poor rates and duration of response. There remains a great challenge in risk stratification of these cancers. Cluster of differentiation (CD) 5 has shown prognostic implication in many subtypes of B-cell lymphoma; however, its role in TCLs is not known. Methods: We performed a single-institution retrospective analysis of newly diagnosed patients with TCL. CD5 positivity was determined based on positive results via immunohistochemistry and/or flow cytometry. We used univariate and multivariable analysis of biological factors to assess their association with survival outcomes. Results: A total of 194 patients with TCL spanning 14 subtypes were identified. CD5 positivity was noted in 63% of patients, with the highest proportion of CD5 expression in TFH TCL (93.9%), PTCL-NOS (82.9%), and ATLL (77.8%) ( p = 0.00004). Older age at diagnosis ( p = 0.001), stage III or IV disease ( p = 0.05), and bone marrow involvement ( p = 0.003) were also associated with CD5 expression. Complete response rates were numerically lower in patients with CD5+ TCL across all subtypes. OS/PFS was not statistically associated with CD5 status in the overall cohort; however there was significantly decreased OS in CD5+ TFH TCL ( p = 0.04) and CD5+ ATLL ( p = 0.04) patients. Conclusions: This study represents the first to examine CD5 expression as a prognostic biomarker for outcomes in TCL. The frequent expression of CD5 in the most common nodal TCL in the Western world underpins its potential as an attractive target for cellular therapies. Confirmation of these findings in a larger cohort and investigation of potential pathophysiological mechanisms explaining our observations are planned.
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- 2024
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9. Analysis of Histologic, Immunohistochemical and Genomic Features of Large B Cell Lymphoma Tumors May Predict Response to Polatuzumab Vedotin Based Therapy in Patients With Relapsed/Refractory Disease.
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Schneider M, Nasta SD, Barta SK, Chong EA, Svoboda J, Schuster SJ, and Landsburg DJ
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Background: Large B cell lymphoma (LBCL) is the most common form of lymphoma. Polatuzumab vedotin (polatuzumab) is an effective therapy for patients diagnosed with LBCL; however, only limited information regarding pathologic features detected by clinical laboratory assays is available to determine which patients are most likely to benefit from polatuzumab based therapies., Patients and Methods: We collected data from real world patients with relapsed or refractory LBCL whose tumors underwent next generation sequencing and were treated with polatuzumab based therapy at a single large academic cancer center. Tumor and patient characteristics were analyzed to look for factors that predict response to polatuzumab based therapies., Results: We identified high grade B cell lymphoma (HGBL) -NOS or MYC/BCL2 histology and presence of MYC rearrangement as factors that predict inferior response to polatuzumab based therapy. Patients with germinal center B cell of origin (GCB COO) LBCL without these factors had a high response rate (73%) to polatuzumab based therapy., Conclusion: In a single center real world retrospective analysis of R/R LBCL patients with available genomic data, polatuzumab based therapy may be less effective in patients with HGBL-NOS or MYC/BCL2 histology and MYC rearrangements, but not in patients with GCB COO LBCL without these features. Routine performance of more comprehensive pathologic analysis of tumors may inform the use of polatuzumab based therapy in patients with LBCL., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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10. Immune-related adverse events associated with mogamulizumab: a comprehensive review of the literature.
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Silva GS, Kim EJ, Barta SK, and Chung J
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- Humans, Receptors, CCR4, Graft vs Host Disease, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized administration & dosage
- Abstract
Introduction: Mogamulizumab is an anti-C-C chemokine receptor 4 antibody that is increasingly being used to treat T-cell malignancies such as cutaneous T-cell lymphoma, adult T-cell leukemia-lymphoma, and peripheral T-cell lymphoma. Because CCR4 is expressed on both malignant T-cells and regulatory T-cells (Tregs), mogamulizumab can be associated with increased immune-related adverse events (irAEs). While there is abundant literature on mogamulizumab-associated rash (MAR) and graft-versus-host disease (GVHD), other reported irAEs have not been collated into a single review., Areas Covered: This narrative review covers irAEs associated with mogamulizumab in patients with T-cell lymphomas, focusing on events other than MAR and GVHD. We searched PubMed and Google Scholar for case reports, case series, chart reviews, and clinical trials published from inception to March 2024. Identified events include alopecia, vitiligo, arthritis, psoriasis, myocarditis, myositis/polymyositis, hepatitis, and others., Expert Opinion: Mogamulizumab's ability to augment the host immune response through Treg depletion adds to its efficacy but has wide-ranging implications for autoimmunity across multiple organ systems, similar to immune checkpoint inhibitor therapy. Occurrence of irAEs may be associated with improved overall clinical response, although long-term follow-up studies are needed.
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- 2024
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11. Immunologic Predictors of Vaccine Responsiveness in Patients With Lymphoma and Chronic Lymphocytic Leukemia.
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Chong EA, Kumashie KG, Chong ER, Fabrizio J, Gupta A, Svoboda J, Barta SK, Walsh KM, Napier EB, Lundberg RK, Nasta SD, Gerson JN, Landsburg DJ, Gonzalez J, Gaano A, Weirick ME, McAllister CM, Awofolaju M, John GN, Kammerman SC, Novacek J, Pajarillo R, Lundgreen KA, Tanenbaum N, Gouma S, Drapeau EM, Adamski S, D'Andrea K, Pattekar A, Hicks A, Korte S, Sharma H, Herring S, Williams JC, Hamilton JT, Bates P, Hensley SE, Prak ETL, Greenplate AR, Wherry EJ, Schuster SJ, Ruella M, and Vella LA
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- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Prospective Studies, SARS-CoV-2 immunology, Adult, Antibodies, Viral blood, Antibodies, Viral immunology, Vaccination, Immunoglobulin M blood, Lymphoma immunology, Lymphoma therapy, Aged, 80 and over, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage, COVID-19 immunology, COVID-19 prevention & control
- Abstract
Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. Severe acute respiratory syndrome coronavirus 2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic messenger RNA vaccine response in retrospective and prospective cohorts with lymphoma and chronic lymphocytic leukemia, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active treatment, but nonresponse was also common within observation and posttreatment groups. Total immunoglobulin A and immunoglobulin M correlated with successful vaccine response. In individuals treated with anti-CD19-directed chimeric antigen receptor-modified T cells, nonresponse was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to individualize vaccine timing., Competing Interests: Potential conflicts of interest. E. A. C. receives research support from Genentech/Roche and AbbVie and has served as a consultant for Beigene, AstraZeneca, and TG Therapeutics. J. S. has served as a consultant for ATARA, AstraZeneca, Celgene Corporation, Adaptive, and Genmab, and receives research support from AstraZeneca, Merck, Incyte, Bristol-Myers Squibb, Pharmacyclics, TG Therapeutics, Seattle Genetics, and Adaptive. S. K. B. received honoraria from Acrotech, Seagen, Kyowa Kirin, and Daiichi Sankyo. S. D. N. receives research support from Roche, Rafael, ATARA, Pharmacyclics, and Takeda/Millennium; is a data monitoring committee member for Merck; and has served as a consultant for Epizyme and Morphosys. D. J. L. received research funding from Curis and Triphase; is a data and safety monitoring board member for Karyopharm; and has served as a consultant for Morphosys/Incyte, Epizyme, and ADC Therapeutics. J. N. G. received research funding from Loxo and has served as a consultant for Genentech, AbbVie, and Kite. E. L. P. received funding from Roche Diagnostics Corporation for the evaluation of serologic tests for SARS-CoV-2. E. J. W. is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine, and Surface Oncology; is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences; and is an inventor on a patent (US patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. S. J. S. reports research funding from Acerta, Celgene, Genentech/Roche, Merck, Novartis, Pharmacyclics, and TG Therapeutics; received honoraria/consulting fees from Acerta, AstraZeneca, Celgene, Incyte, Janssen, Loxo Oncology, Morphosys, and Nordic Nanovector; is a steering committee member for Celgene, Nordic Nanovector, and Novartis; and has a patent for combination therapies of CAR T cells and PD-1 inhibitors. M. R. holds patents related to CAR T cells; has served as a consultant for nanoString, BMS, GSK, Bayer, Sana Therapeutics, and AbClon; receives research funding from AbClon, nanoString, viTToria biotherapeutics, Oxford Nanoimaging, and Beckman Coulter; and is the scientific founder of viTToria Biotherapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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12. CD5 deletion enhances the antitumor activity of adoptive T cell therapies.
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Patel RP, Ghilardi G, Zhang Y, Chiang YH, Xie W, Guruprasad P, Kim KH, Chun I, Angelos MG, Pajarillo R, Hong SJ, Lee YG, Shestova O, Shaw C, Cohen I, Gupta A, Vu T, Qian D, Yang S, Nimmagadda A, Snook AE, Siciliano N, Rotolo A, Inamdar A, Harris J, Ugwuanyi O, Wang M, Carturan A, Paruzzo L, Chen L, Ballard HJ, Blanchard T, Xu C, Abdel-Mohsen M, Gabunia K, Wysocka M, Linette GP, Carreno B, Barrett DM, Teachey DT, Posey AD, Powell DJ Jr, Sauter CT, Pileri S, Pillai V, Scholler J, Rook AH, Schuster SJ, Barta SK, Porazzi P, and Ruella M
- Subjects
- Animals, Mice, Humans, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen genetics, Cell Line, Tumor, CRISPR-Cas Systems, Female, Immunotherapy, Adoptive methods, CD5 Antigens immunology, T-Lymphocytes immunology, T-Lymphocytes transplantation
- Abstract
Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.
- Published
- 2024
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13. The CNS relapse in T-cell lymphoma index predicts CNS relapse in patients with T- and NK-cell lymphomas.
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Bhansali RS, Ellin F, Relander T, Cao M, Li W, Long Q, Ganesan N, Stuver R, Horwitz SM, Wudhikarn K, Hwang SR, Bennani NN, Chavez J, Sokol L, Saeed H, Duan F, Porcu P, Pullarkat P, Mehta-Shah N, Zain JM, Ruiz M, Brammer JE, Prakash R, Iyer SP, Olszewski AJ, Major A, Riedell PA, Smith SM, Goldin C, Haverkos B, Hu B, Zhuang TZ, Allen PB, Toama W, Janakiram M, Brooks TR, Jagadeesh D, Hariharan N, Goodman AM, Hartman G, Ghione P, Fayyaz F, Rhodes JM, Chong EA, Gerson JN, Landsburg DJ, Nasta SD, Schuster SJ, Svoboda J, Jerkeman M, and Barta SK
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Lymphoma, T-Cell pathology, Lymphoma, T-Cell diagnosis, Lymphoma, T-Cell mortality, Prognosis, Aged, 80 and over, Neoplasm Recurrence, Local, Lymphoma, Extranodal NK-T-Cell diagnosis, Lymphoma, Extranodal NK-T-Cell mortality, Lymphoma, Extranodal NK-T-Cell therapy, Risk Factors, Recurrence, Killer Cells, Natural, Young Adult, Central Nervous System Neoplasms diagnosis, Central Nervous System Neoplasms secondary, Central Nervous System Neoplasms pathology, Central Nervous System Neoplasms mortality
- Abstract
Abstract: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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14. Bendamustine as Lymphodepletion for Brexucabtagene Autoleucel Therapy of Mantle Cell Lymphoma.
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Chong EA, Chong ER, Therwhanger D, Nasta SD, Landsburg DJ, Barta SK, Svoboda J, Gerson JN, Ghilardi G, Paruzzo L, Fraietta JA, Weber E, Stefano N, Porter DL, Frey NV, Garfall AL, Ruella M, and Schuster SJ
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Vidarabine analogs & derivatives, Vidarabine therapeutic use, Vidarabine administration & dosage, Adult, Antineoplastic Agents, Alkylating therapeutic use, Antineoplastic Agents, Alkylating administration & dosage, Antigens, CD19 immunology, Treatment Outcome, Bendamustine Hydrochloride therapeutic use, Bendamustine Hydrochloride administration & dosage, Lymphoma, Mantle-Cell drug therapy, Immunotherapy, Adoptive methods
- Abstract
Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory mantle cell lymphoma (MCL). During a fludarabine shortage, we used bendamustine as an alternative to standard cyclophosphamide/fludarabine (cy/flu) lymphodepletion (LD) prior to brexu-cel. We assessed MCL patient outcomes as well as CAR T-cell expansion and persistence after brexu-cel following bendamustine or cy/flu LD at our center. This was a retrospective single institution study that utilized prospectively banked blood and tissue samples. Clinical efficacy was assessed by 2014 Lugano guidelines. CAR T-cell expansion and persistence in peripheral blood were assessed on day 7 and at ≥month 6 for patients with available samples. Seventeen patients received bendamustine and 5 received cy/flu. For the bendamustine cohort, 14 (82%) received bridging therapy and 4 (24%) had CNS involvement. Fifteen patients (88%) developed CRS with 4 (24%) ≥grade 3 events. Six (35%) patients developed ICANS with 4 (24%) events ≥grade 3. No patient had ≥grade 3 cytopenias at day 90. Best objective (BOR) and complete response (CRR) rates were 82% and 65%, respectively. At 24.5 months median follow-up, 12-month progression-free survival (PFS) was 45%, 24-month PFS was 25%, and median duration of response was 19 months. Median OS was not reached. BOR was 25% (1/4) for patients with CNS involvement. CAR transgene expansion after bendamustine LD was observed on day 7 in all (4/4) patients tested and persisted at ≥6 months (2/2), regardless of response. Bendamustine LD before brexu-cel for MCL is feasible and safe with a lower frequency and shorter duration of cytopenias than reported for cy/flu. Both CAR T-cell expansion and persistence were observed after bendamustine LD. Outcomes appear comparable to the real world outcomes reported with cy/flu LD., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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15. Phase II study of the novel antifolate agent pralatrexate in combination with the histone deacetylase inhibitor romidepsin for the treatment of patients with mature T-cell lymphoma.
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Ryu Tiger YK, Jain S, Barta SK, Tolu S, Estrella B, Sawas A, Lue JK, Francescone MM, Pro B, and Amengual JE
- Subjects
- Humans, Male, Middle Aged, Female, Aged, Adult, Treatment Outcome, Folic Acid Antagonists therapeutic use, Folic Acid Antagonists adverse effects, Folic Acid Antagonists administration & dosage, Aged, 80 and over, Aminopterin analogs & derivatives, Aminopterin therapeutic use, Aminopterin administration & dosage, Aminopterin adverse effects, Depsipeptides administration & dosage, Depsipeptides adverse effects, Depsipeptides therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Lymphoma, T-Cell drug therapy, Lymphoma, T-Cell pathology, Histone Deacetylase Inhibitors therapeutic use, Histone Deacetylase Inhibitors adverse effects, Histone Deacetylase Inhibitors administration & dosage
- Abstract
Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m
2 and romidepsin 12 mg/m2 every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies ( N = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies. Trial Registration: www.clinicaltrials.gov (NCT01947140).- Published
- 2024
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16. Impact of race and social determinants of health on outcomes in patients with aggressive B-cell NHL treated with CAR-T therapy.
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Karmali R, Machhi R, Epperla N, Shouse G, Romancik J, Moyo TK, Kenkre V, Ollila TA, Fitzgerald L, Hess B, David K, Roy I, Zurko J, Chowdhury SM, Annunzio K, Ferdman R, Bhansali RS, Harris EI, Liu J, Nizamuddin I, Ma S, Moreira J, Winter J, Pro B, Stephens DM, Danilov A, Shah NN, Cohen JB, Barta SK, Torka P, and Gordon LI
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Asian, Black or African American, Racial Groups, Retrospective Studies, Treatment Outcome, United States, White, Insurance, Health, Insurance Coverage, Immunotherapy, Adoptive economics, Lymphoma, B-Cell economics, Lymphoma, B-Cell mortality, Lymphoma, B-Cell therapy, Social Determinants of Health economics, Social Determinants of Health ethnology
- Abstract
Abstract: Chimeric antigen receptor (CAR) T-cell (CAR-T) immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care use and outcomes in patients treated with CAR-T therapy for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-Ts were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic, and clinical data were collected and analyzed. In total, 466 adult patients were included in our analysis. Median follow-up after CAR-T therapy was 12.7 months. Median progression-free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months; hazard ratio [HR], 1.56 [1.03-2.4]; P = .04) or Asians (2.7 months; HR, 1.7 [1.02-2.67]; P = .04). Differences in median overall survival (mOS) were not significant. For Medicare (n = 206) vs Medicaid (n = 33) vs private insurance (n = 219) vs self-pay (n = 7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (P < .001), respectively; and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (P < .001), respectively. Our multicenter retrospective analysis showed that race and insurance status can affect outcomes for patients treated with CAR-T therapy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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17. Subsequent malignant neoplasms in patients previously treated with anti-CD19 CAR T-cell therapy.
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Melody M, Epperla N, Shouse G, Romancik J, Allen P, Moyo TK, Kenkre V, Ollila T, Fitzgerald L, Hess B, David K, Herr MM, Odetola O, Lin A, Moreira J, Ma S, Winter JN, Roy I, Stephens D, Danilov A, Shah NN, Barta SK, Cortese M, Cohen JB, Gordon LI, and Karmali R
- Subjects
- Humans, Male, Female, Neoplasms, Second Primary etiology, Neoplasms, Second Primary therapy, Adult, Receptors, Chimeric Antigen, Middle Aged, Neoplasms therapy, Neoplasms immunology, Antigens, CD19 immunology, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive adverse effects
- Published
- 2024
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- View/download PDF
18. Targeted Therapies in the Treatment of Mantle Cell Lymphoma.
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Thomas CJ, Carvajal V, and Barta SK
- Abstract
Mantle cell lymphoma (MCL) is a rare, heterogeneous B-cell non-Hodgkin's lymphoma. The standard front-line treatment utilizes chemotherapy, often followed by consolidation with an autologous hematopoietic cell transplant; however, in most patients, the lymphoma will recur and require subsequent treatments. Additionally, mantle cell lymphoma primarily affects older patients and is frequently chemotherapy-resistant, which has further fostered the necessity for new, chemotherapy-free treatment options. In the past decade, targeted therapies in mantle cell lymphoma have been practice-changing as the treatment paradigm shifts further away from relying primarily on cytotoxic agents. Here, we will review the pathophysiology of mantle cell lymphoma and discuss the emergence of targeted, chemotherapy-free treatments aimed at disrupting the abnormal biology driving its lymphomagenesis. Treatments targeting the constitutive activation of NF-kB, Bruton's Tyrosine Kinase signaling, and anti-apoptosis will be the primary focus as we discuss their clinical data and toxicities. Our review will also focus primarily on the emergence and use of targeted therapies in the relapsed/refractory setting but will also discuss the emergence of their use in front-line therapy and in combination with other agents.
- Published
- 2024
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19. Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel.
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Ghilardi G, Paruzzo L, Patel V, Svoboda J, Chong ER, Fardella E, Chong EA, Gabrielli G, Nasta SD, Landsburg DJ, Carter J, Pajarillo R, Barta SK, White G, Weber E, Napier E, Porter DL, Garfall AL, Schuster SJ, and Ruella M
- Subjects
- Humans, Middle Aged, Male, Female, Aged, Retrospective Studies, Adult, Lymphoma, Large B-Cell, Diffuse drug therapy, Antineoplastic Agents, Alkylating therapeutic use, Antineoplastic Agents, Alkylating adverse effects, Biological Products therapeutic use, Biological Products adverse effects, Aged, 80 and over, Treatment Outcome, Bendamustine Hydrochloride therapeutic use, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive adverse effects
- Abstract
Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile., (© 2024. The Author(s).)
- Published
- 2024
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20. CAR T-Cell Immunotherapy in Minority Patients with Lymphoma.
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Ghilardi G, Williamson S, Pajarillo R, Paruzzo L, Chen L, Grady C, Doucette A, Nemecek E, Gabrielli G, Barta SK, Svoboda J, Chong EA, Yelton R, Nasta SD, Landsburg DJ, Ugwuanyi O, Chen AI, Schachter L, White G, Ballard HJ, Weber E, Curley C, Porter DL, Garfall AL, Hwang WT, Guerra CE, Maziarz RT, Schuster SJ, and Ruella M
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Minority Groups statistics & numerical data, Receptors, Chimeric Antigen immunology, Antigens, CD19 immunology, Antigens, CD19 therapeutic use, Immunotherapy, Adoptive adverse effects
- Abstract
Background: Administration of anti-CD19 chimeric antigen receptor T-cell (CART19) immunotherapy for large B-cell lymphomas (LBCLs), a subset of non-Hodgkin lymphoma (NHL), involves high costs and access to specialized tertiary care centers. We investigated whether minority health populations (MHPs) have equal access to CART19 and whether their outcomes are similar to those of non-MHPs., Methods: We analyzed the prevalence and clinical outcomes of patients treated with commercial CART19 at two geographically and socioeconomically different institutions: the Abramson Cancer Center (ACC, Philadelphia, Pennsylvania) and the Knight Cancer Institute (KCI, Portland, Oregon)., Results: In the ACC catchment area, 8956 patients were diagnosed with NHL between 2015 and 2019 (latest available data from the state registry), including 17.9% MHPs. In the ACC, between 2018 and 2022 (CART became available in 2018), 1492 patients with LBCL were treated, and 194 received CART19. The proportion of MHPs was 15.7% for the entire LBCL cohort but only 6.7% for the CART19 cohort. During the same time, in the KCI catchment area, 4568 patients were diagnosed with NHL, including 4.2% MHPs. In the KCI, 396 patients with LBCL were treated, and 47 received CART19. The proportion of MHPs was 6.6% for the entire LBCL cohort and 4.2% for the CART19 cohort. The 3-month response, survival, and toxicities after CART19 infusion showed similar results, although the number of patients who were treated was limited., Conclusions: This study shows that the access of MHPs to tertiary centers for LBCL care was preserved but appeared reduced for commercial CART19 immunotherapy. Although clinical outcomes of MHPs seemed similar to those of non-MHPs, the small sample size precludes drawing firm conclusions. Further studies are needed. (Funded by the Laffey McHugh Foundation and others.).
- Published
- 2024
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21. T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy.
- Author
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Ghilardi G, Fraietta JA, Gerson JN, Van Deerlin VM, Morrissette JJD, Caponetti GC, Paruzzo L, Harris JC, Chong EA, Susanibar Adaniya SP, Svoboda J, Nasta SD, Ugwuanyi OH, Landsburg DJ, Fardella E, Waxman AJ, Chong ER, Patel V, Pajarillo R, Kulikovskaya I, Lieberman DB, Cohen AD, Levine BL, Stadtmauer EA, Frey NV, Vogl DT, Hexner EO, Barta SK, Porter DL, Garfall AL, Schuster SJ, June CH, and Ruella M
- Subjects
- Humans, Immunotherapy, Adoptive adverse effects, Receptors, Antigen, T-Cell genetics, Antigens, CD19, Receptors, Chimeric Antigen genetics, Lymphoma, B-Cell, Lymphoma, T-Cell, Hematologic Neoplasms, Lung Neoplasms
- Abstract
We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8
+ cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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22. Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency.
- Author
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Aminov S, Giricz O, Melnekoff DT, Sica RA, Polishchuk V, Papazoglu C, Yates B, Wang HW, Sahu S, Wang Y, Gordon-Mitchell S, Leshchenko VV, Schinke C, Pradhan K, Aluri S, Sohn M, Barta SK, Agarwal B, Goldfinger M, Mantzaris I, Shastri A, Matsui W, Steidl U, Brody JD, Shah NN, Parekh S, and Verma A
- Subjects
- Child, Humans, Young Adult, Agammaglobulinaemia Tyrosine Kinase, Chromatin, Immunotherapy, Adoptive, Mitogen-Activated Protein Kinase Kinases, Receptors, Chimeric Antigen, Antigens, CD19 genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Sialic Acid Binding Ig-like Lectin 2 genetics
- Abstract
While therapies targeting CD19 by antibodies, chimeric antigen receptor T cells (CAR-T), and T cell engagers have improved the response rates in B cell malignancies, the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19 immunotoxin. Single-cell RNA-Seq (scRNA-Seq) showed an increase in transcriptionally distinct CD19lo populations among resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19lo-resistant cells. An assay for transposase-accessible chromatin with sequencing (ATAC-Seq) showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B cell acute lymphoblastic leukemia (B-ALL) that relapsed after CD19 CAR-T-targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19lo resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both Bruton's tyrosine kinase (BTK) and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.
- Published
- 2024
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23. Outcomes of marginal zone lymphoma treated with ibrutinib in the first-line setting in the United States: a real-world analysis.
- Author
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Epperla N, Zhao Q, Moyo T, Watkins MP, Tavakkoli M, Bello C, Torka P, Reddy N, Thomas C, Annunzio K, Christian B, Barta SK, Shouse G, Olszewski AJ, and Bartlett NL
- Subjects
- Humans, United States, Adenine, Piperidines, Lymphoma, B-Cell, Marginal Zone pathology
- Published
- 2024
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24. Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines.
- Author
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Ghilardi G, Paruzzo L, Svoboda J, Chong EA, Shestov AA, Chen L, Cohen IJ, Gabrielli G, Nasta SD, Porazzi P, Landsburg DJ, Gerson JN, Carter J, Barta SK, Yelton R, Pajarillo R, Patel V, White G, Ballard HJ, Weber E, Napier E, Chong ER, Fraietta JA, Garfall AL, Porter DL, Milone MC, O'Connor R, Schuster SJ, and Ruella M
- Subjects
- Humans, Bendamustine Hydrochloride adverse effects, CD28 Antigens, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Cyclophosphamide, Cytokines, Lymphoma, Follicular, Biological Products
- Abstract
Abstract: Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
25. Progress and Pitfalls of Chimeric Antigen Receptor T Cell Immunotherapy against T Cell Malignancies.
- Author
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Angelos MG, Patel RP, Ruella M, and Barta SK
- Subjects
- United States, Humans, T-Lymphocytes, Receptors, Antigen, T-Cell genetics, Immunotherapy adverse effects, Receptors, Chimeric Antigen, Neoplasms, Hematologic Neoplasms therapy
- Abstract
Chimeric antigen receptor T cell (CAR-T) immunotherapy has revolutionized the treatment of relapsed and refractory B cell-derived hematologic malignancies. Currently, there are 6 Food and Drug Administration-approved commercial CAR-T products that target antigens exclusively expressed on malignant B cells or plasma cells. However, concurrent advancement for patients with rarer and more aggressive T cell-derived hematologic malignancies have not yet been achieved. CAR-T immunotherapies are uniquely limited by challenges related to CAR-T product manufacturing and intrinsic tumor biology. In this review tailored for practicing clinician-scientists, we discuss the major barriers of CAR-T implementation against T cell-derived neoplasms and highlight specific scientific advancements poised to circumvent these obstacles. We summarize salient early-stage clinical trials implementing novel CAR-T immunotherapies specifically for patients with relapsed and/or refractory T cell neoplasms. Finally, we highlight novel manufacturing and treatment strategies that are poised to have a meaningful future clinical impact., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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26. Real-World Treatment Patterns and Clinical Outcomes With Brentuximab Vedotin or Other Standard Therapies in Patients With Previously Treated Cutaneous T-Cell Lymphoma in the United States.
- Author
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Barta SK, Liu N, DerSarkissian M, Chang R, Ye M, Duh MS, Surinach A, Fanale M, and Yu KS
- Subjects
- Humans, United States, Brentuximab Vedotin therapeutic use, Methotrexate, Retrospective Studies, Lymphoma, T-Cell, Cutaneous pathology, Mycosis Fungoides drug therapy, Immunoconjugates adverse effects, Skin Neoplasms drug therapy, Skin Neoplasms pathology
- Abstract
Introduction/background: Primary cutaneous anaplastic large-cell lymphomas (pcALCLs) are a type of cutaneous T-cell lymphoma (CTCL) in which CD30 is uniformly expressed. In mycosis fungoides (MF), another CTCL, CD30 is heterogeneously expressed. In ALCANZA, patients with pcALCLs or CD30-positive MF randomized to brentuximab vedotin (BV) vs. physician's choice of methotrexate or bexarotene had significantly improved outcomes, including higher objective response rates (ORR) lasting ≥4 months (ORR4), as well as longer median progression-free survival (PFS) and time to next treatment (TTNT). In this study, we sought to assess the real-world impact of treatment with BV in second or later lines of therapy for CTCL., Materials and Methods: This retrospective chart review describes patient characteristics, treatment patterns, clinical outcomes, and healthcare resource use (HRU) in patients with pcALCLs or MF previously treated with ≥1 systemic therapy and subsequently treated with BV (n = 139) or other standard therapy (OST; n = 164)., Results: Most patients in the BV cohort (96.4%) received BV as second-line (2L) systemic therapy. The most common OSTs were methotrexate (11.6%), mogamulizumab (9.1%), and bendamustine (9.1%) monotherapies. For 2L BV and OST, median duration of therapy was 8.4 and 5.2 months, real-world ORR was 82.1% and 66.5%, and real-world ORR4 was 42.5% and 25.0%. Real-world 1- and 2-year PFS, TTNT, and OS were significantly longer (all P < .01) and HRU was lower for BV vs. OST., Conclusion: These real-world outcomes are consistent with ALCANZA results, demonstrating favorable outcomes with BV vs. OST in patients with CTCL previously treated with ≥1 systemic therapy., Competing Interests: Disclosure Stefan K. Barta: Consulting Fees: Affimed, Daiichi Sankyo, and Kyowa Kirin; Payment or honoraria for educational events: Acrotech, Kyowa Kirin, and Seagen Inc.; Membership: NCCN T-Cell and Cutaneous Lymphoma Panel; Nicholas Liu: Employee of Seagen Inc.; Stock/Stock Options: Seagen Inc.; Maral DerSarkissian: Employee of Analysis Group, which received research funding from Seagen Inc. to conduct this study; Rose Chang: Employee of Analysis Group, which received research funding from Seagen Inc. to conduct this study; Mingchen Ye: Employee of Analysis Group, which received research funding from Seagen Inc. to conduct this study; Mei Sheng Duh: Employee of Analysis Group, which received research funding from Seagen Inc. to conduct this study; Andy Surinach: Employee of Genesis Research, which received research funding from Seagen Inc. to conduct this study; Michelle Fanale: Employee of Seagen Inc.; Stock/Stock Options: Seagen Inc.; Kristina S. Yu: Employee of Seagen Inc.; Stock/Stock Options: Seagen Inc., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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27. Pralatrexate injection combined with CHOP for treatment of PTCL: results from the Fol-CHOP dose-finding phase 1 trial.
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Iyer SP, Johnston PB, and Barta SK
- Subjects
- Humans, Aminopterin adverse effects, Treatment Outcome, Fatigue chemically induced, Lymphoma, T-Cell, Peripheral drug therapy
- Abstract
Abstract: Pralatrexate is a folate antagonist that selectively enters cells expressing reduced folate carrier type 1 and competitively inhibits dihydrofolate reductase, leading to interruption of RNA synthesis, DNA replication, and apoptosis. This phase 1 study was conducted to evaluate the maximum tolerated dose (MTD) of pralatrexate in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen (part 1) and the response and pharmacokinetics of 6 cycles of this combination (CHOP + Folotyn 30 mg/m2 [Fol-CHOP]) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL). In part 1, on days 1 and 8 of each cycle, patients were treated with 10, 15, 20, 25, or 30 mg/m2 of pralatrexate in combination with CHOP, per dose escalation, in 5 sequential cohorts. No patients experienced DLTs in cohorts 1, 2, 3, 4, and 5. The pralatrexate dose of 30 mg/m2 was selected to be combined with CHOP for part 2 and administered to 33 additional patients in the expansion cohort. At the MTD, the Fol-CHOP regimen was generally well tolerated in patients with PTCL, with an overall response rate (ORR) of 83.9% (20 complete response and 6 partial response), as assessed by treating investigators. Thirty-five patients (67.3%) experienced grade 3/4 treatment-emergent adverse events, the most common of which were anemia (21.2%), neutropenia (19.2%), febrile neutropenia (11.5%), fatigue, mucosal inflammation, nausea, and vomiting (7.7% each). In conclusion, Fol-CHOP was found to be a safe and effective treatment for newly diagnosed PTCL and deemed worthy of further investigation. This trial was registered at www.ClinicalTrials.gov as #NCT02594267., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2024
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28. Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.
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Gerson JN, Handorf E, Villa D, Gerrie AS, Chapani P, Li S, Medeiros LJ, Wang M, Cohen JB, Churnetski M, Hill BT, Sawalha Y, Hernandez-Ilizaliturri FJ, Kothari S, Vose JM, Bast M, Fenske T, Rao Gari SN, Maddocks KJ, Bond D, Bachanova V, Kolla B, Chavez J, Shah B, Lansigan F, Burns T, Donovan AM, Wagner-Johnston N, Messmer M, Mehta A, Anderson JK, Reddy N, Kovach AE, Landsburg DJ, Glenn M, Inwards DJ, Ristow K, Karmali R, Kaplan JB, Caimi PF, Rajguru S, Evens A, Klein A, Umyarova E, Pulluri B, Amengual JE, Lue JK, Diefenbach C, Fisher RI, and Barta SK
- Subjects
- Adult, Humans, Retrospective Studies, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Risk Assessment, Progression-Free Survival, Lymphoma, Mantle-Cell therapy, Lymphoma, Mantle-Cell drug therapy
- Abstract
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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29. TP53 mutations predict for poor outcomes in patients with newly diagnosed aggressive B-cell lymphomas in the current era.
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Landsburg DJ, Morrissette JJ, Nasta SD, Barta SK, Schuster SJ, Svoboda J, Chong EA, and Bagg A
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- Humans, Rituximab therapeutic use, Vincristine therapeutic use, Mutation, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Tumor Suppressor Protein p53 genetics, Neoplasm Recurrence, Local drug therapy, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Genetic subgroups of diffuse large B-cell lymphoma (DLBCL) have been identified through comprehensive genomic analysis; however, it is unclear whether this can be applied in clinical practice. We assessed whether mutations detected by clinical laboratory mutation analysis (CLMA) were predictive of outcomes in patients with newly diagnosed DLBCL/high-grade B-cell lymphoma (HGBL). Patients diagnosed from 2018 to 2022 whose biopsy samples were subjected to CLMA and who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or rituximab plus etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin were analyzed for overall/complete response rate (ORR/CRR) and estimated progression-free/overall survival (PFS/OS). CLMA was successfully performed in 117 of 122 patient samples (96%), with a median turnaround time of 17 days. Median duration of follow-up was 31.3 months. Of the mutations detected in ≥10% of the samples, only TP53 was associated with both progression and death at 2 years. TP53 mutations were detected in 36% of tumors, and patients with TP53 mutations experienced significantly lower ORR (71% vs 90%; P = .009), CRR (55% vs 77%; P = .01), 2-year PFS (57% vs 77%; P = .006), 2-year OS (70% vs 91%; P = .001), and median OS after relapse (6.1 months vs not yet reached; P = .001) as than those without TP53 mutations. Furthermore, patients with TP53 loss-of-function (LOF) mutations experienced lower rates of 2-year PFS/OS than those with non-LOF mutations and inferior or near-inferior 2-year PFS if harboring high-risk clinicopathologic features. TP53 mutations identified through CLMA can predict for inferior outcomes in patients with newly diagnosed DLBCL/HGBL. Results of CLMA can be used in real time to inform prognosis and/or identify candidates for clinical trials., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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30. Central Nervous System Relapse in T and NK cell Lymphomas.
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Taranto EP, Barta SK, and Bhansali RS
- Subjects
- Humans, Retrospective Studies, Neoplasm Recurrence, Local drug therapy, Killer Cells, Natural, Central Nervous System pathology, Chronic Disease, Central Nervous System Neoplasms epidemiology, Central Nervous System Neoplasms prevention & control, Lymphoma, T-Cell, Peripheral drug therapy, Antineoplastic Agents therapeutic use
- Abstract
Purpose of Review: T and NK cell lymphomas are relatively rare and heterogeneous forms of non-Hodgkin lymphoma that are associated with high rates of mortality. Central nervous system relapse carries significant morbidity, though management is largely extrapolated from literature in B cell neoplasms. As such, outcomes for central nervous system involvement in T/NK cell lymphomas are dismal with no standard of care. In this review, we discuss the epidemiology of central nervous system relapse in T/NK cell lymphomas and critically analyze available literature regarding prophylaxis and treatment., Recent Findings: Retrospective studies of central nervous system involvement in T/NK cell lymphomas have been limited by small sample sizes and heterogeneity of subtypes, though sites of extranodal involvement and disease subtypes are consistently reported as risk factors. Compelling evidence for the use of central nervous system-directed prophylactic therapy has not yet been established, though recent reports of central nervous system activity with novel agents may suggest promising therapeutic options. The overall rarity of T and NK cell lymphomas has precluded adequate study of prophylaxis and treatment of central nervous system relapse. Collaborative efforts are needed to better define strategies to address CNS disease in T/NK cell lymphomas. These should involve the use of targeted agents, which may hold an advantage over traditional cytotoxic drugs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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31. Impact of circulating lymphoma cells at diagnosis on outcomes in patients with marginal zone lymphoma: a multicenter cohort study.
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Annunzio K, Grover NS, Welkie RL, Torka P, Watkins MP, Anampa-Guzmán A, Tavakkoli M, Oh TS, Reves H, Jones D, Hanel W, Christian B, Ramakrishnan Geethakumari P, Karmali R, Barta SK, Bartlett NL, Olszewski AJ, and Epperla N
- Subjects
- Humans, Lymphocytes, Cohort Studies, Lymphoma, B-Cell, Marginal Zone diagnosis, Lymphoma, B-Cell, Marginal Zone pathology
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- 2023
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32. Brentuximab vedotin plus AVD for Hodgkin lymphoma: incidence and management of peripheral neuropathy in a multisite cohort.
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Bowers JT, Anna J, Bair SM, Annunzio K, Epperla N, Pullukkara JJ, Gaballa S, Spinner MA, Li S, Messmer MR, Nguyen J, Ayers EC, Wagner CB, Hu B, Di M, Huntington SF, Furqan F, Shah NN, Chen C, Ballard HJ, Hughes ME, Chong EA, Nasta SD, Barta SK, Landsburg DJ, and Svoboda J
- Subjects
- Humans, Antineoplastic Combined Chemotherapy Protocols adverse effects, Brentuximab Vedotin therapeutic use, Incidence, Retrospective Studies, Hodgkin Disease complications, Hodgkin Disease drug therapy, Hodgkin Disease pathology, Peripheral Nervous System Diseases etiology, Peripheral Nervous System Diseases chemically induced
- Abstract
Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is increasingly used for frontline treatment of stage III/IV classical Hodgkin lymphoma (cHL). Peripheral neuropathy (PN) was the most common and treatment-limiting side effect seen in clinical trials but has not been studied in a nontrial setting, in which clinicians may have different strategies for managing it. We conducted a multisite retrospective study to characterize PN in patients who received BV + AVD for newly diagnosed cHL. One hundred fifty-three patients from 10 US institutions were eligible. Thirty-four patients (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage, performance status, and comorbidities. PN was reported by 80% of patients during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of patients because of PN leading to BV discontinuation in 23%, dose reduction in 17%, and temporary hold in 4%. With a median follow-up of 24 months, PN resolution was documented in 36% and improvement in 33% at the last follow-up. Two-year progression-free survival (PFS) for the advanced-stage patients was 82.7% (95% confidence interval [CI], 0.76-0.90) and overall survival was 97.4% (95% CI, 0.94-1.00). Patients who discontinued BV because of PN did not have inferior PFS. In the nontrial setting, BV + AVD was associated with a high incidence of PN. In our cohort, which includes patients who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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33. Outcomes of patients with secondary central nervous system lymphoma following CAR T-cell therapy: a multicenter cohort study.
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Epperla N, Feng L, Shah NN, Fitzgerald L, Shah H, Stephens DM, Lee CJ, Ollila T, Shouse G, Danilov AV, David KA, Torka P, Hashmi H, Hess B, Barta SK, Romancik JT, Cohen JB, Annunzio K, Kittai AS, Reneau J, Zurko J, Nizamuddin IA, Winter JN, Gordon LI, Ma S, Patel R, Nastoupil L, Ahmed S, and Karmali R
- Subjects
- Humans, Immunotherapy, Adoptive adverse effects, Retrospective Studies, Central Nervous System, Cytokine Release Syndrome, Antigens, CD19, Receptors, Chimeric Antigen therapeutic use, Lymphoma, Central Nervous System Neoplasms therapy, Neoplasms, Second Primary, Lymphoma, Large B-Cell, Diffuse
- Abstract
Chimeric antigen receptor T-cell therapy (CAR-T) has been successful in treating relapsed/refractory B-cell lymphomas. However, its role in the treatment of diseases involving the central nervous system (CNS) is not well studied. We performed a multicenter retrospective cohort study to evaluate the outcomes of patients with secondary CNS lymphoma (SCNSL) who received CAR-T. Eligibility required active CNSL at the time of apheresis. The objectives included evaluation of overall survival (OS), progression-free survival (PFS), identification of predictors of complete response (CR) post-CAR-T, and assessment of risk factors for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Sixty-one patients were included in the analysis. The overall response rate was 68% with a CR rate of 57%. In the multivariable analysis, patients who experienced any grade CRS had higher odds of achieving CR (OR = 3.9, 95% CI = 1.01-15.39, p = 0.047). The median PFS was 3.3 months (95% CI = 2.6-6.0 months) with 6- and 12-month PFS rates of 35% and 16%, respectively. The median OS was 7.6 months (95% CI = 5.0-13.5 months) with 6- and 12-month OS rates of 59% and 41%, respectively. Any grade CRS and ICANS were 70% (n = 43) and 57% (n = 34), respectively with grade ≥ 3 CRS and ICANS rates of 16% and 44%. Factors associated with increased risk of CRS and ICANS included receiving axi-cel or having leptomeningeal ± parenchymal + CNS involvement, respectively. Despite achieving high response rates, most patients experience early relapse or death following CAR-T in SCNSL. The current study provides a benchmark for future trials exploring novel therapeutic options in SCNSL., (© 2023. The Author(s).)
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- 2023
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34. 2024 Update: Advances in the risk stratification and management of large B-cell lymphoma.
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Tavakkoli M and Barta SK
- Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with varying clinical outcomes. Our understanding of its molecular makeup continues to improve risk stratification, and artificial-intelligence and ctDNA-based analyses have the potential to enhance risk assessment and disease monitoring. R-CHOP and Pola-R-CHP are used in the frontline setting; chimeric antigen receptor therapy (CART) is now the new standard-of-care for most with primary refractory disease; both CART and autologous stem cell transplantation are utilized in the relapsed and refractory setting. In this review, we summarize the classification and management of DLBCL with an emphasis on recent advances in the field., (© 2023 Wiley Periodicals LLC.)
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- 2023
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35. Impact of detectable monoclonal protein at diagnosis on outcomes in marginal zone lymphoma: a multicenter cohort study.
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Epperla N, Zhao Q, Karmali R, Torka P, Shea L, Oh TS, Anampa-Guzmán A, Reves H, Tavakkoli M, Greenwell IB, Hansinger E, Umyarova E, Annunzio K, Sawalha Y, Christian B, Thomas C, Barta SK, Geethakumari PR, Bartlett NL, Grover NS, and Olszewski AJ
- Subjects
- Humans, Rituximab therapeutic use, Retrospective Studies, Neoplasm Recurrence, Local drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma drug therapy
- Abstract
Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein at diagnosis. After adjusting for factors associated with inferior PFS in univariate models, presence of M-protein remained significantly associated with inferior PFS (hazard ratio, 1.74; 95% confidence interval, 1.20-2.54; P = .004). We observed no significant difference in the PFS based on the type or quantity of M-protein at diagnosis. There were differential outcomes in PFS based on the first-line therapy in patients with M-protein at diagnosis, in that, those receiving immunochemotherapy had better outcomes compared with those receiving rituximab monotherapy. The cumulative incidence of relapse in stage 1 disease among the recipients of local therapy was higher in the presence of M-protein; however, this did not reach statistical significance. We found that M-protein at diagnosis was associated with a higher risk of histologic transformation. Because the PFS difference related to presence of M-protein was not observed in patients receiving bendamustine and rituximab, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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36. SOHO State of the Art Updates and Next Questions | Challenging Cases in Rare T-Cell Lymphomas.
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Bhansali RS and Barta SK
- Subjects
- Adult, Humans, Lymphoma, T-Cell, Peripheral diagnosis, Lymphoma, T-Cell, Peripheral therapy, Lymphoma, T-Cell, Peripheral pathology, Lymphoma, Extranodal NK-T-Cell pathology, Lymphoma, Large-Cell, Anaplastic pathology, Panniculitis pathology
- Abstract
Mature T- and NK-cell neoplasms (MTNKN) collectively represent a rare disorder, representing less than 15% of all non-Hodgkin lymphoma (NHL) cases and qualifying for orphan disease designation by the U.S. Food and Drug Administration (FDA). These consist of 9 families in the fifth revised WHO classification of lymphoid neoplasms, which are made up of over 30 disease subtypes, underscoring the heterogeneity of clinical features, molecular biology, and genetics across this disease group. Moreover, the 5 most common subtypes (peripheral T-cell lymphoma, not otherwise specified; nodal TFH cell lymphoma, angioimmunoblastic type; extranodal NK-cell/T-cell lymphoma; adult T-cell leukemia/lymphoma; and ALK-positive or -negative anaplastic large cell lymphoma) comprise over 75% of MTNKN cases, so other subtypes are exceedingly rare in the context of all NHL diagnoses and consequently often lack consensus on best practices in diagnosis and management. In this review, we discuss the following entities-enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and primary cutaneous ɣδ T-cell lymphoma (PCGD-TCL) - with an emphasis on clinical and diagnostic features and options for management., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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37. Survival Outcomes for Patients with Relapsed/ Refractory Aggressive B Cell Lymphomas Following Receipt of High-Dose Chemotherapy/Autologous Stem Transplantation and/or Chimeric Antigen Receptor-Modified T Cells.
- Author
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Landsburg DJ, Nasta SD, Svoboda J, Gerson JN, Schuster SJ, Barta SK, Chong EA, Difilippo H, Weber E, Cunningham K, Catania C, Garfall AL, Stadtmauer EA, Frey NV, and Porter DL
- Subjects
- Humans, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Transplantation, Autologous methods, T-Lymphocytes, Hematopoietic Stem Cell Transplantation, Receptors, Chimeric Antigen therapeutic use, Lymphoma, Large B-Cell, Diffuse therapy
- Abstract
Patients diagnosed with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBL) may achieve prolonged survival following receipt of high-dose chemotherapy/autologous stem cell transplantation (HDC/ASCT) or CD19-directed chimeric antigen receptor modified T cell therapy (CART19). Although early results from randomized clinical trials suggest that assignment to CART19 versus salvage immunochemotherapy as second-line therapy results in improved survival, analysis of a large series of patients who actually received HDC/ASCT or CART19 has yet to be performed. Such an analysis may inform future research efforts to optimize the risk stratification of R/R DLBCL/HGBL patients who are candidates for either therapy. The aim of this study was to evaluate clinicopathologic factors predictive of freedom from treatment failure (FFTF) for R/R DLBCL/HGBL patients following receipt of HDC/ASCT or CART19, and to compare patterns of treatment failure (TF) in R/R DLBCL/HGBL patients receiving HDC/ASCT and those receiving CART19. THE STUDY GROUP COMPRISED: patients age ≤75 years with R/R DLBCL/HGBL who received HDC/ASCT demonstrating partial or complete metabolic response to salvage immunochemotherapy and/or CART19 in the standard of care setting at the University of Pennsylvania between 2013 and 2021. Survival analyses were performed from the time of infusion of either HDC/ASCT or CART19, as well as at landmark time points postinfusion for patients who achieved FFTF. For 100 HDC/ASCT patients with a median follow-up of 62.7 months, the estimated 36-month FFTF and overall survival (OS) rates were 59% and 81%, respectively. For 109 CART19 patients with a median follow-up of 37.6 months, the estimated 36-month FFTF and OS rates were 24% and 48%, respectively. HDC/ASCT patients had significantly higher rates of estimated 36-month FFTF when they achieved actual FFTF at 3, 6, 12 and 24 months. Additionally, the rates of baseline characteristics predictive of TF at 36 months for either HDC/ASCT or CART19 patients were either similar to or significantly lower for CART19 patients compared to HDC/ASCT patients who achieved actual FFTF at 3, 6, 12, and 24 months. Patients with R/R DLBCL/HGBL achieving response to salvage immunochemotherapy who received HDC/ASCT had a high rate of estimated FFTF regardless of whether they harbored features predictive of resistance to salvage immunochemotherapy, which may be more durable than that of R/R DLBCL/HGBL patients receiving CART19. These findings support further investigation of disease characteristics, such as molecular features, that may predict response to salvage immunochemotherapy in patients fit for HDC/ASCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2023
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38. Peri-CAR-T practice patterns and survival predictors for all CAR-T patients and post-CAR-T failure in aggressive B-NHL.
- Author
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Zurko J, Nizamuddin I, Epperla N, David K, Cohen JB, Moyo TK, Ollila T, Hess B, Roy I, Ferdman R, Liu J, Chowdhury SM, Romancik J, Bhansali RS, Harris EI, Sorrell M, Masel R, Kittai AS, Denlinger N, Sigmund AM, Fitzgerald L, Galvez C, Ma S, Winter J, Pro B, Gordon LI, Danilov A, Stephens D, Shah NN, Kenkre V, Barta SK, Torka P, Shouse G, and Karmali R
- Subjects
- Humans, Retrospective Studies, Immunotherapy, Adoptive methods, Progression-Free Survival, Receptors, Chimeric Antigen therapeutic use, Lymphoma, B-Cell
- Abstract
Most patients receiving chimeric antigen receptor T-cell therapy (CAR-T) for aggressive B-cell non-Hodgkin lymphoma (B-NHL) do not experience a durable remission. Several novel agents are approved to treat relapsed, refractory aggressive B-NHL; however, it remains unclear how to sequence these therapies pre- and post-CAR-T. We conducted a multicenter retrospective analysis to describe peri-CAR-T practice patterns and survival predictors for patients receiving CD19-directed CAR-T. Patients (n = 514) from 13 centers treated with CAR-T for B-NHL between 2015-2021 were included in the study. Survival curves were constructed using Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of the variables on survival outcomes. For all patients receiving CAR-T, a greater number of lines of therapy pre-CAR-T apheresis and bridging therapy were predictive of inferior progression-free survival (PFS) and overall survival (OS). The median PFS and OS from the time of CAR-T cell infusion were 7.6 and 25.6 months, respectively. From the time of progression post-CAR-T, the median OS was 5.5 months. The median PFS of treatments administered in the first-line post-CAR-T failure was 2.8 months. Patients with refractory disease on day 30 had inferior OS and were less likely to receive subsequent treatment(s) than other patients with CAR-T failure. Allogeneic hematopoietic cell transplantation for selected patients at any time following CAR-T failure led to durable responses in over half of patients at 1 year. These data provide a benchmark for future clinical trials in patients with post-CAR-T cell progression, which remains an unmet clinical need., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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39. Impact of diagnosis to treatment interval in patients with newly diagnosed mantle cell lymphoma.
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Epperla N, Switchenko J, Bachanova V, Gerson JN, Barta SK, Gordon MJ, Danilov AV, Grover NS, Mathews S, Burkart M, Karmali R, Sawalha Y, Hill BT, Ghosh N, Park SI, Bond DA, Hamadani M, Fenske TS, Martin P, Malecek MK, Kahl BS, Flowers CR, Link BK, Kaplan LD, Inwards DJ, Feldman AL, Hsi ED, Maddocks K, Blum KA, Bartlett NL, Cerhan JR, Leonard JP, Habermann TM, Maurer MJ, and Cohen JB
- Subjects
- Adult, Humans, Risk Assessment, Prognosis, Combined Modality Therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Mantle-Cell therapy, Lymphoma, Mantle-Cell drug therapy
- Abstract
The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p<0.0001) and overall survival (7.8 years vs. 11.8 years, p<0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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40. Impact of early relapse within 24 months after first-line systemic therapy (POD24) on outcomes in patients with marginal zone lymphoma: A US multisite study.
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Epperla N, Welkie RL, Torka P, Shouse G, Karmali R, Shea L, Anampa-Guzmán A, Oh TS, Reaves H, Tavakkoli M, Lindsey K, Greenwell IB, Hansinger E, Thomas C, Chowdhury SM, Annunzio K, Christian B, Barta SK, Geethakumari PR, Bartlett NL, Herrera AF, Grover NS, and Olszewski AJ
- Subjects
- Humans, Rituximab therapeutic use, Antibodies, Monoclonal, Recurrence, Immunotherapy, Lymphoma
- Abstract
Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis., (© 2023. The Author(s).)
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- 2023
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41. Is it prime time for T-cell lymphoma?
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Barta SK
- Subjects
- Humans, CD8-Positive T-Lymphocytes, Azacitidine, Lymphoma, T-Cell, Lymphoma, T-Cell, Peripheral
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- 2023
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42. Central Nervous System Progression/Relapse in Mature T- and NK-Cell Lymphomas.
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Bhansali RS and Barta SK
- Abstract
Non-Hodgkin lymphomas (NHL) are cancers of mature B-, T-, and NK-cells which display marked biological heterogeneity between different subtypes. Mature T- and NK-cell neoplasms are an often-aggressive subgroup of NHL and make up approximately 15% of all NHL. Long-term follow up studies have demonstrated that patients with relapsed/refractory disease have dismal outcomes; in particular, secondary central nervous system (CNS) involvement is associated with higher mortality, though it remains controversial whether this independently confers worse outcomes or if it simply reflects more aggressive systemic disease. Possible risk factors predictive of CNS involvement, such as an elevated lactate dehydrogenase and more than two sites of extranodal involvement, may suggest the latter, though several studies have suggested that discrete sites of anatomic involvement or tumor histology may be independent risk factors as well. Ultimately, small retrospective case series form the basis of our understanding of this rare but devastating event but have not yet demonstrated a consistent benefit of CNS-directed prophylaxis in preventing this outcome. Nonetheless, ongoing efforts are working to establish the epidemiology of CNS progression/relapse in mature T- and NK-cell lymphomas with the goal of identifying clinicopathologic risk factors, which may potentially help discern which patients may benefit from CNS-directed prophylactic therapy or more aggressive systemic therapy.
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- 2023
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43. Salvage radiotherapy for relapsed/refractory non-Hodgkin lymphoma following CD19 chimeric antigen receptor T-cell (CART) therapy.
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Yegya-Raman N, Wright CM, LaRiviere MJ, Baron JA, Lee DY, Landsburg DJ, Svoboda J, Nasta SD, Gerson JN, Barta SK, Chong EA, Schuster SJ, Maity A, Facciabene A, Paydar I, and Plastaras JP
- Abstract
Background and Purpose: CD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting., Materials and Methods: Of 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n = 9 [43 %], all disease encompassable within an RT field) and advanced disease (n = 12 [57 %]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed., Results: Median time from CART infusion to SRT was 4.0 months (range, 0.6-11.5 months). In the locoregional disease group, 8/9 patients (89 %) were treated with comprehensive SRT to a median dose of 37.5 Gy in a median of 15 fractions. In the advanced disease group, all patients (n = 12) were treated with focal SRT to a median dose of 20.8 Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2 months. In-field response was observed in 8/9 (89 %) in the locoregional disease and 8/9 (89 %) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94 %) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4 months; 21 months for locoregional disease versus 2.4 months for advanced disease (p = 0.0002). Median PFS was 1.1 month, and similarly poor regardless of group. No grade ≥ 3 toxicities occurred., Conclusions: SRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)
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- 2023
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44. Postibrutinib relapse outcomes for patients with marginal zone lymphoma.
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Epperla N, Zhao Q, Chowdhury SM, Shea L, Moyo TK, Reddy N, Sheets J, Weiner DM, Geethakumari PR, Kandarpa M, Bruno XJ, Thomas C, Churnetski MC, Hsu A, Zurbriggen L, Tan XC, Lindsey K, Maakaron J, Caimi PF, Torka P, Bello C, Ayyappan S, Oh TS, Karmali R, Kim SH, Kress A, Kothari S, Sawalha Y, Christian B, David KA, Greenwell IB, Janakiram M, Kenkre VP, Olszewski AJ, Cohen JB, Palmisiano N, Umyarova E, Wilcox RA, Awan FT, Alderuccio JP, Barta SK, Grover NS, Ghosh N, Bartlett NL, Herrera AF, and Shouse G
- Subjects
- Humans, Disease-Free Survival, Chronic Disease, Neoplasm Recurrence, Local drug therapy, Lymphoma, B-Cell, Marginal Zone drug therapy, Lymphoma, B-Cell, Marginal Zone pathology
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- 2023
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45. Allogeneic haematopoietic cell transplant in patients with relapsed/refractory anaplastic large cell lymphoma.
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Furqan F, Ahn KW, Chen Y, Kaur M, Abutalib SA, Ahmed N, Ahmed S, Kharfan-Dabaja MA, Friedberg J, Gregory T, Hill L, Sterling C, Barta SK, Shadman M, Perales MA, Zain J, Herrera AF, Sauter C, and Hamadani M
- Subjects
- Adult, Humans, Adolescent, Neoplasm Recurrence, Local, Progression-Free Survival, Prognosis, Chronic Disease, Transplantation Conditioning, Retrospective Studies, Hematopoietic Stem Cell Transplantation, Lymphoma, Large-Cell, Anaplastic therapy, Graft vs Host Disease etiology
- Abstract
The prognosis of relapsed/refractory (R/R) anaplastic large cell lymphoma (ALCL) is poor. Large studies evaluating outcomes of allogeneic haematopoietic cell transplantation (allo-HCT) in systemic R/R ALCL are not available. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we evaluated outcomes of 182 adults (aged ≥18 years) with R/R ALCL undergoing allo-HCT between 2008 and 2019. Non-relapse mortality (NRM), disease relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modelled using Cox proportional hazards models. The median (range) follow-up of survivors was 62 (3-148) months. The 1-year NRM was 18%. The 5-year REL, PFS and OS were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6-4.8; p < 0.001) and refractory disease at allo-HCT (HR 3.2, 95% CI 1.6-6.2; p < 0.001) were predictive of inferior OS. Similarly, African-American race (HR 2.1, 95% CI 1.3-3.4; p = 0.003), other minority race (HR 2.5, 95% CI 1.2-5.3; p = 0.02) and refractory disease (HR 2.2, 95% CI 1.2-4.3; p = 0.01) were predictive of inferior PFS. These data, demonstrate that allo-HCT can result in durable disease control in a sizable proportion of patients with R/R ALCL. Refractory disease and racial minority status predicted inferior allo-HCT outcomes. Whether the inferior outcomes of racial minorities with R/R ALCL after allo-HCT are driven by differences in disease biology or disparities in post allo-HCT care, or both, requires further investigation., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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46. Mutation analysis performed on tumor biopsies from patients with newly-diagnosed germinal center aggressive B cell lymphomas.
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Landsburg DJ, Morrissette JJD, Schuster SJ, Nasta SD, Gerson JN, Barta SK, Svoboda J, Chong EA, and Lim MS
- Subjects
- Humans, Biopsy, B-Lymphocytes, Mutation, Germinal Center, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Comprehensive genomic analyses of tumor biopsies from patients with newly-diagnosed germinal center B cell (GCB) diffuse large B cell/high grade B cell lymphoma (DLBCL/HGBL) have identified molecular subtypes predictive of inferior survival, which are characterized by somatic mutations that can be detected through clinical laboratory mutation analysis (CLMA). To determine the frequency and predictive value of individual genetic mutations associated with these experimentally-defined poor-risk subgroups, we reviewed the findings from CLMA performed on tumors from patients with newly-diagnosed GCB DLBCL/HGBL who were previously treated at our institution. CLMA was successfully performed on 58/59 patient tumor biopsies with a median turnaround time of 16 days, and 51 on which CLMA was routinely performed with adequate clinical follow-up were analyzed. Patients whose tumors demonstrated CREBBP mutation experienced a lower estimated rate of 2-year disease free survival (DFS) as compared to those whose tumors did not (45% [95% CI 18-68%] vs. 67% [95% CI 44-83%], P = 0.045). CREBBP mutations may be frequent and predict for inferior DFS in patients with newly-diagnosed GCB DLBCL/HGBL. Furthermore, CLMA may be practically-applied to translate experimental findings into those with more direct application to risk stratification and clinical trial design in subsets of patients with DLBCL/HGBL.
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- 2022
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47. Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.
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Ghilardi G, Chong EA, Svoboda J, Wohlfarth P, Nasta SD, Williamson S, Landsburg JD, Gerson JN, Barta SK, Pajarillo R, Myers J, Chen AI, Schachter L, Yelton R, Ballard HJ, Hodges Dwinal A, Gier S, Victoriano D, Weber E, Napier E, Garfall A, Porter DL, Jäger U, Maziarz RT, Ruella M, and Schuster SJ
- Subjects
- Cyclophosphamide therapeutic use, Cytokine Release Syndrome drug therapy, Humans, Bendamustine Hydrochloride adverse effects, Bendamustine Hydrochloride therapeutic use, Immunotherapy, Adoptive methods, Lymphocyte Depletion methods, Lymphoma, Large B-Cell, Diffuse therapy, Receptors, Antigen, T-Cell therapeutic use
- Abstract
Background: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T., Patients and Methods: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading., Results: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide., Conclusions: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization., Competing Interests: Disclosure MR holds patents related to CD19 CAR T cells, served as a consultant for NanoString, Bristol Myers Squibb (BMS), GlaxoSmithKline, Bayer, and AbClon, receives research funding from AbClon, NanoString, and Beckman Coulter, and is the scientific founder of viTToria Biotherapeutics. JS served as a consultant for Genmab, Adaptive, AstraZeneca, BMS, Imbrium, ADCT, Atara, Pharmacyclics, Seattle Genetics and received research funding from AstraZeneca, BMS, Incyte, Merck, Seattle Genetics, Pharmacyclics, and TG therapeutics. RTM served as an advisor or consultant for AlloVir, Artiva, CRISPR Therapeutics, Incyte, and Novartis, reports honoraria from BMS/Celgene, Incyte, Intellia, and Kite, has received research support from BMS, AlloVir, and Novartis, has participated in data and safety monitoring boards for Athersys, Vor Pharma, and Novartis, and has a patent with Athersys. EAC served as consultant for Novartis, Beigene, KITE, Tessa, Juno/BMS. SKB served as consultant to Acrotech, Kyowa Kirin, Daiichi Sankyo, and Seagen. SDN received research funding from Pharmacyclics, Roche, Rafael, FortySeven/Gilead. UJ served as a consultant to Novartis, received research funding from Novartis and honoraria from Novartis, BMS/Celgene, Gilead, Janssen, and Miltenyi. JDL received research funding from Curis, Takeda, and Triphase, served on Board of Directors or advisory committees or data and safety monitoring board for Incyte, ADCT, Karyopharm, and Morphosis. SJS served as a consultant to AstraZeneca, BeiGene, Celgene, Genentech, Genmab, Fate Therapeutics, Roche, Incyte, Juno Therapeutics, Legend Biotech, Loxo Oncology, MorphoSys, Mustang Biotech, Nordic Nanovector, Novartis, and Regeneron, received research funding from AbbVie, Adaptive Biotechnologies, Celgene, DTRM, Genentech, Roche, Juno Therapeutics, Merck, Novartis, Incyte, Pharmacyclics, and TG Therapeutics, received honoraria from Celgene and Novartis, and holds patents related to CD19 CAR T cells and autologous co-stimulated T cells. JNG: Kite: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy. AG: Amgen: Honoraria; Tmunity Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Novartis: Research Funding. DLP: National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; American Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria: UJ has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 945393. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and from the Medical-Scientific Funds of the City of Vienna, Cancer Research Funds Project—Nr. 21098. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
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- 2022
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48. Outcomes of Tisagenlecleucel in Lymphoma Patients With Predominant Management in an Ambulatory Setting.
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Nasta SD, Hughes ME, Namoglu EC, Garfall A, DiFilippo H, Ballard HJ, Barta SK, Chong EA, Frey NV, Gerson JN, Landsburg DJ, Ruella M, Schuster SJ, Svoboda J, Weber E, and Porter DL
- Subjects
- Adult, Antigens, CD19, Cytokines, Humans, Immunotherapy, Adoptive, Retrospective Studies, Lymphoma, Follicular drug therapy, Receptors, Antigen, T-Cell
- Abstract
Introduction: Chimeric antigen receptor T-cell therapy (CAR T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, substantial resources are necessary for administration and care of these patients. Our institution has administered tisagenlecleucel primarily in an outpatient setting, and here we report our clinical outcomes., Patients and Methods: We conducted a single institution, retrospective study investigating outcomes of adult lymphoma patients treated with commercial tisagenlecleucel between 10/2017 and 12/2020. We analyzed patient characteristics and outcomes of efficacy and safety including overall response rate, progression-free survival, overall survival and cytokine-release syndrome, neurotoxicity, and hospitalizations., Results: Seventy-two patients with relapsed or refractory non-Hodgkin lymphoma (NHL) who received commercial tisagenlecleucel were identified; 68 (94.4%) patients received outpatient tisagenlecleucel. The overall response rate was 43% with a complete response observed in 25 patients (34.7%). At a median follow-up of 9.1 months, the median progression-free survival was 3.3 months. Grade 3-4 cytokine release syndrome was not observed in the study group and two patients had grade 3-4 neurotoxicity. Twenty-six patients (36.1%) were admitted within 30 days after infusion with a median length of stay of 5 days. Fourteen patients (19.4%) were admitted within 72 hours of infusion. No patient died of CAR T cell-related toxicity., Conclusion: Our experience affirms treatment with tisagenlecleucel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, adverse events were manageable and the majority of patients did not require hospitalization., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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49. Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study.
- Author
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Epperla N, Zhao Q, Chowdhury SM, Shea L, Moyo TK, Reddy N, Sheets J, Weiner DM, Geethakumari PR, Kandarpa M, Bruno XJ, Thomas C, Churnetski MC, Hsu A, Zurbriggen L, Tan C, Lindsey K, Maakaron J, Caimi PF, Torka P, Bello C, Ayyappan S, Karmali R, Kim SH, Kress A, Kothari S, Sawalha Y, Christian B, David KA, Greenwell IB, Janakiram M, Kenkre VP, Olszewski AJ, Cohen JB, Palmisiano N, Umyarova E, Wilcox RA, Awan FT, Alderuccio JP, Barta SK, Grover NS, Ghosh N, Bartlett NL, Herrera AF, and Shouse G
- Subjects
- Adenine analogs & derivatives, Cohort Studies, Humans, Neoplasm Recurrence, Local drug therapy, Piperidines, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Treatment Outcome, Lymphoma, B-Cell, Marginal Zone drug therapy, Lymphoma, B-Cell, Marginal Zone pathology
- Abstract
Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23-7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03-8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17-37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15-12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies., (© 2022. The Author(s).)
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- 2022
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50. Usage and safety of topical tacrolimus in patients with mycosis fungoides.
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Weiner DM, Clark AK, Bhansali RS, Pappas-Taffer L, Barta SK, Villasenor-Park J, Haun PL, Vittorio CC, Rook AH, Kim EJ, and Samimi SS
- Subjects
- Humans, Tacrolimus adverse effects, Mycosis Fungoides drug therapy, Skin Neoplasms drug therapy
- Published
- 2022
- Full Text
- View/download PDF
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