231 results on '"Noelle V. Frey"'
Search Results
2. Cardiovascular Effects of CAR T Cell Therapy
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Bénédicte Lefebvre, MD, Yu Kang, MD, PhD, Amanda M. Smith, MA, Noelle V. Frey, MD, Joseph R. Carver, MD, and Marielle Scherrer-Crosbie, MD, PhD
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cardio-oncology ,cardiovascular ,CAR T cells ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Anti-CD19 chimeric antigen receptor (CAR) T cell therapy holds great promise in the treatment of patients with hematologic malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CAR T cell therapy. Objectives: The aim of this study was to define the occurrence of major adverse cardiovascular events (MACE) in adult patients treated with CAR T cell therapy and assess the relationships among clinical factors, echocardiographic parameters, laboratory values, and cardiovascular outcomes. Methods: Baseline clinical, laboratory, and echocardiographic parameters were collected in 145 adult patients undergoing CAR T cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and de novo cardiac arrhythmia. Baseline parameters associated with MACE were identified using Cox proportional cause-specific hazards regression analysis. Results: Thirty-one patients had MACE (41 events) at a median time of 11 days (interquartile range: 6 to 151 days) after CAR T cell infusion. The median follow-up period was 456 days (interquartile range: 128 to 1,214 days). Sixty-one patients died. Cytokine release syndrome (CRS) occurred 176 times in 104 patients; the median time to CRS was 6 days (interquartile range: 1 to 8 days). The Kaplan-Meier estimates for MACE and CRS at 30 days were 17% and 53%, respectively. The Kaplan-Meier estimates for survival at 1 year was 71%. Multivariable Cox proportional cause-specific hazards regression analysis determined that baseline creatinine and grade 3 or 4 CRS were independently associated with MACE. Conclusions: Patients treated with CAR T cell therapy are at an increased risk for MACE and may benefit from cardiovascular surveillance. Further large prospective studies are needed to confirm the incidence and risk factors predictive of MACE.
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- 2020
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3. Paving the Road for Chimeric Antigen Receptor T Cells: American Society for Transplantation and Cellular Therapy 80/20 Task Force Consensus on Challenges and Solutions to Improving Efficiency of Clinical Center Certification and Maintenance of Operations for Commercially Approved Immune Effector Cell Therapies
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Sarah Nikiforow, Matthew J. Frigault, Noelle V. Frey, Rebecca A. Gardner, Krishna V. Komanduri, Miguel-Angel Perales, Partow Kebriaei, Phyllis Irene Warkentin, Marcelo Pasquini, Joy Lynn Aho, Bruce L. Levine, Helen E. Heslop, Tracey L. Hlucky, Karen Habucky, Mecide Gharibo, Madan Jagasia, and Frederick L. Locke
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
4. Clofarabine and Busulfan Myeloablative Conditioning in Allogeneic Hematopoietic Cell Transplantation for Patients With Active Myeloid Malignancies
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Matthew P. Connor, Alison W. Loren, Elizabeth O. Hexner, Mary Ellen Martin, Saar I. Gill, Selina M. Luger, James K. Mangan, Alexander E. Perl, Shannon R. McCurdy, Keith W. Pratz, Colleen Timlin, Craig W. Freyer, Alison Carulli, Christopher Catania, Jacqueline Smith, Lauren Hollander, Alexis M. Zebrowski, Edward A. Stadtmauer, David L. Porter, and Noelle V. Frey
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Abstract
Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.
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- 2023
5. Low-Dose Total Body Irradiation Added to Fludarabine and Busulfan Reduced-Intensity Conditioning Reduces Graft Failure in Patients with Myelofibrosis
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Craig W. Freyer, Daria V. Babushok, Noelle V. Frey, Saar I. Gill, Alison W. Loren, Selina M. Luger, Amit Maity, Mary Ellen Martin, John P. Plastaras, David L. Porter, and Elizabeth O. Hexner
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Adult ,Transplantation ,Graft vs Host Disease ,Cell Biology ,Hematology ,Primary Myelofibrosis ,Humans ,Transplantation, Homologous ,Molecular Medicine ,Immunology and Allergy ,Busulfan ,Vidarabine ,Whole-Body Irradiation ,Retrospective Studies - Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is indicated for patients with intermediate-risk or high-risk myelofibrosis (MF) and remains the sole potential cure. Reduced-intensity conditioning (RIC) is commonly used because of older patient age, comorbidities, and a high incidence of transplantation-related mortality. Patients with MF are at increased risk of graft failure (GF), which is more common with RIC regimens, and is associated with shortened overall survival (OS). Owing to the high rate of GF with conventional fludarabine (Flu) and busulfan (Bu) RIC, we added low-dose total body irradiation (TBI; 200 cGy) for patients with MF. We retrospectively compared alloHCT outcomes in adult patients with MF who received RIC with Flu/Bu/TBI and those who received RIC with Flu/Bu. The primary endpoint was the incidence of GF. Secondary endpoints included time to engraftment, acute and chronic graft-versus-host disease (GVHD), hepatic sinusoidal obstruction syndrome (SOS), nonrelapse mortality, overall response rate, progression-free survival, and OS. Of 33 patients who underwent alloHCT, 8 received Flu/Bu RIC and 25 received Flu/Bu/TBI RIC. GF occurred in 50% of the Flu/Bu recipients (all secondary GF) and in 4% of the Flu/Bu/TBI recipients (1 case of primary GF; relative risk, .08; 95% confidence interval [CI], .01 to .62; P = .0016). GF incidence was similar with related or unrelated donors and in patients who did and did not receive Janus-associated kinase inhibitors prior to alloHCT. Molecular remission and donor chimerism ≥99% were significantly more common with Flu/Bu/TBI. No significant differences in acute GVHD, chronic GVHD, or time to engraftment were observed. SOS occurred in none of the 8 patients who received Flu/Bu and in 6 of the 25 patients who received Flu/Bu/TBI, but this difference did not reach statistical significance. Progression or relapse at 1 year was less common with Flu/Bu/TBI (0% versus 63%; P.001). The median OS was 49 months for Flu/Bu/TBI recipients and 30.8 months for Flu/Bu recipients (hazard ratio, .98; 95% CI, .33 to 2.88; P = .97). Flu/Bu/TBI resulted in a significant reduction in GF and a significant improvement in the frequency of molecular remission and full donor chimerism compared with Flu/Bu. The addition of low-dose TBI to Flu/Bu successfully mitigates against GF in patients with MF without increased rates of complications.
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- 2022
6. Real-world effectiveness of CPX-351 vs venetoclax and azacitidine in acute myeloid leukemia
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Andrew H. Matthews, Alexander E. Perl, Selina M. Luger, Alison W. Loren, Saar I. Gill, David L. Porter, Daria V. Babushok, Ivan P. Maillard, Martin P. Carroll, Noelle V. Frey, Elizabeth O. Hexner, Mary Ellen Martin, Shannon R. McCurdy, Edward A. Stadtmauer, Vikram R. Paralkar, Ximena Jordan Bruno, Wei-Ting Hwang, David Margolis, and Keith W. Pratz
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Leukemia, Myeloid, Acute ,Sulfonamides ,Daunorubicin ,Azacitidine ,Cytarabine ,Quality of Life ,Humans ,Prospective Studies ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,Aged ,Retrospective Studies - Abstract
CPX-351 and venetoclax and azacitidine (ven/aza) are both indicated as initial therapy for acute myeloid leukemia (AML) in older adults. In the absence of prospective randomized comparisons of these regimens, we used retrospective observational data to evaluate various outcomes for patients with newly diagnosed AML receiving either CPX-351 (n = 217) or ven/aza (n = 439). This study used both a nationwide electronic health record (EHR)-derived de-identified database and the University of Pennsylvania EHR. Our study includes 217 patients who received CPX-351 and 439 who received ven/aza. Paitents receiving ven/aza were older, more likely to be treated in the community, and more likely to have a diagnosis of de novo acute myeloid leukemia. Other baseline covariates were not statistically significantly different between the groups. Median overall survival (OS) for all patients was 12 months and did not differ based on therapy (13 months for CPX-351 vs 11 months for ven/aza; hazard ratio, 0.88; 95% confidence interval, 0.71-1.08; P = .22). OS was similar across multiple sensitivity analyses. Regarding safety outcomes, early mortality was similar (10% vs 13% at 60 days). However, documented infections were higher with CPX-351 as were rates of febrile neutropenia. Hospital length of stay, including any admission before the next cycle of therapy, was more than twice as long for CPX-351. In this large multicenter real-world dataset, there was no statistically significant difference in OS. Prospective randomized studies with careful attention to side effects, quality of life, and impact on transplant outcomes are needed in these populations.
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- 2022
7. 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
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Daniel J Landsburg, Sunita D Nasta, Jakub Svoboda, James N Gerson, Stephen J Schuster, Stefan K Barta, Elise A Chong, Heather Difilippo, Elizabeth Weber, Kathleen Cunningham, Christopher Catania, Alfred L Garfall, Edward A Stadtmauer, Noelle V Frey, and David L Porter
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
8. Figure S6 from Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
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Marco Ruella, Saar Gill, Carl H. June, Stephan A. Grupp, Shannon L. Maude, Noelle V. Frey, Matthew D. Weitzman, Ophir Shalem, Shelley L. Berger, Charly R. Good, Karen Thudium Mueller, Elena J. Orlando, Shunichiro Kuramitsu, Sangya Agarwal, Raymone Pajarillo, Xueqing Maggie Lu, Seok Jae Hong, Katharina E. Hayer, Pranali Ravikumar, Olga Shestova, Yong Gu Lee, and Nathan Singh
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GSEA of transcriptomic and epigenomic sequencing of CART19 cells exposed to either WT or BIDKO Nalm6.
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- 2023
9. Table S3 from Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
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Marco Ruella, Saar Gill, Carl H. June, Stephan A. Grupp, Shannon L. Maude, Noelle V. Frey, Matthew D. Weitzman, Ophir Shalem, Shelley L. Berger, Charly R. Good, Karen Thudium Mueller, Elena J. Orlando, Shunichiro Kuramitsu, Sangya Agarwal, Raymone Pajarillo, Xueqing Maggie Lu, Seok Jae Hong, Katharina E. Hayer, Pranali Ravikumar, Olga Shestova, Yong Gu Lee, and Nathan Singh
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Genes used to define exhaustion
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- 2023
10. Data from Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
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Marco Ruella, Saar Gill, Carl H. June, Stephan A. Grupp, Shannon L. Maude, Noelle V. Frey, Matthew D. Weitzman, Ophir Shalem, Shelley L. Berger, Charly R. Good, Karen Thudium Mueller, Elena J. Orlando, Shunichiro Kuramitsu, Sangya Agarwal, Raymone Pajarillo, Xueqing Maggie Lu, Seok Jae Hong, Katharina E. Hayer, Pranali Ravikumar, Olga Shestova, Yong Gu Lee, and Nathan Singh
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Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction.Significance:Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy.See related commentary by Green and Neelapu, p. 492.
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- 2023
11. Real World Effectiveness of '7 + 3' Intensive Chemotherapy Vs Venetoclax and Hypomethylating Agent for Initial Therapy in Adult Acute Myeloid Leukemia
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Andrew Matthews, Alexander E. Perl, Selina M. Luger, Saar Gill, Catherine Lai, David L. Porter, Sarah Skuli, Ximena Jordan Bruno, Craig W. Freyer, Alison Carulli, Martin P. Carroll, Daria V. Babushok, Noelle V. Frey, Elizabeth O. Hexner, Mary Ellen Martin, Shannon R. McCurdy, Edward A. Stadtmauer, Alison W. Loren, Vikram R Paralkar, Ivan Maillard, and Keith W. Pratz
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Fried's Frailty Phenotype Predicts Mortality and Survival for Newly Diagnosed Older Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
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Cristian C. Taborda, Shannon H Gier, Avery W Stivale, Alexander E. Perl, Saar Gill, Daria V. Babushok, Elizabeth O. Hexner, Noelle V. Frey, Catherine Lai, Ximena Jordan Bruno, Mary Ellen Martin, Ivan Maillard, David L. Porter, Alison W. Loren, Keith W. Pratz, Selina M. Luger, Phyllis A. Gimotty, and Shannon R. McCurdy
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
13. Supplementary Data from Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies
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Pamela A. Shaw, Stephan A. Grupp, David L. Porter, Hongyan Liu, Allison Barz Leahy, Regina M. Myers, Noelle V. Frey, David T. Teachey, Shannon L. Maude, Wei-Ting Hwang, and Yimei Li
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Supplementary Data from Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies
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- 2023
14. Data from Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies
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Pamela A. Shaw, Stephan A. Grupp, David L. Porter, Hongyan Liu, Allison Barz Leahy, Regina M. Myers, Noelle V. Frey, David T. Teachey, Shannon L. Maude, Wei-Ting Hwang, and Yimei Li
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Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.
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- 2023
15. Supplementary Table from Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies
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Pamela A. Shaw, Stephan A. Grupp, David L. Porter, Hongyan Liu, Allison Barz Leahy, Regina M. Myers, Noelle V. Frey, David T. Teachey, Shannon L. Maude, Wei-Ting Hwang, and Yimei Li
- Abstract
Supplementary Table from Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies
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- 2023
16. Supplementary Data from Functional Unresponsiveness and Replicative Senescence of Myeloid Leukemia Antigen–specific CD8+ T Cells After Allogeneic Stem Cell Transplantation
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Robert H. Vonderheide, David L. Porter, F. Brad Johnson, Noelle V. Frey, Barbara A. Vance, Theresa A. Colligon, Kunal P. Patel, Ran Reshef, Jasmine S. Smith, and Gregory L. Beatty
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Supplementary Data from Functional Unresponsiveness and Replicative Senescence of Myeloid Leukemia Antigen–specific CD8+ T Cells After Allogeneic Stem Cell Transplantation
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- 2023
17. Data from Functional Unresponsiveness and Replicative Senescence of Myeloid Leukemia Antigen–specific CD8+ T Cells After Allogeneic Stem Cell Transplantation
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Robert H. Vonderheide, David L. Porter, F. Brad Johnson, Noelle V. Frey, Barbara A. Vance, Theresa A. Colligon, Kunal P. Patel, Ran Reshef, Jasmine S. Smith, and Gregory L. Beatty
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Purpose: The therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myeloid malignancies has been attributed in part to a graft-versus-leukemia effect that is dependent on donor T lymphocytes. CD8+ T-cell responses to MHC class I–restricted tumor epitopes, not just allogeneic antigens, may help mediate antileukemia effects after HSCT, but the specificity and function of such cells are not completely understood.Experimental Design: We examined the diversity, phenotype, and functional potential of leukemia-associated antigen-specific CD8+ T cells in patients with myeloid leukemia following allogeneic HSCT. Screening for antigen-specific T cells was accomplished with a peptide/MHC tetramer library.Results: Patients with acute myelogenous leukemia or chronic myelogenous leukemia in remission following HSCT exhibited significant numbers of peripheral blood CD8+ T cells that recognized varying combinations of epitopes derived from leukemia-associated antigens. However, these cells failed to proliferate, release cytokines, or degranulate in response to antigen-specific stimuli. As early as 2 months after HSCT, CD8+ T cells from patients were predominantly CD28− CD57+ and had relatively short telomeres, consistent with cellular senescence.Conclusions: Circulating leukemia-specific CD8+ T cells are prominent in myeloid leukemia patients after HSCT, but such cells are largely functionally unresponsive, most likely due to replicative senescence. These findings carry important implications for the understanding of the graft-versus-leukemia effect and for the rational design of immunotherapeutic strategies for patients with myeloid leukemias.
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- 2023
18. Venetoclax in combination with hypomethylating agents or low dose cytarabine for relapsed and refractory acute myeloid leukemia
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Molly E. Graveno, Alison Carulli, Craig W. Freyer, Brendan L. Mangan, Robert Nietupski, Alison W. Loren, Noelle V. Frey, David L. Porter, Saar I. Gill, Elizabeth O. Hexner, Selina M. Luger, Mary Ellen Martin, Shannon R. McCurdy, Alexander E. Perl, Daria V. Babushok, and Keith W. Pratz
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Leukemia, Myeloid, Acute ,Sulfonamides ,Cancer Research ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Cytarabine ,Humans ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,Retrospective Studies - Abstract
Limited treatment options exist for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Venetoclax (VEN) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC) has been recently approved for treatment-naïve patients unfit for intensive induction. Limited data are available to characterize the efficacy of VEN combinations in R/R AML. We retrospectively analyzed 77 patients with a median of 1 prior therapy (range 0-5) treated with VEN combinations for R/R AML or AML secondary to myelodysplastic syndrome (MDS) progressing after HMA monotherapy. The median overall survival (OS) was 13.1 months (95% CI 9.2-15.1). The median progression-free survival (PFS) was 12 months (95% CI 8.2-15.4) with a median duration of response of 8.9 months (95% CI 5.7-13.9). Overall response rate (ORR) was 68% with a composite complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 53%. VEN combination therapy is efficacious in R/R AML and further prospective studies are warranted.
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- 2022
19. Day 4 vs. day 12 G-CSF administration following reduced intensity peripheral blood allogeneic stem cell transplant
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Rachel V. Hatch, Craig W. Freyer, Alison Carulli, Gretchen Redline, Daria V. Babushok, Noelle V. Frey, Saar I. Gill, Elizabeth O. Hexner, Selina M. Luger, Mary Ellen Martin, Shannon R. McCurdy, Alexander E. Perl, David L. Porter, Keith W. Pratz, Edward A. Stadtmauer, and Alison W. Loren
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Mucositis ,Methotrexate ,Oncology ,Granulocyte Colony-Stimulating Factor ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Humans ,Transplantation, Homologous ,Pharmacology (medical) ,Bone Marrow Transplantation ,Retrospective Studies - Abstract
Introduction Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis. Methods We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017–2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis. Results Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19–32) with day + 4 initiation vs. 24 days (21–30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups. Conclusion Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.
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- 2022
20. Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide
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Craig W. Freyer, Alison Carulli, Shannon Gier, Alex Ganetsky, Colleen Timlin, Mindy Schuster, Daria Babushok, Noelle V. Frey, Saar I. Gill, Elizabeth O. Hexner, Selina M. Luger, James K. Mangan, Mary Ellen Martin, Shannon R. McCurdy, Alexander E. Perl, David L. Porter, Keith Pratz, Jacqueline Smith, Edward A. Stadtmauer, and Alison W. Loren
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Adult ,Cancer Research ,Hematopoietic Stem Cell Transplantation ,Cytomegalovirus ,Graft vs Host Disease ,Hematology ,Acetates ,Oncology ,Valacyclovir ,Cytomegalovirus Infections ,Quinazolines ,Humans ,Unrelated Donors ,Cyclophosphamide ,Retrospective Studies - Abstract
Patients undergoing haploidentical or mismatched unrelated donor (haplo/MMUD) allogeneic hematopoietic cell transplantation (alloHCT) receiving post-transplant cyclophosphamide (PTCy) are at high risk of cytomegalovirus (CMV) infection. Experience with letermovir (LET) in this population is limited. This single center retrospective cohort study compared CMV and transplant outcomes between LET and a historical control with high-dose valacyclovir (HDV) prophylaxis in adults undergoing haplo/MMUD alloHCT. Thirty-eight CMV seropositive patients were included, 19 in each arm. LET reduced the incidence of CMV infection (5% vs. 53%, RR 0.01, 95% CI 0.014-0.71
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- 2022
21. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells
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J. Joseph Melenhorst, Gregory M. Chen, Meng Wang, David L. Porter, Changya Chen, McKensie A. Collins, Peng Gao, Shovik Bandyopadhyay, Hongxing Sun, Ziran Zhao, Stefan Lundh, Iulian Pruteanu-Malinici, Christopher L. Nobles, Sayantan Maji, Noelle V. Frey, Saar I. Gill, Alison W. Loren, Lifeng Tian, Irina Kulikovskaya, Minnal Gupta, David E. Ambrose, Megan M. Davis, Joseph A. Fraietta, Jennifer L. Brogdon, Regina M. Young, Anne Chew, Bruce L. Levine, Donald L. Siegel, Cécile Alanio, E. John Wherry, Frederic D. Bushman, Simon F. Lacey, Kai Tan, and Carl H. June
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Multidisciplinary - Published
- 2022
22. Relapsed ALL: CAR T vs transplant vs novel therapies
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Noelle V, Frey
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Antigens, CD19 ,Receptors, Antigen, T-Cell ,Humans ,Transplantation, Homologous ,Hematology ,Neoplasm Recurrence, Local ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,ALL: New Directions for Adult Patients ,Immunotherapy, Adoptive ,Stem Cell Transplantation - Abstract
Chimeric antigen receptor T-cell therapy targeting CD19 (CART19) has expanded the treatment options for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). The approval of tisagenlecleucel for pediatric and young adult patients with r/r ALL has allowed broader access for some patients, but the treatment of older adults is available (at the time of this writing) only within a clinical trial. High remission rates have been consistently observed with varied CART19 products and treatment platforms, but durability of remissions and thus the potential role of a consolidative allogeneic stem cell transplant (SCT) is more uncertain and likely to vary by product and population treated. The immunologic characteristics of CARTs that confer high response rates also account for the life-threatening toxicities of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, the severity of which also varies by patient and disease characteristics and product. Further considerations informing a decision to treat include feasibility of leukapheresis and timeline of manufacture, alternative treatment options available, and the appropriateness of a potential consolidative allogeneic SCT. Advances in the field are under way to improve rate and duration of responses and to mitigate toxicity.
- Published
- 2021
23. Long Term Neurologic Outcomes for Patients Receiving CAR-T Therapy for Non-Hodgkin’s Lymphoma Who Developed Severe Neurotoxicity
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Herman van Besien, David L. Porter, Sunita D. Nasta, Jakub Svoboda, Stefan K. Barta, Stephen J. Schuster, Elise Chong, Lauren Hollander, Colleen Kucharczuk, Alison Carulli, Edward A. Stadtmauer, Alfred L. Garfall, Noelle V. Frey, and Daniel J. Landsburg
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
24. The Effect of Donor Graft Cryopreservation on Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center for International Blood and Marrow Transplant Research Analysis. Implications during the COVID-19 Pandemic
- Author
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Jack W. Hsu, Mary M. Horowitz, Bronwen E. Shaw, Nirali N. Shah, John R. Wingard, Brent R. Logan, Nosha Farhadfar, Galen E. Switzer, Noelle V. Frey, Steven M. Devine, Hemant S. Murthy, Stephanie Bo-Subait, Joshua D. Schwanke, Steven C. Goldstein, Stephen R. Spellman, and Hillard M. Lazarus
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Context (language use) ,Hematopoietic stem cell transplantation ,Gastroenterology ,Article ,Cryopreservation ,Bone Marrow ,Internal medicine ,Clinical endpoint ,Humans ,Immunology and Allergy ,Medicine ,Pandemics ,Transplantation ,SARS-CoV-2 ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,COVID-19 ,Cell Biology ,Hematology ,medicine.anatomical_structure ,Cohort ,Molecular Medicine ,Bone marrow ,business - Abstract
The COVID-19 pandemic has resulted in the increased use of cryopreserved grafts for allogeneic hematopoietic cell transplantation (HCT). However, information about the effect of cryopreservation on outcomes for patients receiving allogeneic donor grafts is limited. We evaluated outcomes of HCT recipients who received either fresh or cryopreserved allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) grafts reported to the Center for International Blood and Marrow Transplant Research. A total of 7397 patients were included in the analysis. Recipients of cryopreserved graft were divided into 3 cohorts based on graft source: HLA-matched related PBSC donors (n = 1051), matched unrelated PBSC donors (n = 678), and matched related or unrelated BM donors (n = 154). These patients were propensity score matched with 5514 patients who received fresh allografts. The primary endpoint was engraftment. Multivariate analyses showed no significant increased risk of delayed engraftment, relapse, nonrelapse mortality (NRM), or survival with cryopreservation of BM grafts. In contrast, cryopreservation of related donor PBSC grafts was associated with decreased platelet recovery (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.68 to 0.78; P < .001) and an increased risk of grade II-IV (HR, 1.27; 95% CI, 1.09 to 1.48; P = .002) and grade III-IV (HR, 1.48; 95% CI, 1.19 to 1.84; P < .001) acute graft-versus-host disease. Cryopreservation of unrelated PBSC grafts was associated with delayed engraftment of neutrophils (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001) and platelets (HR, 0.61; 95% CI, 0.56 to 0.66; P < .001) as well as an increased risk of NRM (HR, 1.4; 95% CI, 1.18 to 1.66; P < .001) and relapse (HR, 1.32; 95% CI, 1.11 to 1.58; P = .002) and decreased progression-free survival (HR, 1.36; 95% CI, 1.20 to 1.55; P < .001) and overall survival (OS) (HR, 1.38; 95% CI, 1.22 to 1.58; P < .001). Reasons for cryopreservation were not routinely collected; however, in a subset of unrelated donor HCT recipients, the reason was typically a change in patient condition. Products cryopreserved for patient reasons were significantly associated with inferior OS in multivariate analysis (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). We conclude that cryopreservation is associated with slower engraftment of PBSC grafts, which may be associated with inferior transplantation outcomes in some patient populations. However, the small numbers in the cryopreserved BM cohort and the lack of information on the reason for cryopreservation in all patients suggests that these data should be interpreted with caution, particularly in the context of the risks associated with unexpected loss of a graft during the pandemic. Future analyses addressing outcomes when cryopreservation is universally applied are urgently required.
- Published
- 2021
25. CD22-Targeted CAR-Modified T-Cells Safely Induce Remissions in Children and Young Adults with Relapsed, CD19-Negative B-ALL after Treatment with CD19-Targeted CAR T-Cells
- Author
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Regina M. Myers, Amanda M. DiNofia, Yimei Li, Caroline Diorio, Richard Aplenc, Diane Baniewicz, Jennifer L Brogdon, Colleen Callahan, Boris Engels, Joseph A. Fraietta, Vanessa Gonzalez, Emma Iannone, Allison Barz Leahy, Hongyan Liu, Susan E. McClory, Susan R. Rheingold, Laura Shinehouse, Gerald Wertheim, Lisa Wray, Noelle V. Frey, Shannon L. Maude, and Stephan A. Grupp
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
26. Patient-Reported Outcome Measures in Newly Diagnosed Acute Myeloid Leukemia: An Exploratory Analysis of Real-World Data
- Author
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Xin Wang, Peter Gabriel, Abigail Doucette, Phyllis A. Gimotty, Kelly D. Getz, Samuel Takvorian, Alexander E. Perl, Shannon R. McCurdy, Selina M. Luger, Noelle V. Frey, Alison W. Loren, Elizabeth O. Hexner, Daria V. Babushok, David L. Porter, Keith W. Pratz, and Catherine Lai
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
27. Outer Retinopathy and Microangiopathy in Acute Myelogenous Leukemia
- Author
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Charles G. Miller, Alexander J. Brucker, Linda M. Perry, Benjamin J. Kim, Mary Ellen Martin, Noelle V. Frey, and Tomas S. Aleman
- Subjects
Ophthalmology ,General Medicine - Published
- 2022
28. Central line-associated Rhizobium radiobacter bloodstream infection in two allogeneic hematopoietic cell transplant recipients
- Author
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Rachel E Hartman, Craig W Freyer, Vasilios Athans, Shannon R McCurdy, and Noelle V Frey
- Subjects
Oncology ,Pharmacology (medical) - Abstract
Introduction Rhizobium radiobacter is a gram-negative, opportunistic phytopathogen that rarely causes human infections. We report two cases of Rhizobium radiobacter central line-associated bloodstream infection (CLABSI) in allogeneic hematopoietic cell transplantation (alloHCT) recipients. We review previous reports and common microbiological characteristics associated with this organism. Case reports Two adult males developed R. radiobacter CLABSIs at day +81 and day +77 post-alloHCT. Patient one was asymptomatic on presentation while patient two was febrile. One patient had a polymicrobial infection, which has not been previously described. The presence of high-level ceftazidime resistance in both patients suggests third-generation cephalosporin resistance may be more common than previously recognized. Management and outcome For both patients, microbiologic clearance was achieved through peripherally inserted central catheter removal and initiation of intravenous cefepime. Antibiotic therapy was narrowed to oral levofloxacin for a total 14-day course from the time of first negative blood culture. There has been no subsequent recurrence of R. radiobacter infection at 12 and 5 months of follow-up for patients one and two, respectively. Discussion These two cases add to the scant literature characterizing R. radiobacter infection following alloHCT. Immunosuppressive agents for graft-versus-host disease prophylaxis may have predisposed these patients to R. radiobacter infection. Our reports, and previously reported cases, suggest R. radiobacter exhibits low virulence, mild symptom burden, and does not confer a high mortality risk. In the alloHCT setting, further accumulation of cases is needed to aid in understanding clinical features and characteristics of R. radiobacter infection.
- Published
- 2023
29. Frailty Phenotype Declines in Older Patients after Allogeneic Transplantation and Predicts Subsequent Overall Survival
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Shannon R. McCurdy, Shannon H. Gier, Saar Gill, Mary Ellen Martin, Catherine Lai, Noelle V. Frey, Elizabeth O. Hexner, Selina M. Luger, David L. Porter, Alison W. Loren, and Phyllis Gimotty
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
30. Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia
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Saar Gill, Vanessa Vides, Noelle V. Frey, Elizabeth O. Hexner, Susan Metzger, Megan O'Brien, Wei-Ting Hwang, Jennifer L. Brogdon, Megan M. Davis, Joseph A. Fraietta, Avery L. Gaymon, Whitney L. Gladney, Simon F. Lacey, Anne Lamontagne, Anthony R. Mato, Marcela V. Maus, J. Joseph Melenhorst, Edward Pequignot, Marco Ruella, Maksim Shestov, John C. Byrd, Stephen J. Schuster, Donald L. Siegel, Bruce L. Levine, Carl H. June, and David L. Porter
- Subjects
Neoplasm, Residual ,Pyrimidines ,hemic and lymphatic diseases ,T-Lymphocytes ,Antigens, CD19 ,Humans ,Pyrazoles ,Hematology ,Prospective Studies ,Leukemia, Lymphocytic, Chronic, B-Cell ,Disease-Free Survival - Abstract
In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.
- Published
- 2022
31. Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies
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Yimei Li, Wei-Ting Hwang, Shannon L. Maude, David T. Teachey, Noelle V. Frey, Regina M. Myers, Allison Barz Leahy, Hongyan Liu, David L. Porter, Stephan A. Grupp, and Pamela A. Shaw
- Subjects
Cancer Research ,Clinical Trials as Topic ,Receptors, Chimeric Antigen ,Oncology ,Neoplasms ,T-Lymphocytes ,Hematopoietic Stem Cell Transplantation ,Humans ,Immunotherapy, Adoptive ,Article - Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.
- Published
- 2022
32. Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia
- Author
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Xinhe Shan, Elizabeth O. Hexner, Noelle V. Frey, Daniel J. Landsburg, Simon F. Lacey, Carl H. June, Saar Gill, Sunita D. Nasta, Jakub Svoboda, Edward A. Stadtmauer, Anthony R. Mato, Alison W. Loren, Elizabeth Veloso, Avery L. Gaymon, Wei-Ting Hwang, Bruce L. Levine, Stephen J. Schuster, J. Joseph Melenhorst, David L. Porter, and Edward Pequignot
- Subjects
Male ,Cart ,Oncology ,Cancer Research ,medicine.medical_specialty ,T-Lymphocytes ,Antigens, CD19 ,Dose-Response Relationship, Immunologic ,Relapsed chronic lymphocytic leukemia ,Immunotherapy, Adoptive ,immune system diseases ,Recurrence ,Internal medicine ,Long term outcomes ,medicine ,Humans ,In patient ,Aged ,Receptors, Chimeric Antigen ,business.industry ,ORIGINAL REPORTS ,Middle Aged ,Leukemia, Lymphocytic, Chronic, B-Cell ,Progression-Free Survival ,Chimeric antigen receptor ,Survival Rate ,Dose optimization ,Female ,Refractory Chronic Lymphocytic Leukemia ,Cytokine Release Syndrome ,business - Abstract
PURPOSE To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups ( P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not ( P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR ( P < .0001). Toxicity was comparable in both dose groups. CONCLUSION In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.
- Published
- 2020
33. Cardiovascular Effects of CAR T Cell Therapy
- Author
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Joseph R. Carver, Yu Kang, Noelle V. Frey, Marielle Scherrer-Crosbie, Amanda M. Smith, and Bénédicte Lefebvre
- Subjects
CAR T cells ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.medical_specialty ,Acute coronary syndrome ,cardio-oncology ,business.industry ,cardiovascular ,Incidence (epidemiology) ,Retrospective cohort study ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lcsh:RC254-282 ,Cytokine release syndrome ,Oncology ,lcsh:RC666-701 ,Interquartile range ,Internal medicine ,Heart failure ,medicine ,cardiovascular diseases ,Cardiology and Cardiovascular Medicine ,Prospective cohort study ,business ,Mace - Abstract
Background Anti-CD19 chimeric antigen receptor (CAR) T cell therapy holds great promise in the treatment of patients with hematologic malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CAR T cell therapy. Objectives The aim of this study was to define the occurrence of major adverse cardiovascular events (MACE) in adult patients treated with CAR T cell therapy and assess the relationships among clinical factors, echocardiographic parameters, laboratory values, and cardiovascular outcomes. Methods Baseline clinical, laboratory, and echocardiographic parameters were collected in 145 adult patients undergoing CAR T cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and de novo cardiac arrhythmia. Baseline parameters associated with MACE were identified using Cox proportional cause-specific hazards regression analysis. Results Thirty-one patients had MACE (41 events) at a median time of 11 days (interquartile range: 6 to 151 days) after CAR T cell infusion. The median follow-up period was 456 days (interquartile range: 128 to 1,214 days). Sixty-one patients died. Cytokine release syndrome (CRS) occurred 176 times in 104 patients; the median time to CRS was 6 days (interquartile range: 1 to 8 days). The Kaplan-Meier estimates for MACE and CRS at 30 days were 17% and 53%, respectively. The Kaplan-Meier estimates for survival at 1 year was 71%. Multivariable Cox proportional cause-specific hazards regression analysis determined that baseline creatinine and grade 3 or 4 CRS were independently associated with MACE. Conclusions Patients treated with CAR T cell therapy are at an increased risk for MACE and may benefit from cardiovascular surveillance. Further large prospective studies are needed to confirm the incidence and risk factors predictive of MACE.
- Published
- 2020
34. Venous thromboembolism following pegaspargase in adults receiving antithrombin supplementation
- Author
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Alison Carulli, Shannon R. McCurdy, Alexander E. Perl, Mitchell E. Hughes, Noelle V. Frey, Saar Gill, Selina M. Luger, Elizabeth O. Hexner, Alison W. Loren, Keith W. Pratz, Tracy M. Krause, Mary Ellen Martin, James K. Mangan, David L. Porter, Craig W. Freyer, Alex Ganetsky, and Colleen Timlin
- Subjects
Adult ,Cancer Research ,Asparaginase ,medicine.medical_specialty ,Lymphoblastic Leukemia ,Gastroenterology ,Antithrombins ,Polyethylene Glycols ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,PEG ratio ,medicine ,Humans ,Prospective Studies ,cardiovascular diseases ,Pegaspargase ,business.industry ,Antithrombin ,hemic and immune systems ,Venous Thromboembolism ,Hematology ,equipment and supplies ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Dietary Supplements ,business ,Venous thromboembolism ,030215 immunology ,medicine.drug - Abstract
Pegaspargase (PEG) increases venous thromboembolism (VTE) in acute lymphoblastic leukemia (ALL) potentially due to depletion of anticoagulation factors, including antithrombin (AT). The benefit and cost of AT supplementation in adults is unclear. We aimed to characterize VTE incidence and risk factors following AT and determine the characteristics and costs of supplementation. Fifty-three adults received PEG and AT. VTE occurred in 21% (grade ≥3 8%). T cell ALL and patients receiving prednisone during induction were at highest risk. Repeat AT levels post supplementation were subtherapeutic forty-four percent of the time. A median of 18 days elapsed between PEG and two sequential therapeutic AT levels despite supplementation. Patients received a median of 2 AT doses per PEG dose at a median cost of $11,145. VTE remains common in adults despite AT supplementation. More aggressive AT supplementation may reduce VTE but warrant prospective evaluation given the significant cost.
- Published
- 2020
35. Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
- Author
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Nathan Singh, Xueqing Maggie Lu, Matthew D. Weitzman, Noelle V. Frey, Marco Ruella, Pranali Ravikumar, Shelley L. Berger, Sangya Agarwal, Olga Shestova, Stephan A. Grupp, Elena Orlando, Katharina E. Hayer, Seok Jae Hong, Shannon L. Maude, Shunichiro Kuramitsu, Ophir Shalem, Carl H. June, Raymone Pajarillo, Saar Gill, Karen Thudium Mueller, Charly R. Good, and Yong Gu Lee
- Subjects
0301 basic medicine ,Receptors, Chimeric Antigen ,business.industry ,Receptors, Death Domain ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Chimeric antigen receptor ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Antigen ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Humans ,Signal transduction ,Receptor ,business ,Cytotoxicity ,Gene ,Progressive disease ,Signal Transduction - Abstract
Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. Significance: Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy. See related commentary by Green and Neelapu, p. 492.
- Published
- 2020
36. Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia
- Author
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Nirav N. Shah, Elizabeth O. Hexner, Selina M. Luger, Pamela A. Shaw, David L. Porter, Carl H. June, Simon F. Lacey, Alison W. Loren, J. Joseph Melenhorst, Joan Gilmore, Bruce L. Levine, Saar Gill, Stephan A. Grupp, Noelle V. Frey, Alexander E. Perl, Edward Pequignot, James K. Mangan, and Shannon L. Maude
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Receptors, Antigen, T-Cell ,Immunotherapy, Adoptive ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Antigen ,medicine ,Humans ,Receptor ,Survival rate ,Aged ,Chemotherapy ,business.industry ,Age Factors ,Immunotherapy ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Chimeric antigen receptor ,Survival Rate ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Chimeric Antigen Receptor T-Cell Therapy ,business - Abstract
PURPOSE The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.
- Published
- 2020
37. CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration
- Author
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Christopher L. Nobles, John K. Everett, Joseph A. Fraietta, Bruce L. Levine, Noelle V. Frey, Don L. Siegel, Shantan Reddy, Carl H. June, Stephan A. Grupp, J. Joseph Melenhorst, David L. Porter, Simon F. Lacey, Shannon L. Maude, Scott Sherrill-Mix, Saar Gill, and Frederic D. Bushman
- Subjects
Male ,0301 basic medicine ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,T cell ,Antigens, CD19 ,Genetic Vectors ,Receptors, Antigen, T-Cell ,Biology ,Immunotherapy, Adoptive ,CD19 ,Viral vector ,Insertional mutagenesis ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,hemic and lymphatic diseases ,medicine ,Humans ,Gene ,General Medicine ,Immunotherapy ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Research Article - Abstract
Chimeric antigen receptor–engineered T cells targeting CD19 (CART19) provide an effective treatment for pediatric acute lymphoblastic leukemia but are less effective for chronic lymphocytic leukemia (CLL), focusing attention on improving efficacy. CART19 harbor an engineered receptor, which is delivered through lentiviral vector integration, thereby marking cell lineages and modifying the cellular genome by insertional mutagenesis. We recently reported that vector integration within the host TET2 gene was associated with CLL remission. Here, we investigated clonal population structure and therapeutic outcomes in another 39 patients by high-throughput sequencing of vector-integration sites. Genes at integration sites enriched in responders were commonly found in cell-signaling and chromatin modification pathways, suggesting that insertional mutagenesis in these genes promoted therapeutic T cell proliferation. We also developed a multivariate model based on integration-site distributions and found that data from preinfusion products forecasted response in CLL successfully in discovery and validation cohorts and, in day 28 samples, reported responders to CLL therapy with high accuracy. These data clarify how insertional mutagenesis can modulate cell proliferation in CART19 therapy and how data on integration-site distributions can be linked to treatment outcomes.
- Published
- 2019
38. SARS-CoV-2 Spike-Specific T-Cell Responses in Patients With B-Cell Depletion Who Received Chimeric Antigen Receptor T-Cell Treatments
- Author
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Wei-Ting Hwang, Noelle V. Frey, Wenzhao Meng, Kalpana Parvathaneni, Ali Naji, Vijay Bhoj, and Kyabeth Torres-Rodriguez
- Subjects
Cancer Research ,2019-20 coronavirus outbreak ,B-Lymphocytes ,Receptors, Chimeric Antigen ,Coronavirus disease 2019 (COVID-19) ,business.industry ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,T cell ,T-Lymphocytes ,COVID-19 ,Virology ,Immunotherapy, Adoptive ,Chimeric antigen receptor ,B cell depletion ,medicine.anatomical_structure ,Oncology ,Spike Glycoprotein, Coronavirus ,medicine ,Research Letter ,Humans ,Spike (database) ,In patient ,business - Abstract
This cohort study examines the ability of patients receiving chimeric antigen receptor T-cell treatments to mount T-cell immunity in response to messenger RNA vaccines for severe acute respiratory syndrome coronavirus 2 despite substantial B-cell depletion.
- Published
- 2021
39. Author Correction: Decade-long leukaemia remissions with persistence of CD4+ CAR T cells
- Author
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J. Joseph Melenhorst, Gregory M. Chen, Meng Wang, David L. Porter, Changya Chen, McKensie A. Collins, Peng Gao, Shovik Bandyopadhyay, Hongxing Sun, Ziran Zhao, Stefan Lundh, Iulian Pruteanu-Malinici, Christopher L. Nobles, Sayantan Maji, Noelle V. Frey, Saar I. Gill, Alison W. Loren, Lifeng Tian, Irina Kulikovskaya, Minnal Gupta, David E. Ambrose, Megan M. Davis, Joseph A. Fraietta, Jennifer L. Brogdon, Regina M. Young, Anne Chew, Bruce L. Levine, Donald L. Siegel, Cécile Alanio, E. John Wherry, Frederic D. Bushman, Simon F. Lacey, Kai Tan, and Carl H. June
- Subjects
Multidisciplinary - Published
- 2022
40. Consolidation Therapy with Blinatumomab Improves Overall Survival in Newly Diagnosed Adult Patients with B-Lineage Acute Lymphoblastic Leukemia in Measurable Residual Disease Negative Remission: Results from the ECOG-ACRIN E1910 Randomized Phase III National Cooperative Clinical Trials Network Trial
- Author
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Mark R. Litzow, Zhuoxin Sun, Elisabeth Paietta, Ryan J. Mattison, Hillard M Lazarus, Jacob M. Rowe, Daniel A. Arber, Charles G. Mullighan, Cheryl L Willman, Yanming Zhang, Matthew Wieduwilt, Michaela Liedtke, Julie Bergeron, Keith W. Pratz, Shira Dinner, Noelle V. Frey, Steven D. Gore, Bhavana Bhatnagar, Ehab L. Atallah, Geoffrey L. Uy, Deepa Jeyakumar, Tara L. Lin, Richard F. Little, Selina M. Luger, and Martin S. Tallman
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
41. A Bridge To CAR
- Author
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Noelle V, Frey
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2022
42. Characterizing the Incidence of Pneumonitis in Haploidentical Vs. HLA-Matched Allogeneic Hematopoietic Stem Cell Transplants Receiving Total Body Irradiation
- Author
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Shannon R. McCurdy, Jacob A Radcliff, Danielle A. Cenin, Noelle V. Frey, Daria V. Babushok, Mary Ellen Martin, Elizabeth O. Hexner, Shwetha H. Manjunath, Alexander E. Perl, Mitchell E. Hughes, Saar Gill, John P. Plastaras, Edward A. Stadtmauer, Craig W. Freyer, Keith W. Pratz, Amit Maity, David L. Porter, Selina M. Luger, Alison W. Loren, Alison Carulli, and Colleen Timlin
- Subjects
Transplantation ,business.industry ,Incidence (epidemiology) ,Hematopoietic stem cell ,Cell Biology ,Hematology ,Human leukocyte antigen ,Total body irradiation ,medicine.disease ,medicine.anatomical_structure ,Immunology ,medicine ,Molecular Medicine ,Immunology and Allergy ,business ,Pneumonitis - Published
- 2021
43. Hypogammaglobulinemia and Infection Risk in Chronic Lymphocytic Leukemia (CLL) Patients Treated with CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cells
- Author
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Megan Davis, Lester Lledo, Noelle V. Frey, Don L. Siegel, Bruce L. Levine, Saar Gill, Wei-Ting Hwang, Elizabeth O. Hexner, Natalie F. Uy, David L. Porter, Alison W. Loren, Stephan A. Grupp, J. Joseph Melenhorst, Simon F. Lacey, Joan Gilmore, Stephen J. Schuster, Edward Pequignot, Joseph A. Fraietta, and Carl H. June
- Subjects
Infection risk ,biology ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,CD19 ,Chimeric antigen receptor ,Hypogammaglobulinemia ,biology.protein ,Medicine ,Car t cells ,business ,health care economics and organizations - Abstract
INTRODUCTION Anti-CD19 CAR T-cell immunotherapy is promising for patients with relapsed/refractory CLL. Hypogammaglobinemia can result from normal CD19+ B-cell depletion by CAR-T cells. CLL patients are already at risk for infections due to impaired immune function, lymphodepletion prior to CAR-T cells infusion, and immunosuppressive therapies. Intravenous immunoglobulin (IVIG) is used to manage hypogammaglobulinemia, although standard criteria for IVIG administration in this setting has not been established. We studied the incidence of hypogammaglobinemia and report infectious complications, risk factors, IVIG use, and clinical outcomes for CLL patients treated with anti-CD19 CAR-T cells. METHODS Adult CLL patients who received CD19-directed CAR-T therapy in 3 clinical trials (NCT01029366, NCT01747486, NCT02640209) from July 2010 to February 2020 were included. We reviewed demographics, available IgG levels, IVIG use, and clinical outcomes with a particular focus on infectious complications. Hypogammaglobulinemia was defined as IgG RESULTS Records of 71 adult patients with CLL were reviewed; 4 were excluded from further analysis as they did not have IgG levels after CAR-T. The median age at time of CAR-T was 63 years (range 43-78 years). 31 patients (46%) were alive, 31 (46%) were deceased, and 5 (7%) were lost to follow up at time of review. Median follow up for all patients was 33 months (range 2-114 months). Of the 55 patients with an IgG level prior to CAR-T infusion, 24 (44%) had hypogammaglobulinemia at baseline After CAR-T infusion, 54 of 67 patients (81%) developed new or persistent hypogammaglobulinemia, and 40 of these patients (74%) received IVIG (Table 1). Forty-eight patients (72%) received at least one infusion of IVIG after CAR-T. Median time to initiation of IVIG after CAR-T infusion was 2.8 months (range 0.1-71.2 months). IVIG was used in 29 of 35 (83%) responders (defined as PR or CR) vs 19 of 32 (59%) in non-responders (defined as NR or PD) (p=0.056). There was no difference in survival observed based on whether or not patients had hypogammaglobulinemia (Figure). 42 patients (63%) had documented infections not related to chemotherapy-induced neutropenia. Fifteen (22%) had one documented infection, and 27 (40%) had more than one documented infection. There were 13 infections documented in patients who did not have hypogammaglobulinemia; the most common were ENT/sinus infections (5), bacteremia (2), URI (2), and other (2). There were 94 infections documented in patients who developed or had persistent hypogammaglobulinemia; the most common were lower respiratory tract infection/pneumonia (21), URI (20), and ENT/sinus infections (13). Complete and partial responders had more infections compared to non-responders or those who progressed (p = 0.01). Patients with hypogammaglobulinemia after CAR-T had an average of 1.74 (range 0-15) infections vs 1 (range 0-3) in patients without hypogammaglobulinemia. Patients who received IVIG had more infections (p=0.003); without IVIG the average number of infections was 0.58 (range 0-3), and with IVIG, the average number of infections was 2.00 (range 0-15). CONCLUSION Evaluating clinical outcomes with infections after CAR-T and potential strategies to minimize infection risk may improve morbidity and mortality in CLL patients. Use of IVIG was driven by individual practice, with heterogeneity regarding indication, frequency, and duration of treatment, though there was no difference in patient characteristics or response in patients who did or did not develop hypogammaglobulinemia. Patients who responded to CAR-T had more frequent infections, as might be expected in the setting of transient or persistent B- cell aplasia or hypoplasia. Patients who had more infections were more likely to receive IVIG. Further studies to define criteria for IVIG repletion in CLL patients treated with CD19-directed CAR-T cells may be incorporated in a standard clinical management algorithm. Table 1 Disclosures Frey: Amgen: Consultancy, Honoraria; Syntax: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria. Davis:Tmunity Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding; Cellares Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Institutes for Biomedical Research: Patents & Royalties. Hexner:Blueprint Medicines Corporation: Other: serves on a data safety monitoring committee, Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding; American Board of Internal Medicine: Other: member of the hematology exam committee. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Gill:Fate: Consultancy; Sensei: Consultancy; Aileron: Consultancy; Tmunity Therapeutics: Research Funding; Carisma Therapeutics: Patents & Royalties, Research Funding; Novartis: Research Funding. Grupp:Servier: Research Funding; Kite/Gilead: Research Funding; Roche: Consultancy; GlaxoSmithKline: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Jazz: Other: SSC; Adaptimmune: Other: SAB; TCR2: Other: SAB; Cellectis: Other; Juno/BMS: Other; Janssen/JnJ: Consultancy; CRISPR Therapeutics/Vertex Pharmaceuticals: Other; Allogene: Other; Novartis: Consultancy, Other: SSC, Research Funding. Melenhorst:Johnson & Johnson: Consultancy, Other: Speaker; Novartis: Other: Speaker, Research Funding; Kite Pharma: Research Funding; IASO Biotherapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida Therapeutics: Consultancy; Simcere of America: Consultancy. Lacey:Novartis: Patents & Royalties: CAR T cells, Research Funding; Tmunity: Research Funding; Cabaletta: Research Funding; Carisma: Research Funding. Fraietta:Tmunity: Research Funding. Hwang:Novartis: Research Funding; Tmunity Therapeutics: Research Funding. Siegel:Novartis: Patents & Royalties; Tmunity: Patents & Royalties; Poseida: Membership on an entity's Board of Directors or advisory committees; Vetigenics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Levine:Terumo: Consultancy; Novartis: Consultancy, Patents & Royalties: Dr. Levine has a patent Methods for treatment of cancer (US 8906682) (US 8916381)(US 9101584) with royalties paid to University of Pennsylvania, a patent Compositions for treatment of cancer (US 8911993) (US 9102761) (US 9102760) with royalties paid to U; Lilly Asia Ventures: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees; Patheon: Membership on an entity's Board of Directors or advisory committees; Immuneel: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Ori Biotech: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Current equity holder in private company, Research Funding. June:Bluesphere Bio: Membership on an entity's Board of Directors or advisory committees; Cabaletta Bio: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cellares: Membership on an entity's Board of Directors or advisory committees; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; DeCART Therapeutics: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Current equity holder in private company; Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Ziopharm Oncology: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Porter:Tmunity: Patents & Royalties; Novartis: Honoraria, Other: Advisory board, Patents & Royalties: CAR T cells for CD19+ malignancies, Research Funding; American Board of Internal Medicine: Other: Member, exam writing committee (end date Oct 2019); National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Advisory board; Genentech/Roche: Current equity holder in publicly-traded company, Other: Spouse employment (ended Sept 2020); her salary includes stock/options; Glenmark: Other: Advisory board; Adicet bio: Other: Advisory board; Incyte: Other: Advisory board; Kite/Gilead: Other: Advisory board. OffLabel Disclosure: CAR T cells for CLL
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- 2020
44. Decade-long remissions of leukemia sustained by the persistence of activated CD4+ CAR T-cells
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Irina Kulikovskaya, Christopher L. Nobles, Anne Chew, Shovik Bandyopadhyay, Noelle V. Frey, David L. Porter, David E Ambrose, Saar Gill, Lifeng Tian, Joseph A. Fraietta, Jennifer Brogdon, Sayantan Maji, Gregory M. Chen, Simon F. Lacey, Regina M. Young, Kai Tan, Peng Gao, Meng Wang, J. Joseph Melenhorst, Frederic D. Bushman, Cecile Alanio, Bruce L. Levine, Iulian Pruteanu-Malinici, Carl H. June, Don L. Siegel, E. J. Wherry, Megan Davis, and Minnal Gupta
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Leukemia ,Immunology ,medicine ,Car t cells ,Biology ,medicine.disease ,Persistence (computer science) - Abstract
The adoptive transfer of T lymphocytes reprogrammed to target tumor cells has demonstrated significant potential in various malignancies. However, little is known about the long-term potential and the clonal stability of the infused cells. Here, we studied the longest persisting CD19 redirected chimeric antigen receptor (CAR) T cells to date in two chronic lymphocytic leukemia (CLL) patients who achieved a complete remission in 2010. CAR T-cells were still detectable up to 10+ years post-infusion, with sustained remission in both patients. Surprisingly, a prominent, highly activated CD4+ population developed in both patients during the years post-infusion, dominating the CAR T-cell population at the late time points. This transition was reflected in the stabilization of the clonal make-up of CAR T-cells with a repertoire dominated by few clones. Single cell multi-omics profiling via Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) with TCR sequencing of CAR T-cells obtained 9.3 years post-infusion demonstrated that these long-persisting CD4+ CAR T-cells exhibited cytotoxic characteristics along with strong evidence of ongoing functional activation and proliferation. Our data provide novel insight into the CAR T-cell characteristics associated with long-term remission in leukemia.
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- 2021
45. Decade-long leukaemia remissions with persistence of CD4
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J Joseph, Melenhorst, Gregory M, Chen, Meng, Wang, David L, Porter, Changya, Chen, McKensie A, Collins, Peng, Gao, Shovik, Bandyopadhyay, Hongxing, Sun, Ziran, Zhao, Stefan, Lundh, Iulian, Pruteanu-Malinici, Christopher L, Nobles, Sayantan, Maji, Noelle V, Frey, Saar I, Gill, Alison W, Loren, Lifeng, Tian, Irina, Kulikovskaya, Minnal, Gupta, David E, Ambrose, Megan M, Davis, Joseph A, Fraietta, Jennifer L, Brogdon, Regina M, Young, Anne, Chew, Bruce L, Levine, Donald L, Siegel, Cécile, Alanio, E John, Wherry, Frederic D, Bushman, Simon F, Lacey, Kai, Tan, and Carl H, June
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CD4-Positive T-Lymphocytes ,Leukemia ,Receptors, Chimeric Antigen ,Time Factors ,Antigens, CD19 ,Humans ,Cell Separation ,CD8-Positive T-Lymphocytes ,Immunotherapy, Adoptive - Abstract
The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers
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- 2021
46. Paraneoplastic Focal Segmental Glomerulosclerosis Associated With Acute Lymphocytic Leukemia
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Anushya Jeyabalan, Jonathan J. Hogan, Noelle V. Frey, Matthew D. Palmer, and Abdallah S. Geara
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Pathology ,medicine.medical_specialty ,Focal segmental glomerulosclerosis ,Nephrology ,business.industry ,Acute lymphocytic leukemia ,medicine ,medicine.disease ,business ,Nephrology Round - Published
- 2019
47. Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy
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Noelle V. Frey and David L. Porter
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medicine.drug_class ,T cell ,Cell- and Tissue-Based Therapy ,CD19 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Tocilizumab ,otorhinolaryngologic diseases ,medicine ,Humans ,B cell ,Transplantation ,Receptors, Chimeric Antigen ,biology ,business.industry ,Hematology ,medicine.disease ,Receptor antagonist ,Chimeric antigen receptor ,Cytokine release syndrome ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Chimeric Antigen Receptor T-Cell Therapy ,Cytokine Release Syndrome ,business ,030215 immunology - Abstract
Chimeric antigen receptor (CAR)-modified T cells (CAR-Ts) targeting CD19 have resulted in unprecedented durable remissions for patients with relapsed and refractory B cell malignancies. Cytokine release syndrome (CRS), resulting from rapid immune activation induced by CAR-Ts, is the most significant treatment-related toxicity. CRS initially manifests with fever and can progress to life-threatening capillary leak with hypoxia and hypotension. The clinical signs of CRS correlate with T cell activation and high levels of cytokines including IL-6. Tocilizumab, an anti-IL-6 receptor antagonist, is the standard for CRS management, but optimal timing of administration is unclear. The development of a supportive infrastructure by treatment centers is important to maintain safe administration as access expands. Collaborative efforts are underway to harmonize the definition and grading of CRS to allow for better interpretation of toxicities across CAR-T products and clinical trials and allow for informed management algorithms.
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- 2019
48. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells
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Karl S. Peggs, William Y. Go, Noelle V. Frey, Jennifer N. Brudno, Elena Mead, Bianca Santomasso, Rebecca Gardner, Steven Z. Pavletic, Marcelo C. Pasquini, Sattva S. Neelapu, Stephan A. Grupp, Kevin J. Curran, Frederick L. Locke, Daniel W. Lee, Cameron J. Turtle, Marcel R.M. van den Brink, Krishna V. Komanduri, Jae H. Park, Armin Ghobadi, Marcela V. Maus, John F. DiPersio, and Lamis K. Eldjerou
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Oncology ,Transplantation ,medicine.medical_specialty ,business.industry ,T cell ,Hematology ,medicine.disease ,Chimeric antigen receptor ,Clinical trial ,Cell therapy ,03 medical and health sciences ,Cytokine release syndrome ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Chimeric Antigen Receptor T-Cell Therapy ,business ,030215 immunology - Abstract
Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.
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- 2019
49. Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Transplantation and Cellular Therapy
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Shahrukh K. Hashmi, Paul A. Carpenter, Christian Chabannon, Michel Sadelain, Mohamed A. Kharfan-Dabaja, Saad S. Kenderian, Miguel Perales, Ankit Kansagra, Theodore W. Laetsch, Laura Johnston, Noelle V. Frey, John F. DiPersio, David L. Porter, Chiara Bonini, Veronika Bachanova, Catherine M. Bollard, Bipin N. Savani, Helen E. Heslop, Ghulam J. Mufti, Steven Z. Pavletic, Partow Kebriaei, Elizabeth J. Shpall, Mohamad Mohty, Merav Bar, Nirali N. Shah, David G. Maloney, Mahmoud Aljurf, Elad Jacoby, John A. Barrett, Arnon Nagler, Dennis A. Gastineau, Mark R. Litzow, Krishna V. Komanduri, Ali Bazarbachi, Stephan A. Grupp, Saar Gill, Michael Hudecek, Joshua A. Hill, Hien D. Liu, Armin Ghobadi, and Leslie A. Andritsos
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Oncology ,Transplantation ,medicine.medical_specialty ,business.industry ,Genetic enhancement ,medicine.medical_treatment ,T cell ,Hematology ,Disease ,medicine.disease ,Chimeric antigen receptor ,Cell therapy ,03 medical and health sciences ,Leukemia ,0302 clinical medicine ,medicine.anatomical_structure ,Cancer immunotherapy ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,Young adult ,business ,030215 immunology - Abstract
On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
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- 2019
50. Extended CCR5 Blockade for Graft-versus-Host Disease Prophylaxis Improves Outcomes of Reduced-Intensity Unrelated Donor Hematopoietic Cell Transplantation: A Phase II Clinical Trial
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Robin Blauser, Noelle V. Frey, Edward P. Acosta, Edward A. Stadtmauer, Alison W. Loren, David L. Porter, James A. Hoxie, Lisa Crisalli, Robert H. Vonderheide, Selina M. Luger, James K. Mangan, Jessica Mcgraw, Alex Ganetsky, Rosemarie Mick, Elizabeth O. Hexner, and Ran Reshef
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Receptors, CCR5 ,Graft vs Host Disease ,Gastroenterology ,Article ,Maraviroc ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Internal medicine ,medicine ,Humans ,Aged ,Transplantation ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Blockade ,Clinical trial ,Treatment Outcome ,surgical procedures, operative ,Graft-versus-host disease ,chemistry ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,CCR5 Receptor Antagonists ,Female ,Unrelated Donors ,Complication ,business ,030215 immunology - Abstract
Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD. We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies. Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P = .009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P = .037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD. An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.
- Published
- 2019
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