86 results on '"Sindhu Cherian"'
Search Results
2. Myeloid lineage switch following CD7-targeted chimeric antigen receptor T-cell therapy in relapsed/refractory T-cell acute lymphoblastic leukemia
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Ibrahim Aldoss, Parastou Tizro, Davsheen Bedi, James K. Mangan, Mary C. Clark, David Spencer, Joo Y. Song, Sindhu Cherian, Raju Pillai, Young Kim, Nitin Mahajan, Ketevan Gendzekhadze, Mike James, Kenneth Jacobs, Jan Davidson-Moncada, Stephen J. Forman, Huan-You Wang, and Michelle Afkhami
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy
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Vinodh Pillai, Kavitha Muralidharan, Wenzhao Meng, Asen Bagashev, Derek A. Oldridge, Jaclyn Rosenthal, John Van Arnam, Jos J. Melenhorst, Diwakar Mohan, Amanda M. DiNofia, Minjie Luo, Sindhu Cherian, Jonathan R. Fromm, Gerald Wertheim, Andrei Thomas-Tikhonenko, Michele Paessler, Carl H. June, Eline T. Luning Prak, Vijay G. Bhoj, Stephan A. Grupp, Shannon L. Maude, and Susan R. Rheingold
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell product targeting CD19 is approved for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the impact of pretreatment variables, such as CD19 expression level, on leukemic blasts, the presence of CD19– subpopulations, and especially prior CD19-targeted therapy, on the response to CAR T-cell therapy has not been determined. We analyzed 166 patients treated with CAR T-cell therapy at our institution. Eleven patients did not achieve a minimal residual disease (MRD)– deep remission, whereas 67 patients had a recurrence after achieving a MRD– deep remission: 28 patients with CD19+ leukemia and 39 patients with CD19– leukemia. Return of CD19+ leukemia was associated with loss of CAR T-cell function, whereas CD19– leukemia was associated with continued CAR T-cell function. There were no significant differences in efficacy of CAR T cells in CD19-dim B-ALL, compared with CD19-normal or -bright B-ALL. Consistent with this, CAR T cells recognized and lysed cells with very low levels of CD19 expression in vitro. The presence of dim CD19 or rare CD19– events by flow cytometry did not predict nonresponse or recurrence after CAR T-cell therapy. However, prior therapy with the CD19-directed, bispecific T-cell engager blinatumomab was associated with a significantly higher rate of failure to achieve MRD– remission or subsequent loss of remission with antigen escape. Finally, immunophenotypic heterogeneity and lineage plasticity were independent of underlying clonotype and cytogenetic abnormalities.
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- 2019
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4. Durable preservation of antiviral antibodies after CD19-directed chimeric antigen receptor T-cell immunotherapy
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Joshua A. Hill, Elizabeth M. Krantz, Kevin A. Hay, Sayan Dasgupta, Terry Stevens-Ayers, Rachel A. Bender Ignacio, Merav Bar, Joyce Maalouf, Sindhu Cherian, Xueyan Chen, Greg Pepper, Stanley R. Riddell, David G. Maloney, Michael J. Boeckh, and Cameron J. Turtle
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: The long-term effects of CD19-targeted chimeric antigen receptor–modified T-cell immunotherapy (CD19-CARTx) for B-cell malignancies on humoral immunity are unclear. We examined antiviral humoral immunity in 39 adults with B-cell malignancies who achieved durable complete remission without additional therapy for >6 months after CD19-CARTx. Despite CD19+ B-cell aplasia in all patients, the incidence of viral infections occurring >90 days post–CD19-CARTx was low (0.91 infections per person-year). Because long-lived plasma cells are CD19− and should not be direct targets of CD19-targeted chimeric antigen receptor T cells, we tested the hypothesis that humoral immunity was preserved after CD19-CARTx based on linear mixed-effects models of changes in serum total immunoglobulin G (IgG) concentration, measles IgG concentration, and the number of viruses or viral epitopes to which serum IgG was directed (the “antivirome”) using the novel VirScan assay. Samples were tested pre–CD19-CARTx and ∼1, 6, and 12 months post–CD19-CARTx. Although total IgG concentration was lower post–CD19-CARTx (mean change, −17.5%), measles IgG concentration was similar (mean change, 1.2%). Only 1 participant lost measles seroprotection post–CD19-CARTx but had undergone allogeneic hematopoietic cell transplantation before CD19-CARTx. The antivirome was also preserved, with mean absolute losses of 0.3 viruses and 6 viral epitopes detected between pre- and post–CD19-CARTx samples. Most participants gained IgG to ≥2 epitopes for ≥2 viruses, suggesting that humoral immunity to some viruses may be maintained or recover after successful CD19-CARTx. These findings may differ in children. Studies of immunoglobulin replacement and vaccination after CARTx are warranted.
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- 2019
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5. Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy
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Mazyar Shadman, Jordan Gauthier, Kevin A. Hay, Jenna M. Voutsinas, Filippo Milano, Ang Li, Alexandre V. Hirayama, Mohamed L. Sorror, Sindhu Cherian, Xueyan Chen, Ryan D. Cassaday, Brian G. Till, Ajay K. Gopal, Brenda M. Sandmaier, David G. Maloney, and Cameron J. Turtle
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Allogeneic hematopoietic cell transplantation (allo-HCT) is offered to selected patients after chimeric antigen receptor–modified T-cell (CAR-T) therapy. Lymphodepleting chemotherapy and CAR-T therapy have immunosuppressive and immunomodulatory effects that could alter the safety profile of subsequent allo-HCT. We reviewed our experience with 32 adults (acute lymphoblastic leukemia [ALL], n = 19; B-cell non-Hodgkin lymphoma [NHL]/chronic lymphocytic leukemia [CLL], n = 13) who received an allo-HCT after CAR-T therapy, with a focus on posttransplant toxicities. Myeloablative conditioning (MAC) was used in 74% of ALL patients and 39% of NHL/CLL patients. The median time from CAR-T therapy to allo-HCT was 72 days in ALL patients and 122 days in NHL/CLL patients. Cumulative incidences of grade 3-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 25% and 10%, respectively. All patients had neutrophil recovery (median, 18.5 days) and all but 3 had platelet recovery (median, 12 days). Twenty-two percent had viral or systemic fungal infection within 100 days after allo-HCT. The 100-day and 1-year cumulative incidences of NRM were 16% and 21%, respectively, for ALL patients and 15% and 33%, respectively, for NHL/CLL patients. In ALL patients, later utilization of allo-HCT after CAR-T therapy was associated with higher mortality. In NHL/CLL patients, MAC was associated with higher mortality. Toxicities did not exceed the expected incidences in this high-risk population.
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- 2019
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6. Flow cytometric assessment for minimal/measurable residual disease in B lymphoblastic leukemia/lymphoma in the era of immunotherapy
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Xueyan Chen, Qi Gao, Mikhail Roshal, and Sindhu Cherian
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Histology ,Cell Biology ,Pathology and Forensic Medicine - Published
- 2023
7. Mature B‐ and plasma‐cell flow cytometric analysis: A review of the impact of targeted therapy
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Qi Gao, Xueyan Chen, Sindhu Cherian, and Mikhail Roshal
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Histology ,Cell Biology ,Pathology and Forensic Medicine - Abstract
Flow cytometry has been indispensable in diagnosing B cell lymphoma and plasma cell neoplasms. The advances in novel multicolor flow cytometry have also made this technology a robust tool for monitoring minimal/measurable residual disease in chronic lymphocytic leukemia and multiple myeloma. However, challenges using conventional gating strategies to isolate neoplastic B or plasma cells are emerging due to the rapidly increasing number of antibody therapeutics targeting single or multiple classic B/plasma cell-lineage markers, such as CD19, CD20, and CD22 in B cells and CD38 in plasma cells. This review is the first of a two-part series that summarizes the most current targeted therapies used in B and plasma cell neoplasms and proposes detailed alternative approaches to overcome post-targeted therapy analysis challenges by flow cytometry. The second review in this series (Chen et al.) focuses on challenges encountered in the use of targeted therapy in precursor B cell neoplasms.
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- 2022
8. Cerebrospinal fluid flow cytometry and risk of central nervous system relapse after hyperCVAD in adults with acute lymphoblastic leukemia
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Kelsey‐Leigh A. Garcia, Sindhu Cherian, Philip A. Stevenson, Christen H. Martino, Andrei R. Shustov, Pamela S. Becker, Mary‐Elizabeth M. Percival, Vivian G. Oehler, Anna B. Halpern, Roland B. Walter, Johnnie J. Orozco, Siobán B. Keel, Elihu H. Estey, and Ryan D. Cassaday
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Adult ,Central Nervous System ,Cancer Research ,Oncology ,Recurrence ,Antineoplastic Combined Chemotherapy Protocols ,Cytarabine ,Humans ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Flow Cytometry - Abstract
Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited.This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment.Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra-CSF chemotherapy (P.001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF- (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF- patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2-10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event-free survival.MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility.
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- 2021
9. Comparison of Blood Counts and Markers of Inflammation and Coagulation in Patients With and Without COVID-19 Presenting to the Emergency Department in Seattle, WA
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Daniel E. Sabath, Molly C. Reid, Kerstin L. Edlefsen, Sindhu Cherian, and Christopher M Chandler
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Adult ,Male ,medicine.medical_specialty ,Neutrophils ,Lymphocyte ,Serum albumin ,030204 cardiovascular system & hematology ,Gastroenterology ,Laboratory testing ,Leukocyte Count ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Severity of illness ,medicine ,Humans ,Platelet ,Lymphocyte Count ,Lymphocytes ,030212 general & internal medicine ,Neutrophil to lymphocyte ratio ,Blood Coagulation ,Inflammation ,biology ,medicine.diagnostic_test ,Platelet Count ,SARS-CoV-2 ,Emergency department ,business.industry ,COVID-19 ,Complete blood count ,Red blood cell distribution width ,Original Articles ,General Medicine ,Middle Aged ,Blood Cell Count ,medicine.anatomical_structure ,biology.protein ,Hemoglobin ,Emergency Service, Hospital ,business ,Biomarkers ,AcademicSubjects/MED00690 - Abstract
Objectives We compared complete blood count (CBC) with differential and markers of inflammation and coagulation in patients with and without coronavirus disease 2019 (COVID-19) presenting to emergency departments in Seattle, WA. Methods We reviewed laboratory values for 1 week following each COVID-19 test for adult patients who received a standard severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) test before April 13, 2020. Results were compared by COVID-19 status and clinical course. Results In total 1,027 patients met inclusion criteria. Patients with COVID-19 (n = 155) had lower leukocytes (P < .0001), lymphocytes (P < .0001), platelets (P < .0001), and higher hemoglobin (P = .0140) than those without, but absolute differences were small. Serum albumin was lower in patients with COVID-19 (P < .0001) and serum albumin, neutrophil to lymphocyte ratio (NLR), and red cell distribution width (RDW) were each associated with disease severity. NLR did not differ between patients with COVID-19 and those without (P = .8012). Conclusions Patients with COVID-19 had modestly lower leukocyte, lymphocyte, and platelet counts and higher hemoglobin values than patients without COVID-19. The NLR, serum albumin, and RDW varied with disease severity, regardless of COVID-19 status.
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- 2021
10. A Cytometrist's Guide to Coordinating and Performing Effective <scp>COVID</scp> ‐19 Research
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Jonathan M. Irish, Cherie Green, Pratip K. Chattopadhyay, Evan R. Jellison, Virginia Litwin, Guido Ferrari, Andrew Filby, and Sindhu Cherian
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0301 basic medicine ,SARS‐CoV2 ,immune monitoring ,Biomedical Research ,Histology ,Process management ,Coronavirus disease 2019 (COVID-19) ,Information Dissemination ,Pathology and Forensic Medicine ,Translational Research, Biomedical ,03 medical and health sciences ,Biosafety ,0302 clinical medicine ,Procurement ,COVID‐19 ,Commentaries ,Humans ,SARS-CoV-2 ,pandemic ,flow cytometry ,COVID-19 ,Cell Biology ,Containment of Biohazards ,Research findings ,Data sharing ,030104 developmental biology ,Workflow ,Infectious disease (medical specialty) ,030220 oncology & carcinogenesis ,Commentary ,Business - Abstract
Cytometry is playing a crucial role in addressing the COVID‐19 pandemic. In this commentary ‐ written by a variety of stakeholders in the cytometry, immunology, and infectious disease communities ‐ we review cytometry's role in the COVID‐19 response, and discuss workflow issues critical to planning and executing effective research in this emerging field. We discuss sample procurement and processing, biosafety, technology options, data sharing, and the translation of research findings into clinical environments. This article is protected by copyright. All rights reserved.
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- 2020
11. Multiparameter Flow Cytometry (MFC) of Cerebrospinal Fluid (CSF) from Adults Receiving Hypercvad for Acute Lymphoblastic Leukemia/Lymphoma (ALL) Identifies Patients at Higher Risk of Central Nervous System (CNS) Relapse: A Single-Center Retrospective Analysis
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Elihu H. Estey, Andrei R. Shustov, Johnnie J. Orozco, Roland P Walter, Christen N. Martino, Colin D. Godwin, Sioban Keel, Vivian G. Oehler, Mary-Beth M. Percival, Pamela S. Becker, Ryan D. Cassaday, Philip A. Stevenson, Kelsey-Leigh A. Garcia, Anna B. Halpern, and Sindhu Cherian
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medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Immunology ,Hazard ratio ,Context (language use) ,Cell Biology ,Hematology ,Single Center ,Biochemistry ,Chemotherapy regimen ,Internal medicine ,medicine ,Ommaya reservoir ,Cytarabine ,Cumulative incidence ,business ,medicine.drug - Abstract
BACKGROUND: CNS directed chemotherapy (chemo) reduces the risk of CNS relapse of ALL, but the optimal way to measure baseline CNS involvement is controversial. Baseline CSF testing can provide risk stratification and often dictates CNS prophylaxis (ppx) during initial treatment. Despite advances, up to 10% of adults still suffer CNS relapse (Blood 2008;112:1646, Cancer 2014;120:3660). Testing typically focuses on conventional cytospin (CC) of CSF, but CC is limited by interobserver variability and insensitivity (Blood 2014;124:3799). Alternatively, MFC is more sensitive (ASH 2018, #658). A previous study in children with ALL found leukemia detection in the CNS by CC or MFC at diagnosis to be associated with an increased risk of both isolated bone marrow and any CNS relapse (ASH 2018, #657). To our knowledge, this use of MFC has not specifically been studied in hyperCVAD, a commonly used chemotherapy regimen for the initial treatment of adult ALL. We hypothesized that baseline lymphoblast detection in the CSF by MFC is predictive of CNS relapse. METHODS: We included data collected from 11/6/07 to 6/22/20. Patients (pts) ≥18 years old who received ≥4 cycles (equivalent of cycle 2B) of hyperCVAD as first-line therapy were eligible. Pts must have had MFC done on CSF at baseline. Pts with mixed phenotype or insufficient follow-up data were excluded. CNS ppx with hyperCVAD historically uses intra-CSF (ie, intrathecal or intraventricular) methotrexate 12 mg on day 2 and cytarabine 100 mg on day 8 of each cycle for 6-12 doses without cranial radiation, though all patients were treated per physician discretion. CC and MFC results were taken from clinical reports and verified by an independent hematopathologist (Dr. Cherian). Baseline CSF positivity (CSF+) and negativity (CSF-) were defined by MFC, with any percentage of lymphoblasts considered CSF+. COG definitions of CNS status by CC were also used (J Clin Oncol 2016;34:2380). Univariate Cox models evaluated associations to CNS relapse. Kaplan-Meier curves were used to estimate the probabilities of overall survival (OS) and cumulative incidence of CNS relapse. RESULTS: We identified 92 eligible pts. Disease and treatment characteristics are summarized in Table 1, and results of initial CSF testing are shown in Table 2. Twenty-one pts were CSF+ by MFC at baseline: by CC, 6 of these were positive, 6 were negative, 7 were equivocal (ie, morphologic review was unable to rule out blasts), and 2 did not have baseline CC. None were positive by CC but negative by MFC. Eight of 29 (38%) with circulating blasts had a traumatic (>10 RBC/uL of CSF) first lumbar puncture (LP). Of these 8, 4 (50%) were CSF+. Five (5%) pts had an Ommaya reservoir placed during treatment. Pts received a median of 8 doses of intra-CSF chemo (range, 5-52). All but 7 pts (8%) received a combination of methotrexate and cytarabine like above. Twenty CSF+ pts (95%) achieved CSF- after a median of 1 dose of intra-CSF chemo (range, 1-5). Out of the 71 CSF- pts, none became CSF+ during initial treatment despite being tested a median of 5 times (range, 2-10). Eight pts (9%) had CNS relapse (3 isolated, 5 concurrent medullary relapse). Comparisons between baseline CSF testing, intra-CSF treatment, and CNS relapse are shown in Table 2. CSF+ pts received significantly greater doses of intra-CSF chemo. Of the 21 CSF+ pts, 5 (24%) had CNS relapse (2 isolated, 3 concurrent), and out of the 71 CSF- pts, 3 (4%) had CNS relapse (1 isolated, 2 concurrent; p=0.014). Among univariate models of CSF+ vs -, traumatic LP vs not, B vs T lineage, LDH, and WBC, only CSF+ was significantly associated with CNS relapse (hazard ratio 4.8, 95% confidence interval [CI] 1.2-20, p=0.031). Estimated 3-year cumulative incidence of CNS relapse for CSF+ was 15% vs 3.3% for CSF- (Figure 1). Median OS for the whole cohort was not reached, with estimated 3-year OS of 74% (95% CI, 65%-84%). CONCLUSIONS: MFC of CSF is more predictive of CNS relapse risk than CC in the context of front-line hyperCVAD, questioning the use of CC if MFC is performed. Further, CNS relapses were significantly more frequent when CSF+ despite administration of significantly more intra-CSF chemo. Traumatic LP per se did not increase risk of CNS relapse if CSF- by MFC. Surveillance during treatment by MFC in CSF- pts identified no cases of occult CNS relapse, arguing against this routine practice. Future studies should consider incorporating MFC of CSF into risk-adapted CNS-directed treatment strategies. Disclosures Shustov: Seattle Genetics: Research Funding. Becker:Accordant Health Services/Caremark: Membership on an entity's Board of Directors or advisory committees; Cardiff Oncology: Research Funding; SecuraBio: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; JW Pharmaceutical: Research Funding; Glycomimetics: Research Funding; Abbvie: Research Funding; Bristol Myers Squibb: Research Funding; Invivoscribe: Research Funding. Oehler:Takeda: Consultancy; BMS: Consultancy; Pfizer, Inc: Research Funding. Halpern:Bayer: Other; Novartis: Other; Jazz Pharmaceuticals: Other; Imago BioSciences: Other; Tolero Pharmaceuticals: Research Funding. Walter:Amgen: Consultancy, Research Funding; Arog: Research Funding; Argenx: Consultancy; Aptevo: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Agios: Consultancy, Research Funding; StemLine: Research Funding; Selvita: Research Funding; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Kite: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy. Godwin:Pfizer Inc.: Research Funding; Immunogen Inc.: Research Funding. Cassaday:Kite/Gilead: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pfizer: Honoraria, Research Funding.
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- 2020
12. <scp>ICCS</scp> Women in Cytometry—Impact 10 years later: A call to promote gender equity
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Abigail S. Kelliher, Julianne Qualtieri, Melanie O'Donahue, Teri Oldaker, Sindhu Cherian, Maryalice Stetler-Stevenson, Lama Kdouh, Silvia T Bunting, Jonni S. Moore, Heather Harricharran, Katherine Devitt, and Sara Maremont
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Gender Equity ,Gerontology ,Gender equity ,Sex Factors ,Histology ,MEDLINE ,Humans ,Female ,Cell Biology ,Flow Cytometry ,Psychology ,Cytometry ,Pathology and Forensic Medicine - Published
- 2020
13. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy
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Qian Wu, Mazyar Shadman, Stanley R. Riddell, Utkarsh Acharya, Hans-Peter Kiem, Jordan Gauthier, Sindhu Cherian, Aesha Vakil, Ted Gooley, Jorge Ramos, Alexandre V. Hirayama, Barbara S. Pender, David G. Maloney, Ryan D. Cassaday, Xueyan Chen, Reed M. Hawkins, Gary Schoch, Rachel N. Steinmetz, Daniel Li, Jenna M. Voutsinas, Brian G. Till, Cameron J. Turtle, Aude G. Chapuis, and Kevin A. Hay
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Antigens, CD19 ,Immunology ,Hematopoietic stem cell transplantation ,Immunotherapy, Adoptive ,Biochemistry ,Disease-Free Survival ,Lymphocyte Depletion ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,B cell ,Salvage Therapy ,Chemotherapy ,Receptors, Chimeric Antigen ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Immunotherapy ,Middle Aged ,Chimeric antigen receptor ,Fludarabine ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Chimeric Antigen Receptor T-Cell Therapy ,business ,medicine.drug - Abstract
Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
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- 2019
14. Immunophenotypic Features of Myeloid Neoplasms Associated with Chromosome 7 Abnormalities
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Xueyan Chen, Sindhu Cherian, and Brent L. Wood
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Histology ,Myeloid ,Adolescent ,Immunophenotyping ,Pathology and Forensic Medicine ,Flow cytometry ,Young Adult ,hemic and lymphatic diseases ,medicine ,Humans ,Child ,Aged ,Retrospective Studies ,Aged, 80 and over ,Chromosome Aberrations ,Chromosome 7 (human) ,medicine.diagnostic_test ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,Cell Biology ,Middle Aged ,Flow Cytometry ,medicine.disease ,medicine.anatomical_structure ,Leukemia, Myeloid ,Myelodysplastic Syndromes ,Female ,Abnormality ,business ,Cytometry ,Chromosomes, Human, Pair 7 - Abstract
BACKGROUND Abnormalities involving chromosome 7 are one of the most frequent chromosomal aberrations in myeloid neoplasms including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) and are associated with an adverse prognosis. Immunophenotyping by flow cytometry provides data that can assist in the diagnosis and classification of myeloid neoplasms. The immunophenotypic features of myeloid neoplasms with monosomy 7 or del(7q) have not been previously described in a comprehensive fashion. METHODS We retrospectively analyzed flow cytometric data of myeloid neoplasms with monosomy 7 or del(7q) and summarized associated immunophenotypic features. RESULTS Myeloid neoplasms with monosomy 7 typically demonstrate multiple immunophenotypic abnormalities on myeloid blasts and maturing myelomonocytic cells. Increased CD14 expression on maturing granulocytic cells was characteristically seen in myeloid neoplasms with monosomy 7. This abnormality was significantly more frequent in myeloid neoplasms with monosomy 7 than in those with del(7q) (92.9% vs. 8.2%, P
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- 2019
15. How I Diagnose Minimal/Measurable Residual Disease in B Lymphoblastic Leukemia/Lymphoma by Flow Cytometry
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Lorinda Soma and Sindhu Cherian
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Disease ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Bone Marrow ,Molecular genetics ,Internal medicine ,medicine ,Humans ,medicine.diagnostic_test ,business.industry ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Flow Cytometry ,Prognosis ,Minimal residual disease ,Lymphoma ,Leukemia ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,Hematopathology - Abstract
Objectives Assessment for minimal/measurable residual disease (MRD) is a powerful prognostic factor in B lymphoblastic leukemia/lymphoma (B-LL/L) that is quickly becoming standard of care in assessing patients with B-LL/L posttherapy. MRD can be assessed using methodologies including flow cytometry and molecular genetics, with the former being rapid, relatively inexpensive, and widely applicable in many hematopathology/flow cytometry laboratories. Methods This article presents an approach to MRD detection in B-LL/L by flow cytometry through case presentations with illustration of several potential pitfalls. We review normal maturation patterns, antigens used for assessment, flow panels that can be utilized, considerations to be made during therapy, and clinical impact. The benefits and drawbacks when using the “different from normal” and “leukemia associated phenotype” approaches are considered. Results Evaluation for MRD in B-LL/L by flow cytometry relies on a knowledge of normal immunophenotypic patterns associated with B-cell maturation in states of rest and marrow regeneration so that one can identify patterns of antigen expression that differentiate abnormal, leukemic populations from regenerating hematogones or B-cell precursors. The nature of therapy can affect normal patterns, a phenomenon especially important to take into consideration given the increased use of targeted therapies in the treatment of B-LL/L. Conclusions Flow cytometry is widely available in many laboratories and is a cost-effective way to evaluate for B-LL/L MRD. However, panel validation and interpreter education are crucial for accurate assessment.
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- 2020
16. CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy
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Asen Bagashev, Michele Paessler, Andrei Thomas-Tikhonenko, Carl H. June, Wenzhao Meng, John S. Van Arnam, Eline T. Luning Prak, Minjie Luo, Sindhu Cherian, Derek A. Oldridge, Amanda M. DiNofia, Vinodh Pillai, Jaclyn Rosenthal, Stephan A. Grupp, J. Joseph Melenhorst, Vijay Bhoj, Gerald Wertheim, Susan R. Rheingold, Diwakar Mohan, Shannon L. Maude, Jonathan R. Fromm, and Kavitha Muralidharan
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Oncology ,Adult ,Cytotoxicity, Immunologic ,Male ,medicine.medical_specialty ,Neoplasm, Residual ,Immunobiology and Immunotherapy ,Adolescent ,medicine.medical_treatment ,T-Lymphocytes ,Antigens, CD19 ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Immunotherapy, Adoptive ,Immunophenotyping ,Young Adult ,Antineoplastic Agents, Immunological ,Antigen ,immune system diseases ,Recurrence ,Internal medicine ,hemic and lymphatic diseases ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Antibodies, Bispecific ,Medicine ,Humans ,Child ,business.industry ,Infant ,hemic and immune systems ,Hematology ,Immunotherapy ,medicine.disease ,Minimal residual disease ,Combined Modality Therapy ,Chimeric antigen receptor ,Leukemia ,Prior Therapy ,Treatment Outcome ,Child, Preschool ,Blinatumomab ,Female ,business ,medicine.drug - Abstract
Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell product targeting CD19 is approved for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the impact of pretreatment variables, such as CD19 expression level, on leukemic blasts, the presence of CD19(–) subpopulations, and especially prior CD19-targeted therapy, on the response to CAR T-cell therapy has not been determined. We analyzed 166 patients treated with CAR T-cell therapy at our institution. Eleven patients did not achieve a minimal residual disease (MRD)(–) deep remission, whereas 67 patients had a recurrence after achieving a MRD(–) deep remission: 28 patients with CD19(+) leukemia and 39 patients with CD19(–) leukemia. Return of CD19(+) leukemia was associated with loss of CAR T-cell function, whereas CD19(–) leukemia was associated with continued CAR T-cell function. There were no significant differences in efficacy of CAR T cells in CD19-dim B-ALL, compared with CD19-normal or -bright B-ALL. Consistent with this, CAR T cells recognized and lysed cells with very low levels of CD19 expression in vitro. The presence of dim CD19 or rare CD19(–) events by flow cytometry did not predict nonresponse or recurrence after CAR T-cell therapy. However, prior therapy with the CD19-directed, bispecific T-cell engager blinatumomab was associated with a significantly higher rate of failure to achieve MRD(–) remission or subsequent loss of remission with antigen escape. Finally, immunophenotypic heterogeneity and lineage plasticity were independent of underlying clonotype and cytogenetic abnormalities.
- Published
- 2019
17. Trends in Bone Marrow Sampling and Core Biopsy Specimen Adequacy in the United States and Canada
- Author
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Michel R. Nasr, Neerja Vajpayee, Alan D. Hutson, Michael R. Lewis, Claudiu V. Cotta, James E. Coad, Gregory E. Wilding, Kieran Sultan, Sinisa Ivelja, John T Grantham, Richard Cheney, Gratian Salaru, Mihai Merzianu, Guilherme Brandao, Prabhjot Kaur, Valentin G. Robu, Shanxiang Zhang, John Lazarchick, Attilio Orazi, Sindhu Cherian, LoAnn Peterson, Ling Zhang, Robert W. McKenna, Jerome B. Myers, Jeffrey A. Vos, Ridas Juskevicius, Elizabeth L. Courville, Adrienne Groman, Rodney R. Miles, Elisa Brega, Robert E. Hutchison, David D. Grier, Vishnu Reddy, Daniela Hoehn, Guang Fan, Russell K. Brynes, Manjula Balasubramanian, Horatiu Olteanu, Ramila Amre, Julie Teruya-Feldstein, Kedar V. Inamdar, Hina Naushad Qureishi, David R. Czuchlewski, and Le Aye
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,Cross-sectional study ,business.industry ,Retrospective cohort study ,General Medicine ,Bone marrow examination ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Multicenter study ,030220 oncology & carcinogenesis ,Biopsy ,Medicine ,Bone marrow sampling ,Radiology ,Bone marrow ,business ,Core biopsy ,030215 immunology - Abstract
Objectives To assess bone marrow (BM) sampling in academic medical centers. Methods Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed. Results BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent. Conclusions CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.
- Published
- 2018
18. Infectious complications of CD19-targeted chimeric antigen receptor–modified T-cell immunotherapy
- Author
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Michael Boeckh, Margaret L. Green, Stanley R. Riddell, Kevin A. Hay, David G. Maloney, Daniel Li, Sindhu Cherian, Xueyan Chen, Joshua A. Hill, and Cameron J. Turtle
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,T-Lymphocytes ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Immunology ,Cell- and Tissue-Based Therapy ,Receptors, Antigen, T-Cell ,Infections ,Severity of Illness Index ,Biochemistry ,Gastroenterology ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Internal medicine ,medicine ,Humans ,Aged ,Chemotherapy ,business.industry ,Lymphoma, Non-Hodgkin ,Cell Biology ,Hematology ,Immunotherapy ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Chemotherapy regimen ,United States ,Chimeric antigen receptor ,Cytokine release syndrome ,Leukemia ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business ,Follow-Up Studies - Abstract
Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62). There were 43 infections in 30 of 133 patients (23%) within 28 days after CAR-T-cell infusion with an infection density of 1.19 infections for every 100 days at risk. There was a lower infection density of 0.67 between days 29 and 90 (P = .02). The first infection occurred a median of 6 days after CAR-T-cell infusion. Six patients (5%) developed invasive fungal infections and 5 patients (4%) had life-threatening or fatal infections. Patients with ALL, ≥4 prior antitumor regimens, and receipt of the highest CAR-T-cell dose (2 × 107 cells per kg) had a higher infection density within 28 days in an adjusted model of baseline characteristics. Cytokine release syndrome (CRS) severity was the only factor after CAR-T-cell infusion associated with infection in a multivariable analysis. The incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
- Published
- 2018
19. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor–modified T-cell therapy
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W. Conrad Liles, Mark M. Wurfel, Xueyan Chen, Kevin A. Hay, David G. Maloney, Daniel Li, Dominic W. Chung, Cameron J. Turtle, Susanna Harju-Baker, Stanley R. Riddell, Junmei Chen, José A. López, Juliane Gust, Sindhu Cherian, and Laila-Aicha Hanafi
- Subjects
Male ,0301 basic medicine ,Oncology ,Immunobiology and Immunotherapy ,T-Lymphocytes ,medicine.medical_treatment ,Immunotherapy, Adoptive ,Biochemistry ,0302 clinical medicine ,Risk Factors ,Syndrome ,Hematology ,Blood Coagulation Disorders ,Middle Aged ,Fludarabine ,Cytokine release syndrome ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cytokines ,Female ,Neurotoxicity Syndromes ,Chimeric Antigen Receptor T-Cell Therapy ,medicine.drug ,Adult ,medicine.medical_specialty ,Fever ,Cyclophosphamide ,T cell ,Immunology ,Receptors, Antigen, T-Cell ,Young Adult ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,otorhinolaryngologic diseases ,medicine ,Humans ,Lymphocyte Count ,Aged ,Chemotherapy ,business.industry ,Hemodynamics ,Endothelial Cells ,Cell Biology ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,Hematopoiesis ,Kinetics ,030104 developmental biology ,Multivariate Analysis ,business - Abstract
Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor–modified (CAR) T cells has produced impressive antitumor responses in patients with refractory CD19+ B-cell malignancies but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation of and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR T cells. CRS developed in 70% of patients, including 62.5% with grade 1 to 3 CRS (grade 1, 26%; grade 2, 32%; grade 3, 4.5%), 3.8% with grade 4, and 3.8% with grade 5. A majority of cases of grade ≥4 CRS occurred during CAR T-cell dose finding. Multivariable analysis of baseline characteristics identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS. Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. Angiopoietin-2 and von Willebrand factor, which are biomarkers of endothelial activation, were increased during severe CRS and also before lymphodepletion in patients who subsequently developed CRS. We describe a classification-tree algorithm to guide studies of early intervention after CAR T-cell infusion for patients at high risk of severe CRS. These data provide a framework for early intervention studies to facilitate safer application of effective CD19 CAR T-cell therapy.
- Published
- 2017
20. Assessing the added value of bone marrow morphologic evaluation beyond flow cytometry for disease detection in the setting of acute myeloid leukemia after chemotherapy
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Ashley M Eckel, Jennifer Y Ju, Sindhu Cherian, Mary-Elizabeth M. Percival, Lorinda Soma, and Kerstin L. Edlefsen
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Pathology ,medicine.medical_specialty ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Myeloid leukemia ,General Medicine ,medicine.disease ,Chemotherapy regimen ,Flow cytometry ,Haematopoiesis ,medicine.anatomical_structure ,Carcinoma ,Medicine ,Bone marrow ,Differential diagnosis ,business - Abstract
Complete response after acute myeloid leukemia (AML) therapy historically requires a decrease in bone marrow (BM) blasts to 200 cells), blast count, trilineage hematopoiesis, dysplastic features, focal/patchy disease, and any non-hematopoietic or alternative diagnoses that would not have been discovered by the associated MFC study. The MFC data for each case was separately reviewed by two hematopathologists. Six of the 47 cases showed >5% blasts by morphology (range 8%-70%); in all six cases, >5% abnormal blasts were also identified by MFC (range 23%-78%). Of cases with 5% abnormal blasts in four cases and 5% blasts). In the remaining three cases with dysplasia, ancillary molecular studies supported molecular evidence of residual disease in one case (NPM1 mutation and FLT3-ITD positivity by PCR). No unexpected carcinomas or other findings that would not be detected by the associated MFC study were identified. In conclusion, in our study, morphologic evaluation did not definitively identify any additional cases of residual/recurrent AML that were not identified by MFC. Morphologic evaluation detected dysplasia without abnormal blasts in three cases; however, the significance was unclear without supportive molecular studies. Reducing the number of cases for morphologic evaluation could save resources and improve turnaround time if MFC can provide the relevant details to assess response.
- Published
- 2021
21. Evaluation of primary mediastinal large B cell lymphoma by flow cytometry
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Jonathan R. Fromm and Sindhu Cherian
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Histology ,CD30 ,T cell ,Population ,Biology ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Immunophenotyping ,immune system diseases ,hemic and lymphatic diseases ,medicine ,education ,B cell ,education.field_of_study ,Cell Biology ,medicine.disease ,Lymphoma ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Diffuse large B-cell lymphoma ,CD8 - Abstract
Background Primary mediastinal large B cell lymphoma (PMLBCL) is a B cell non-Hodgkin lymphoma (B-NHL) that shows morphologic, immunophenotypic, and genetic similarities to classical Hodgkin lymphoma (CHL). We evaluated the neoplastic and reactive infiltrate of PMLBCL by flow cytometry (FC). Methods A total of 24 cases of PMLBCL were retrospectively characterized using FC combinations for B-NHL, T-NHL, and CHL. Results The CHL assay identified the neoplastic population (NP) in all cases, while the B-NHL assay identified the NP in 18 of 24 cases. In four cases, the neoplastic population was retrospectively identified in the B-NHL tube, given the CHL tube-derived immunophenotype. Neoplastic cells of PMLBCL displayed a B cell immunophenotype (CD19/CD20+), with CD40 consistently and brightly expressed. Most cases lacked immunoglobulin light chains, CD10, and CD15; CD30 was frequently expressed. All cases showed expression of CD71 and CD95. The reactive infiltrate in PMLBCL showed increases in T cells relative to reactive tissues. Lower CD4/CD8 ratios in PMLBCL relative to CHL and reactive tissues were also observed. Although not seen as commonly as with CHL, 41% of cases showed a reactive CD3/CD4/CD7bright/CD45bright+ T cell population. Reactive populations seen in PMLBCL were similar to that seen in diffuse large B cell lymphoma, not otherwise specified. Conclusions FC can detect the NP of PMLBCL and a FC assay for CHL performed better than a B-NHL assay in this regard. The neoplastic cells showed a B cell immunophenotype with over-expression of CD40. The reactive infiltrate in PMLBCL shows unique features including a prominent CD8+ T cell infiltrate. © 2017 International Clinical Cytometry Society
- Published
- 2017
22. Common flow cytometry pitfalls in diagnostic hematopathology
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Ben Hedley, Sindhu Cherian, and Michael Keeney
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Histology ,Computer science ,Population ,Computational biology ,Pathology and Forensic Medicine ,Flow cytometry ,Single tube ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Hematopoietic Neoplasms ,education ,education.field_of_study ,medicine.diagnostic_test ,Data interpretation ,Cell Biology ,Standard methods ,Flow Cytometry ,Hematologic Diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,Identification (biology) ,Hematopathology - Abstract
Flow cytometry (FC) has proven to be an extremely versatile and useful tool in the diagnosis and monitoring of hematological diseases in addition to numerous other applications. Major advances in electronics, software, and reagents over the past years have simplified some aspects of FC, while at the same time the ability to combine 8-10 antibodies in a single tube can create both technical and interpretation issues that are more difficult to detect when using only 3-4 color combinations. Use of multiparameter panels can facilitate identification of abnormal populations; however, characteristics of the neoplastic population may create potential diagnostic pitfalls. An understanding of normal immunophenotypic patterns in states of rest, recovery, and activation is a critical first step in order to appropriately identify the abnormal populations that characterize hematopoietic neoplasms. Additionally, incorporation of newer therapeutic strategies, in particular targeted therapies, can confound standard methods for flow cytometric data analysis and knowledge of the impact of therapy on flow cytometric data is critical for accurate data interpretation. This manuscript will review preanalytical, instrument, and interpretation issues that may lead to incorrect interpretation of results.
- Published
- 2019
23. Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy
- Author
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Brenda M. Sandmaier, Mohamed L. Sorror, Ajay K. Gopal, Kevin A. Hay, Ryan D. Cassaday, David G. Maloney, Brian G. Till, Jordan Gauthier, Sindhu Cherian, Cameron J. Turtle, Filippo Milano, Alexandre V. Hirayama, Xueyan Chen, Jenna M. Voutsinas, Ang Li, and Mazyar Shadman
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,T-Lymphocytes ,Population ,Antigens, CD19 ,Receptors, Antigen, T-Cell ,Graft vs Host Disease ,Gastroenterology ,Immunotherapy, Adoptive ,Young Adult ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Transplantation, Homologous ,education ,Aged ,Chemotherapy ,education.field_of_study ,Transplantation ,Receptors, Chimeric Antigen ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Immunotherapy ,Middle Aged ,medicine.disease ,Prognosis ,Lymphoma ,Graft-versus-host disease ,surgical procedures, operative ,Treatment Outcome ,Chimeric Antigen Receptor T-Cell Therapy ,Female ,business - Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is offered to selected patients after chimeric antigen receptor-modified T-cell (CAR-T) therapy. Lymphodepleting chemotherapy and CAR-T therapy have immunosuppressive and immunomodulatory effects that could alter the safety profile of subsequent allo-HCT. We reviewed our experience with 32 adults (acute lymphoblastic leukemia [ALL], n = 19; B-cell non-Hodgkin lymphoma [NHL]/chronic lymphocytic leukemia [CLL], n = 13) who received an allo-HCT after CAR-T therapy, with a focus on posttransplant toxicities. Myeloablative conditioning (MAC) was used in 74% of ALL patients and 39% of NHL/CLL patients. The median time from CAR-T therapy to allo-HCT was 72 days in ALL patients and 122 days in NHL/CLL patients. Cumulative incidences of grade 3-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 25% and 10%, respectively. All patients had neutrophil recovery (median, 18.5 days) and all but 3 had platelet recovery (median, 12 days). Twenty-two percent had viral or systemic fungal infection within 100 days after allo-HCT. The 100-day and 1-year cumulative incidences of NRM were 16% and 21%, respectively, for ALL patients and 15% and 33%, respectively, for NHL/CLL patients. In ALL patients, later utilization of allo-HCT after CAR-T therapy was associated with higher mortality. In NHL/CLL patients, MAC was associated with higher mortality. Toxicities did not exceed the expected incidences in this high-risk population.
- Published
- 2019
24. Flow cytometric features of incidental indolent T lymphoblastic proliferations
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Kerstin L. Edlefsen, Sindhu Cherian, Lori Soma, David Wu, Jonathan R. Fromm, and Brent L. Wood
- Subjects
0301 basic medicine ,Adult ,CD4-Positive T-Lymphocytes ,Male ,Pathology ,medicine.medical_specialty ,Histology ,Biology ,CD8-Positive T-Lymphocytes ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Pathology and Forensic Medicine ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,hemic and lymphatic diseases ,medicine ,Humans ,Lymphoblast ,Castleman disease ,Lymphoma, Non-Hodgkin ,hemic and immune systems ,Cell Biology ,Middle Aged ,Marginal zone ,medicine.disease ,Flow Cytometry ,Immunohistochemistry ,Lymphoproliferative Disorders ,Lymphoma ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Hematopathology ,CD8 - Abstract
Indolent T lymphoblastic proliferations have been reported rarely in extramedullary and extrathymic tissues. Recent work has identified these indolent T lymphoblast populations to be mostly CD4+/CD8+ (characterized by immunohistochemistry), with only limited immunophenotypic evaluation of these populations by flow cytometry (FC). We retrospectively reviewed our institutional FC archives and identified 12 samples from 10 patients with incidental T lymphoblastic populations. Samples were characterized with respect to expression of T-cell antigens, CD45, TdT, CD1a, and T/NK antigens, and light scatter properties. Overall, the proportion of T lymphoblasts was small (range 0.01-8.8% of white cells; mean, 1.7%). Histologic correlation showed scattered immature T lymphoblasts in samples without overt distortion of underlying architecture. T lymphoblasts were identified most frequently in association with Castleman disease (four) or tissues with Castleman features (four), marginal zone B-cell lymphoma (one), or tissue with reactive/atypical changes (three cases). Although three cases were composed predominantly of CD4+/CD8+ T cells, the majority of cases in our cohort (eight) included a major subset of CD4-/CD8- T lymphoblasts by FC (one case CD8+/CD4-), which has not been described previously. There was no evidence of subsequent progression to T lymphoblastic leukemia. Incidental, indolent T lymphoblastic proliferations may be detected by clinical FC. In contrast to reports, we find that these proliferations in clinical samples may contain not only CD4+/CD8+ immature T cells but also CD4-/CD8- immature T cells, expanding the immunophenotypic spectrum of this entity.
- Published
- 2019
25. CD33 expression on natural killer cells is a potential confounder for residual disease detection in acute myeloid leukemia by flow cytometry
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Lorinda Soma, Valerie Miller, Sindhu Cherian, and Ashley M Eckel
- Subjects
0301 basic medicine ,Histology ,Myeloid ,Neoplasm, Residual ,CD33 ,Population ,Sialic Acid Binding Ig-like Lectin 3 ,CD16 ,Pathology and Forensic Medicine ,Flow cytometry ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,education ,Monitoring, Physiologic ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Myeloid leukemia ,Confounding Factors, Epidemiologic ,Cell Biology ,Flow Cytometry ,Prognosis ,Minimal residual disease ,Killer Cells, Natural ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,business - Abstract
Detection of minimal/measurable residual disease (MRD) in acute myeloid leukemia (AML) is important for guiding patient-specific clinical management. Natural killer (NK) cells can express various markers not typically associated with NK lineage, potentially confounding the detection of MRD by flow cytometry. We have observed CD33 expression on NK cells when evaluating for AML MRD in routine clinical practice in multiple patient samples. To characterize CD33 expression on NK cells, 40 peripheral blood or bone marrow samples with NK cells present at >5% of lymphocytes were selected for further assessment of NK cell phenotype and CD33 expression. Seven of the 40 samples (17.5%) were found to have CD33 expression on at least 5% of the NK cells. The CD33-positive NK cell population accounted for an average of 11.4% of NK cells (median 11.9%, range 8.0-15.3%) and 2.2% of total white cells (median 1.1%, range 0.1-10.1%). This NK cell subset expressed bright CD2, bright CD56, and dim CD16. On average, CD33 expression on NK cells was dimmer than on monocytes (mean median fluorescence intensity ratio 0.4; range 0.1-1.0). This study characterizes expression of CD33 on NK cells. Recognition of this pattern of antigen expression is critical in evaluating samples for MRD in patients with myeloid neoplasms, particularly AML.
- Published
- 2019
26. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells
- Author
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Brian G. Till, Cameron J. Turtle, Paul C. Hendrie, Xueyan Chen, Reed M. Hawkins, Stanley R. Riddell, Ryan C. Lynch, Aude G. Chapuis, Hans-Peter Kiem, Kevin A. Hay, Qian Wu, Tejaswini Dhawale, Alexandre V. Hirayama, Daniel Li, Jenna M. Voutsinas, Mazyar Shadman, Barbara S. Pender, Jordan Gauthier, Sindhu Cherian, Ryan D. Cassaday, Ted Gooley, Rachel N. Steinmetz, Utkarsh Acharya, J L Ramos, Aesha Vakil, and David G. Maloney
- Subjects
0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Cyclophosphamide ,medicine.medical_treatment ,Immunology ,Antigens, CD19 ,Cell- and Tissue-Based Therapy ,Receptors, Antigen, T-Cell ,Aggressive Non-Hodgkin Lymphoma ,Biochemistry ,Lymphocyte Depletion ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Survival rate ,business.industry ,Lymphoma, Non-Hodgkin ,Cell Biology ,Hematology ,Immunotherapy ,Middle Aged ,medicine.disease ,Prognosis ,Combined Modality Therapy ,Chimeric antigen receptor ,Fludarabine ,Lymphoma ,Survival Rate ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,Female ,business ,Vidarabine ,medicine.drug ,Follow-Up Studies - Abstract
Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors affecting response and progression-free survival (PFS) in patients with aggressive NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by 2 × 106 CD19-directed CAR T cells/kg. The best overall response rate was 51%, with 40% of patients achieving complete remission. The median PFS of patients with aggressive NHL who achieved complete remission was 20.0 months (median follow-up, 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR T-cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum lactate dehydrogenase (LDH) level and a favorable cytokine profile, defined as serum day 0 monocyte chemoattractant protein-1 (MCP-1) and peak interleukin-7 (IL-7) concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion, and higher intensity of cyclophosphamide and fludarabine lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared with those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH levels above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR T-cell immunotherapy for aggressive B-cell NHL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
- Published
- 2018
27. A novel flow cytometric assay for detection of residual disease in patients with B-lymphoblastic leukemia/lymphoma post anti-CD19 therapy
- Author
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Brent L. Wood, Sindhu Cherian, Vivian McCullouch, Katy Dougherty, Valerie Miller, and Jonathan R. Fromm
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Prognostic variable ,Histology ,medicine.medical_treatment ,CD38 ,Pathology and Forensic Medicine ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,B cell ,CD20 ,biology ,business.industry ,CD24 ,Cell Biology ,medicine.disease ,Minimal residual disease ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,business - Abstract
Background: Residual disease detection following therapy is an important prognostic variable in B-lymphoblastic leukemia (B-LL). Most flow cytometric strategies for detecting B cell malignancy utilize CD19 to identify B cells. With growing use of anti-CD19 targeted therapies, alternative strategies are needed for residual disease detection. We describe an approach for residual disease detection in this setting. Methods: A novel combination was designed using expression of CD22 or CD24 (without CD66b) for B cell detection in combination with markers aberrantly expressed in B-LL (CD10, CD20, CD34, CD38, and CD45). The performance characteristics of this combination were evaluated and compared to a standard, validated B-LL MRD assay using 10 known negative samples, 10 overtly positive samples, and 11 post-therapy samples (prior therapy other than anti-CD19 therapy). Subsequently, results from the first 100 samples on which the new tube was performed were reviewed. Results: The described combination performed well in the initial analysis of 31 samples with all negative and positive samples correctly classified. In positive samples, the percentage of abnormal cells correlated well between the standard and new assay. Evaluation of the first 100 samples demonstrated good performance with adequate detection of CD19-positive and CD19-negative B-LL. Additionally, it was observed that patients receiving anti-CD19 therapies demonstrate an increased proportion of CD19-negative progenitors. Conclusions: These preliminary findings describe a strategy that performs well for residual disease detection in B-LL post anti-CD19 therapy. Such alternative strategies will become more important as the use of targeted immunotherapies becomes more common. This article is protected by copyright. All rights reserved.
- Published
- 2016
28. Detection of non-CLL-like monoclonal B cell lymphocytosis increases dramatically in the very elderly, while detection of CLL-like populations varies by race: findings in a multiethnic population-based cohort of elderly women
- Author
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Brent L. Wood, Anneclaire J. De Roos, Asqual Getaneh, Wenjun Li, Alexander P. Reiner, Sindhu Cherian, Kerstin L. Edlefsen, and Lawrence Lessin
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Population ,B-Lymphocyte Subsets ,Paraproteinemias ,chemical and pharmacologic phenomena ,Sampling Studies ,White People ,Immunophenotyping ,Cohort Studies ,03 medical and health sciences ,Race (biology) ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,education ,neoplasms ,Aged ,Aged, 80 and over ,Clinical Trials as Topic ,education.field_of_study ,Hematology ,business.industry ,Smoking ,Hispanic or Latino ,General Medicine ,Middle Aged ,Flow Cytometry ,bacterial infections and mycoses ,medicine.disease ,Multiethnic population ,Black or African American ,Antigens, Differentiation, B-Lymphocyte ,Postmenopause ,Observational Studies as Topic ,030104 developmental biology ,Socioeconomic Factors ,030220 oncology & carcinogenesis ,Immunology ,Cohort ,Monoclonal B-cell lymphocytosis ,Female ,business ,Cohort study - Abstract
Monoclonal B cell lymphocytosis (MBL) is both a marker of immune senescence and a potential precursor of B cell malignancy. Most MBL populations have a chronic lymphocytic leukemia-like (CLL-like) immunophenotype, but those that are CD5-negative (non-CLL-like) are also recognized and may represent a distinct diagnostic entity. To date, MBL studies have taken place in relatively homogenous populations, although risk of CLL varies across racial groups and geographic regions. We report flow cytometry data from 597 ethnically diverse 64-94-year-old women from across the USA who are participants in the Women's Health Initiative (WHI) Long-Life Study (LLS). Overall, MBL was detected in 26 % of the participants and included 20.9 % with a CLL-like immunophenotype, 5 % with a non-CLL-like immunophenotype, and 1.3 % with both. White and Hispanic women were more than twice as likely to have a CLL-like MBL population detected than African American women, corrected for age (P = 0.003). By contrast, detection of non-CLL-like MBL did not vary significantly by race, but did increase markedly with advancing age, being present in 12.7 % of those aged 85 and older. We provide new evidence that rates of detection of CLL-like MBL are lower in African Americans, and further suggest that non-CLL-like clonal expansions should be regarded as distinct from CLL-like MBL.
- Published
- 2016
29. An unusual case of co-existing classic mantle cell lymphoma and transformed lymphoma with Burkitt-like features with leukemic presentation
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Sindhu Cherian, Geling Li, Xueyan Chen, Yi Zhou, Emily A. Stevens, and Ryan D. Cassaday
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Histology ,Population ,Biology ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Cyclin D1 ,immune system diseases ,hemic and lymphatic diseases ,medicine ,education ,neoplasms ,MYC Gene Rearrangement ,B cell ,education.field_of_study ,Hematology ,medicine.disease ,Virology ,BCL10 ,Lymphoma ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Mantle cell lymphoma ,CD5 ,030215 immunology - Abstract
Mantle cell lymphoma (MCL) is an aggressive mature B cell lymphoma characterized by the t(11;14) IGH-CCND1 translocation. The majority of the MCL harbors secondary genetic aberrations and the MYC gene rearrangement is occasionally detected. We reported a unique case of co-existence of a typical MCL and a transformed component with morphologic and immunophenotypic features resembling a Burkitt lymphoma in leukemic phase at disease presentation. Two distinct abnormal B cell populations were identified in the peripheral blood and bone marrow: a CD5+/CD10− population primarily in the peripheral blood (47.6 %) and a CD5−/CD10+ population predominantly in the marrow (83.8 %), which shared the same surface light chain restriction and identical immunoglobulin gene rearrangements. By cytogenetic studies, the CD10+ cells harbored both t(11;14) IGH-CCND1 and t(8;14) IGH-MYC whereas the CD5+ population only carried t(11;14) IGH-CCND1. The combined findings indicate that the Burkitt-like component represents a transformation from a typical MCL by acquiring t(8;14) and that the MYC rearrangement represents a secondary oncogenic event in MCL that drives the disease progression. This unique case described co-existence of clonally related MCL and a transformed component otherwise typical of a Burkitt lymphoma, both in leukemic phase at disease presentation, which provided direct evidence on the lymphomagenesis of MCL.
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- 2016
30. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
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Barbara S. Pender, Shelly Heimfeld, Ted Gooley, Sindhu Cherian, Brent L. Wood, Xueyan Chen, Michael Hudecek, Emily Robinson, Colette Chaney, Cecilia Yeung, Katherine Melville, David G. Maloney, Stanley R. Riddell, Jianhong Cao, Lorinda Soma, Natalia N Steevens, Carolina Berger, Cameron J. Turtle, Daniel Sommermeyer, Tanya M Budiarto, Laïla Aïcha Hanafi, Michael C. Jensen, and Daniel Li
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Adult ,0301 basic medicine ,T cell ,medicine.medical_treatment ,CD4-CD8 Ratio ,Receptors, Antigen, T-Cell ,Immunotherapy, Adoptive ,Disease-Free Survival ,Lymphocyte Depletion ,CD19 ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,T-Lymphocyte Subsets ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,medicine ,Humans ,B cell ,Aged ,biology ,General Medicine ,Immunotherapy ,Middle Aged ,medicine.disease ,Chimeric antigen receptor ,Tumor Burden ,3. Good health ,Cytokine release syndrome ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Chimeric Antigen Receptor T-Cell Therapy ,Clinical Medicine ,CD8 - Abstract
BACKGROUND. T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR–T cell products were prepared from unselected T cells. METHODS. We conducted a clinical trial to evaluate CD19 CAR–T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy. RESULTS. The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR–T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR–T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell–mediated anti-CAR transgene product immune responses developed after CAR–T cell infusion in some patients, limited CAR–T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR–T cell persistence and disease-free survival. CONCLUSION. Immunotherapy with a CAR–T cell product of defined composition enabled identification of factors that correlated with CAR–T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR–T cell dosing strategies that mitigated toxicity and improved disease-free survival. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01865617","term_id":"NCT01865617"}}NCT01865617. FUNDING. R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation.
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- 2016
31. Small, abnormal B lymphoid blast populations in chronic myelogenous leukemia at diagnosis: Does this finding indicate an accelerated course?
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Cheng Ding, Lori Soma, Vivian G. Oehler, and Sindhu Cherian
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0301 basic medicine ,medicine.medical_specialty ,Pathology ,Histology ,Myeloid ,Population ,CD38 ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Immunophenotyping ,hemic and lymphatic diseases ,medicine ,education ,B cell ,education.field_of_study ,business.industry ,Cell Biology ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Hematopathology ,business ,Cytometry ,Chronic myelogenous leukemia - Abstract
Background The 2008 WHO is not specific regarding subclassification of chronic myelogenous leukemia (CML) with less than 20% abnormal B lymphoid blasts (ABLB), and suggests patients with ABLB often show rapid progression (Swerdlow, 2008). Recent studies have shown variable outcomes when small abnormal B cell populations are seen by flow cytometry (El Rassi et al., Cancer 2015; 121:872–875; Vrotsos et al., Cytometry B Clin Cytom 2015). Methods The hematopathology database was searched (7.4-year period), and patients identified through routine clinical study, who were BCR-ABL1 positive CML and had an ABLB of less than 20%. Flow cytometric (FC) and histologic data was evaluated to determine immunophenotypic abnormalities, immunohistochemical patterns, and percentage of ABLB, hematogones, and mature B cells. Results Seven patients with CML and ABLB identified by FC studies were found, five of which also had available histologic material to review. ABLB by FC ranged from 0.006% to 3.4%, typically demonstrated an immunophenotype with increased CD10, increased CD19, and decreased CD38, without myeloid antigens, abnormalities similar to that reported previously (Vrotsos et al., Cytometry B Clin Cytom 2015). The ABLB population was found only in diagnostic samples and always with more numerous hematogones. By immunohistochemistry, three of five patients showed ≥10% TdT positive cells. All patients showed a response to tyrosine kinase inhibitor therapy, and no patients progressed to clinical lymphoid blast phase. Conclusions Immature B cells, occasionally including a small subset with an abnormal phenotype can be observed in chronic phase CML at diagnosis. We believe an approach incorporating clinical data, cytogenetic/molecular findings, and morphologic evaluation may be helpful when determining the best management of CML patients at diagnosis if small ABLB populations are identified by FC. © 2016 Clinical Cytometry Society
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- 2016
32. Significance of CD10-positive clonal B cell populations identified by flow cytometry in histologically benign gastric biopsies
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Won-Tak Choi, Lorinda Soma, and Sindhu Cherian
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education.field_of_study ,Pathology ,medicine.medical_specialty ,Histology ,medicine.diagnostic_test ,Gastric lymphoma ,Population ,Hematology ,CD38 ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,Flow cytometry ,Lymphoma ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Polyclonal B cell response ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,medicine ,030211 gastroenterology & hepatology ,Clone (B-cell biology) ,education ,B cell - Abstract
Historically, the presence of clonal B cell populations has been associated with malignancy in lymphoid proliferations. However, several studies have demonstrated that clonal B cell populations can be present in histologically reactive settings, but this has not been described in gastric samples. These studies have primarily shown clonality using molecular methods, with only a few studies showing clonality by flow cytometry. We evaluated 16 histologically benign gastric biopsies with CD10+ B cell populations identified by flow cytometry (13 clonal, 3 with kappa skew) and reviewed the morphology, endoscopic findings, and clinical course. Although the presence of clonal populations initially raised a diagnostic possibility of lymphoma in each case, morphologic examination supported a non-neoplastic reactive process. The CD10+ B cell populations typically demonstrated increased or slightly increased CD38 (88 %), increased or slightly increased CD20 (81 %), decreased surface light-chain expression (69 %), normal CD19 (94 %), and those that were studied (n = 12) were BCL-2 negative or indeterminate by flow cytometry. Polyclonal B cells were present, and the CD10+ B cell population comprised less than 50 % of the B cells in all cases. The available clinical information revealed no evidence of lymphoma in all 16 cases (follow-up ranging from 2 months to 10 years). The presence of a CD10+ B cell clone (or light-chain skew) by flow cytometry in a gastric biopsy is not specific for lymphoid neoplasia and should be interpreted in the context of other immunophenotypic features as well as clinical and morphologic data.
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- 2016
33. Expression of CD2 and CD25 on mast cell populations can be seen outside the setting of systemic mastocytosis
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Valerie Miller, Katy Dougherty, Brent L. Wood, Sindhu Cherian, Vivian McCullouch, and Jonathan R. Fromm
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Histology ,Population ,Pathology and Forensic Medicine ,03 medical and health sciences ,Immunophenotyping ,Myeloid stem cell ,medicine ,Systemic mastocytosis ,education ,education.field_of_study ,biology ,CD117 ,business.industry ,Cell Biology ,medicine.disease ,Mast cell ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,biology.protein ,Bone marrow ,Hematopathology ,business - Abstract
Background Systemic mastocytosis (SM) is a diagnosis made using clinical, laboratory, and histologic parameters. Aberrant CD2 and/or CD25 expression on mast cells provides one minor criterion for a diagnosis of SM. To validate a tube (CD45/CD117/CD2/CD25) for mast cell evaluation, flow cytometry (FC) on residual material from marrow aspirates samples submitted to the hematopathology laboratory was performed. Methods Samples evaluated (n = 98) had no clinical or morphologic suspicion for SM. Samples were excluded if there was history of a myeloid stem cell neoplasm. Ten documented cases of SM were evaluated for comparison. Results Among cases without history of SM, 17.3% (n = 17) showed expression of CD2 and/or CD25 on ≥10% of the mast cell population (CD25 alone in 14 cases, CD2 alone in 2 cases, both in one case), while 82.6% (n = 81) showed no expression of these antigens. The percentage of mast cells showing aberrant CD2 and/or CD25 expression respectively ranged from 12.1% to 98.8% and 22.2% to 95.7% Interestingly, all of the cases with evidence of aberrant antigen expression on mast cells were collected post-therapy while 22.1% of the negative samples were collected pre-therapy. A cut-off of 60% CD25 expression on mast cells identified all cases of SM while minimizing false positives. Conclusions These findings demonstrate that aberrant expression of CD2 and/or CD25 may be seen on mast cells outside of the setting of SM. The data suggests that this phenomenon may be seen more commonly following chemotherapy and that FC of mast cells should be interpreted with caution in the post-chemotherapy setting. © 2015 International Clinical Cytometry Society
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- 2015
34. Myeloperoxidase Expression in B-Lymphoblastic Leukemia by Immunohistochemistry as a Diagnostic Confounder
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Ron Thomason, Lorinda Soma, Sindhu Cherian, Jonathan R. Fromm, Kerstin L. Edlefsen, Jing Du, Amanda Moklebust, and K David Li
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medicine.medical_specialty ,Pathology ,biology ,medicine.diagnostic_test ,business.industry ,Confounding ,Cytogenetics ,General Medicine ,medicine.disease ,Flow cytometry ,Leukemia ,Antigen ,Myeloperoxidase ,biology.protein ,medicine ,Immunohistochemistry ,Antibody ,business - Abstract
Background B-lymphoblastic leukemia (BLL) is a B lineage neoplasm that expresses typical immature B cell markers, but may also express myeloid-associated antigens. Myeloperoxidase (MPO) is a heme-containing peroxidase, which has been used as the single most specific myeloid marker when assigning lineage to acute leukemia. MPO positivity by immunohistochemistry (IHC) in BLL has been historically described in a subset of patients; however, further detailed comparison of IHC to flow cytometry and IHC methodology is described herein. Design The University of Washington pathology database was searched for new or relapsed adult BLL from 2011–2019. Cases with blasts >30% of marrow cellularity by morphology were selected. MPO IHC was performed using the Dako, polyclonal antibody (rabbit) on a Ventana instrument with streptavidin-biotin (SB) detection method. MPO IHC SB positive cases were also stained using the same antibody and platform, but a different detection method, multimer-optiview (MO). MPO IHC was called positive when >10% of neoplastic blasts showed expression. MPO positive blast percentage, staining intensity and pattern were assessed. Intensity: 0=negative, 1=mild, 2=moderate, 3=bright/same level as myeloids. Cytoplasmic pattern: homogenous or granular. Concurrent flow cytometry results and cytogenetic and/or molecular studies were reviewed. Results 35 cases were identified. Positive MPO IHC expression was present in 7/35 cases by SB method, with the percentage of MPO positive blasts ranging from 20–90% (majority >70%), all ranged from 1 - 2+ intensity and most (5/7) were homogenous pattern. 4/5 MPO SB positive cases were negative by MO detection method. MPO evaluation by flow cytometry was negative in 3 of 3 cases and myeloid associated antigens were negative or low on a subset. 2/8 BLL, BCR-ABL1 cases were MPO IHC positive by SB. Conclusion MPO staining by IHC in BLL is present in 17% of cases, often present in the majority of blasts, and positive using the SB detection system. This aberrant staining can be negated in most cases with the MO detection system. MPO expression by flow cytometry in MPO IHC SB positive cases were negative (3/3) and were low to absent for other myeloid antigens. We agree with prior studies that MPO IHC using the SB method can be a confounder for lineage assignment in acute leukemia.
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- 2020
35. Flow Cytometric Monitoring for Residual Disease in B Lymphoblastic Leukemia Post T Cell Engaging Targeted Therapies
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Sindhu Cherian and Maryalice Stetler-Stevenson
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0301 basic medicine ,Histology ,Neoplasm, Residual ,medicine.medical_treatment ,T cell ,Sialic Acid Binding Ig-like Lectin 2 ,T-Lymphocytes ,Population ,Antigens, CD19 ,Biochemistry ,Hemolysis ,CD19 ,Article ,Targeted therapy ,Flow cytometry ,Specimen Handling ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Immunotoxin ,immune system diseases ,hemic and lymphatic diseases ,Medicine ,Humans ,Molecular Targeted Therapy ,education ,education.field_of_study ,biology ,medicine.diagnostic_test ,Staining and Labeling ,business.industry ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Flow Cytometry ,Minimal residual disease ,Medical Laboratory Technology ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,business - Abstract
The use of targeted therapy is growing in the setting of hematopoietic neoplasms. Flow cytometry is a cornerstone of residual disease monitoring post therapy in this group of malignancies. Often, there is overlap between antigens targeted by immunotherapies and gating reagents utilized for population identification by flow cytometry. Such overlap can render a previously excellent gating reagent inadequate for disease detection. Recently, several anti-CD19 T cell-engaging immunotherapeutic agents and an anti-CD22 immunotoxin have been FDA approved for use in B lymphoblastic leukemia (B-LL), with an anti-CD22 T cell-engaging agent in development. In the setting of such targeted therapies, CD19 and CD22 expression may be altered, compromising the use of these reagents for identification of abnormal blasts. We describe herein a strategy for flow cytometric monitoring for residual disease in patients with B-LL post T cell-engaging anti-CD19 and anti-CD22 therapies. © 2018 by John Wiley & Sons, Inc.
- Published
- 2018
36. Trends in Bone Marrow Sampling and Core Biopsy Specimen Adequacy in the United States and Canada: A Multicenter Study
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Mihai, Merzianu, Adrienne, Groman, Alan, Hutson, Claudiu, Cotta, Russell K, Brynes, Attilio, Orazi, Vishnu, Reddy, Julie, Teruya-Feldstein, Ramila, Amre, Manjula, Balasubramanian, Guilherme, Brandao, Sindhu, Cherian, Elizabeth, Courville, David, Czuchlewski, Guang, Fan, David, Grier, Daniela, Hoehn, Kedar V, Inamdar, Ridas, Juskevicius, Prabhjot, Kaur, John, Lazarchick, Michael R, Lewis, Rodney R, Miles, Jerome B, Myers, Michel R, Nasr, Hina N, Qureishi, Horatiu, Olteanu, Valentin G, Robu, Gratian, Salaru, Neerja, Vajpayee, Jeffrey, Vos, Ling, Zhang, Shanxiang, Zhang, Le, Aye, Elisa, Brega, James E, Coad, John, Grantham, Sinisa, Ivelja, Robert, McKenna, Kieran, Sultan, Gregory, Wilding, Robert, Hutchison, LoAnn, Peterson, and Richard T, Cheney
- Subjects
Adult ,Aged, 80 and over ,Male ,Canada ,Adolescent ,Infant ,Bone Marrow Examination ,Original Articles ,Middle Aged ,United States ,Young Adult ,Cross-Sectional Studies ,Bone Marrow ,Child, Preschool ,Humans ,Female ,Biopsy, Large-Core Needle ,Child ,Bone Marrow Diseases ,Aged ,Retrospective Studies - Abstract
OBJECTIVES: To assess bone marrow (BM) sampling in academic medical centers. METHODS: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed. RESULTS: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent. CONCLUSIONS: CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.
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- 2018
37. List of Contributors
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Mark J. Arends, Brad Bolon, Carmen J. Booth, Kelli L. Boyd, Cory F. Brayton, Bernard S. Buetow, Robert D. Cardiff, Stephan A. Carey, Cathy S. Carlson, Sindhu Cherian, Martha A. Delaney, Suzanne M. Dintzis, Renee Z. Dintzis, Philip Fleckman, Charles W. Frevert, Rochelle L. Garcia, Katherine N. Gibson-Corley, James J. Going, Paul C. Goodwin, Barry Gusterson, Catherine E. Hagan, Jack R. Harkema, Benjamin Hoch, Renee R. Hukkanen, Christopher Jerome, Sonali Jindal, Brian Johnson, C. Dirk Keene, Lloyd E. King, Sue E. Knoblaugh, Jolanta Kowalewska, Krista Marie DuBray La Perle, Michael A. Laflamme, Denny Liggitt, Michael A. Linden, David K. Meyerholz, Kathleen S. Montine, Thomas H. Morton, Atis Muehlenbachs, Lillian B. Nanney, Isabella Phan, Julie Randolph-Habecker, Mara H. Rendi, Arlin B. Rogers, Rani Sellers, Jessica M. Snyder, Carlos J. Suarez, John P. Sundberg, Henry J. Thompson, Maria Tretiakova, Piper M. Treuting, Lawrence True, Daniel C. Tu, Peter Vogel, James G. Wagner, Jerrold M. Ward, Rachel Wong, Caroline J. Zeiss, Alexander 'Sandy' D. Borowsky, Donna M. Bouley, Virginia L. Godfrey, Harm HogenEsch, Michael Leach, Dave Malarkey, Elisabeth McInnes, David Meyerholz, Alessandra Piersigilli, and Cheryl Scudamore
- Published
- 2018
38. Multivariate Analyses Indicate That the Cytokine Response to Lymphodepletion May be Better Associated Than Lymphodepletion Intensity with the Efficacy of CD19 CAR-T Cell Immunotherapy for Aggressive B-Cell Non-Hodgkin Lymphoma
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Brian G. Till, Qian Wu, Xueyan Chen, Cameron J. Turtle, Reed M. Hawkins, Alyssa Sheih, Rachel N. Steinmetz, Stanley R. Riddell, Paul C. Hendrie, Jordan Gauthier, Sindhu Cherian, Ryan C. Lynch, Alexandre V. Hirayama, Barbara S. Pender, Tinh-Doan Phi, Utkarsh Acharya, Aesha Vakil, Janaki Purushe, Aude G. Chapuis, Tejaswini Dhawale, Jorge Ramos, Kevin A. Hay, Jenna M. Voutsinas, David G. Maloney, Hans-Peter Kiem, Mazyar Shadman, Daniel Li, and Ted Gooley
- Subjects
Transplantation ,medicine.medical_specialty ,biology ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Hematology ,Immunotherapy ,medicine.disease ,Gastroenterology ,CD19 ,Lymphoma ,Fludarabine ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,Cytokine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,B-Cell Non-Hodgkin Lymphoma ,biology.protein ,business ,030215 immunology ,medicine.drug - Abstract
Introduction CD19 chimeric antigen receptor (CAR)-T cell therapy has shown efficacy in Non-Hodgkin lymphoma (NHL), but the factors associated with durable remission have not been identified. Objectives We report multivariate analyses of factors impacting progression-free survival (PFS) in NHL patients (pts) treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion (LD) and CD19 CAR-T cells. Methods We conducted a phase 1/2 open-label clinical trial (NCT01865617) with the primary objective of evaluating the feasibility and safety of a defined composition of CD19 CAR-T cells after LD in pts with R/R CD19+ B-cell malignancies. PFS was defined as the time from CAR-T cell infusion until disease progression or death. Multivariate models using elastic net were performed for analysis of response and PFS. Results Characteristics of the 57 pts in the study are shown in Tbl 1. Thirty-six (63%) received high-intensity (HI) Cy/Flu and 21 (37%) received low-intensity (LI) Cy/Flu LD (Tbl 1). All pts received 2 × 106 CD19 CAR-T cells/kg. The best overall response (OR) rate was 57%, with 48% complete remission (CR). Pts who achieved CR had a median PFS not reached (median follow-up [fu] 20.2 months; mo), with only 1 relapse beyond 12 mo after CAR-T cell infusion (Fig. 1). Eight of 9 pts with indolent NHL achieved CR (89%) and none relapsed (median fu 14.5 mo). For the 47 pts with aggressive NHL, the best OR rate was 51%, with 40% CR. The median PFS of aggressive NHL pts achieving CR was 20.0 mo (median fu 26.9 mo), and 24-mo probabilities of PFS and OS were 46% and 72%, respectively. In aggressive NHL, multivariate analysis showed that the probability of CR was associated with lower pre-LD serum LDH and greater increase in serum MCP-1 concentration from LD to the day of CAR-T cell infusion. HI LD was associated with more CAR-T cells in blood, but there was no difference in response in pts who received HI (CR 14/31, 45%) compared to LI LD (CR 5/16, 31%; P = .53). Multivariate analysis in aggressive NHL showed that lower pre-LD serum LDH and higher day 0 MCP-1 and peak IL-7 after CAR-T cell infusion were associated with better PFS. The IL-7 peak after CAR-T cell infusion (median day 4) correlated with day 0 IL-7, consistent with an effect of LD. MCP-1 and IL-7 increased after LD, independent of prior bridging therapy, and their concentrations correlated with Cy/Flu LD intensity. However, LD intensity was not independently associated with CR or PFS. Independent of LD intensity, a subset of pts had a robust increase in day 0 MCP-1 and peak IL-7 after LD and achieved better responses (CR 10/16, 63%) compared to those with limited cytokine increase (CR 9/30, 30%; P = .06). Conclusion Multivariate analyses show that cytokines associated with effective LD are, unlike the intensity of Cy/Flu LD, independently associated with CR and PFS. Strategies to augment biological LD efficacy could be tested in studies of CD19 CAR-T cells for aggressive NHL.
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- 2019
39. Acute Myeloid Leukemia Immunophenotyping by Flow Cytometric Analysis
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Xueyan Chen and Sindhu Cherian
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Mixed phenotype acute leukemia ,Neoplasm, Residual ,medicine.diagnostic_test ,business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Myeloid leukemia ,Flow Cytometry ,Minimal residual disease ,Flow cytometry ,Immunophenotyping ,03 medical and health sciences ,Leukemia, Myeloid, Acute ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,Humans ,Differential diagnosis ,business ,Routine analysis ,030215 immunology - Abstract
Flow cytometry plays an indispensible role in the diagnosis and subclassification of acute myeloid leukemia (AML). Using a multiparametric approach, flow cytometry immunophenotyping has the advantage of efficiency with high sensitivity. This article reviews the general gating strategy, antibody panels for routine analysis, and additional markers for lineage assignment in the subclassification of AML. Also discussed are diagnostic immunophenotypic features of hard-to-classify entities considered within the differential diagnosis of AML. Finally, briefly presented are the principles underlying the use of flow cytometry for minimal residual disease detection.
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- 2017
40. Multivariable Modeling of Disease and Treatment Characteristics of Adults with B-ALL in MRD-Negative CR after CD19 CAR-T Cells Identifies Factors Impacting Disease-Free Survival
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Alexandre V. Hirayama, Xueyan Chen, Mazyar Shadman, Reed M. Hawkins, Rachel N. Steinmetz, Tinh-Doan Phi, Janaki Purushe, Ted Gooley, Barbara S. Pender, Hans-Peter Kiem, David G. Maloney, Aude G. Chapuis, Jenna M. Voutsinas, Alyssa Sheih, Utkarsh Acharya, Jorge Ramos, Kevin A. Hay, Stanley R. Riddell, Aesha Vakil, Jordan Gauthier, Sindhu Cherian, Daniel Li, Ryan D. Cassaday, Qian Wu, Brian G. Till, and Cameron J. Turtle
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Lower risk ,Biochemistry ,Chemotherapy regimen ,Fludarabine ,Clinical trial ,Transplantation ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Introduction Autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease-negative complete remission (MRD-neg CR) rates in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) patients (pts). Factors associated with durable remission in pts achieving MRD-neg CR after immunotherapy with T cells engineered with a CD19 CAR (FMC63.41bb.3ζ) have not been elucidated. Methods We studied factors impacting disease-free survival (DFS) of adults with B-ALL treated with lymphodepletion chemotherapy and CD19 CAR-T cells in a phase I/II clinical trial (NCT01865617). Pts were eligible for this analysis if they had bone marrow leukemia identified by flow cytometry and/or extramedullary disease before CAR-T cell therapy, and received CAR-T cells at or below the previously determined maximum tolerated dose (MTD; Turtle, JCI 2016). Anti-tumor response after CAR-T cell infusion was assessed by bone marrow aspiration and biopsy, with PET-CT performed in pts with extramedullary disease. High resolution (1:10,000) flow cytometry was used to identify marrow MRD, and marrow from pts in MRD-neg CR was evaluated by high throughput sequencing (HTS) of IGH, IGK, TRB, TRD, and TRG genes. Cox regression univariate and stepwise multivariable modeling were performed to identify factors associated with DFS. Results Of 57 pts who received lymphodepletion and CD19 CAR-T cells, 53 were evaluable for response and 4 were not evaluable (one MRD-neg CR before CAR-T cell infusion; 2 received CAR-T cells above the MTD; one fatal neurotoxicity prior to restaging). Forty-five of 53 restaged pts (85%) achieved MRD-neg CR after CAR-T cell therapy. With a median follow-up of 30.9 months, DFS and overall survival (OS) were longer in pts who achieved MRD-neg CR compared to those who did not (Fig 1A; median DFS, 7.6 vs 0.8 months, P < .0001; median OS, 20.0 vs 5.0 months, P = .014). Twenty-eight of the 45 pts who achieved MRD-neg CR had a leukemic clone identified by HTS prior to CAR-T cell infusion, and in 20 of these pts (71%), the leukemic clone was not detected in marrow 3 weeks after CAR-T cell infusion. DFS was better in MRD-neg CR pts with no detected malignant clone compared to those with a persistent clone by HTS (Fig 1B; median DFS, 8.4 vs 3.6 months, P = .036). We then used stepwise multivariable modeling to determine factors impacting DFS in the pts who achieved MRD-neg CR (n = 45). Better DFS was seen in pts with a higher pre-lymphodepletion platelet count (hazard ratio, HR 0.65 [95% CI; 0.47-0.88] per 50,000/μL increment P = .006), lower pre-lymphodepletion LDH (HR 1.39 [1.12-1.74] per 100 U/L increment, P = .003), and with incorporation of fludarabine into the cyclophosphamide-based lymphodepletion (Cy/Flu; HR 0.34 [0.15-0.78], P = .011). Similar findings were noted in analysis of MRD-neg CR pts who had no malignant clone by HTS after CAR-T cells. Pts with platelets ≥100,000/μL and normal LDH before lymphodepletion who received Cy/Flu (good risk, n = 15) had 2-year point estimates of DFS and OS of 78% and 86%, respectively. Allogeneic hematopoietic cell transplantation (HCT) is standard of care in suitable R/R adult B-ALL pts after achieving MRD-neg CR. Eighteen pts in MRD-neg CR after CAR-T cells underwent HCT a median of 2.3 months after CAR-T cell infusion. We analyzed the effect on DFS of HCT after CAR-T cell therapy by treating HCT as a time-dependent covariate. After adjusting for LDH, platelets, and Cy/Flu lymphodepletion, pts undergoing HCT after CAR-T cell therapy had lower risk of failure for DFS compared to those who did not undergo HCT (Table 1). No significant interaction effect was seen between HCT and risk group (P = .51). With a median follow-up of 28.4 months after HCT, 2-year point estimates of DFS and OS were 61% and 72% respectively. The 2-year cumulative incidence of relapse was 17% and non-relapse mortality was 23%. Conclusion A high rate of MRD-neg CR was seen following CD19 CAR-T cell therapy in adult B-ALL pts and is associated with improved DFS and OS. Absence of the index clone by HTS after CAR-T cells was associated with better DFS, suggesting deeper responses are associated with improved outcomes. Stepwise multivariable modeling identifies better DFS in pts with higher pre-lymphodepletion platelet count and lower LDH, and with use of Cy/Flu lymphodepletion. After adjusting for these factors, HCT after CD19 CAR-T cells may also be associated with better DFS. Disclosures Hay: DAVA Oncology: Honoraria. Hirayama:DAVA Oncology: Honoraria. Li:Juno Therapeutics: Employment, Equity Ownership. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Rocket Pharmaceuticals: Consultancy; Homology Medicine: Consultancy; Magenta: Consultancy. Ramos:Seattle Genetics: Employment, Equity Ownership. Shadman:Qilu Puget Sound Biotherapeutics: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Research Funding; Genentech: Consultancy; Mustang Biopharma: Research Funding; AbbVie: Consultancy; Celgene: Research Funding; Verastem: Consultancy; Acerta Pharma: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding; Gilead Sciences: Research Funding. Cassaday:Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Merck: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Riddell:Adaptive Biotechnologies: Consultancy; NOHLA: Consultancy; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Membership on an entity's Board of Directors or advisory committees. Maloney:Seattle Genetics: Honoraria; Roche/Genentech: Honoraria; GlaxoSmithKline: Research Funding; Janssen Scientific Affairs: Honoraria; Juno Therapeutics: Research Funding. Turtle:Adaptive Biotechnologies: Consultancy; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Gilead: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Caribou Biosciences: Consultancy; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy; Aptevo: Consultancy.
- Published
- 2018
41. Efficacy and Toxicity of JCAR014 in Combination with Durvalumab for the Treatment of Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma
- Author
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Alexandre V. Hirayama, Kevin A. Hay, Jordan Gauthier, Sindhu Cherian, Xueyan Chen, Rachel N. Steinmetz, Mazyar Shadman, Reed M. Hawkins, Barbara S. Pender, Aude G. Chapuis, Hans-Peter Kiem, Stanley R. Riddell, Utkarsh Acharya, Ryan D. Cassaday, David G. Maloney, Aesha Vakil, Tinh-Doan Phi, Alyssa Sheih, Brian G. Till, and Cameron J. Turtle
- Subjects
0301 basic medicine ,Chemotherapy ,medicine.medical_specialty ,Durvalumab ,Cyclophosphamide ,Combination therapy ,business.industry ,medicine.medical_treatment ,Immunology ,Common Terminology Criteria for Adverse Events ,Cell Biology ,Hematology ,Biochemistry ,Fludarabine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Tolerability ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adverse effect ,business ,medicine.drug - Abstract
Introduction Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have shown high overall response rates (ORR) in otherwise treatment-refractory CD19+ B-cell non-Hodgkin lymphoma (NHL); however, not all patients (pts) achieve complete remission (CR). PD-L1 expression on tumor cells and/or other tissues could impair the function of PD-1+ CAR-T cells and the efficacy of CD19 CAR-T cell immunotherapy. PD-1 pathway blockade may enhance the function and antitumor activity of CD19 CAR-T cells. Here we report preliminary data from a phase 1 dose-finding study (NCT02706405) of the safety and feasibility of combination therapy with JCAR014 CD19-specific 4-1BB-costimulated CAR-T cells and escalating doses of durvalumab, an anti-PD-L1 monoclonal antibody, in adults with relapsed/refractory aggressive B-cell NHL. Methods Pts are treated in one of two groups. All pts receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine followed by infusion of JCAR014. Pts in group 1 receive the first infusion of durvalumab (225 mg, 750 mg, or 1500 mg) 21-28 days after treatment with JCAR014. Pts in group 2 receive the first dose of durvalumab (7.5 mg, 22.5 mg, 75 mg, 225 mg, 750 mg, or 1500 mg) 1 day prior to JCAR014 infusion. Up to 10 doses of durvalumab are administered after JCAR014 at the highest identified safe dose at 4-week intervals until toxicity or disease progression. We evaluated the safety, tolerability, and efficacy of the combination therapy and the pharmacokinetic profile of JCAR014 after infusion. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, with the exception of cytokine release syndrome (CRS), which was graded according to consensus criteria (Lee, Blood 2014). Positron emission tomography/computed tomography was performed approximately 1, 2, 4, 6, 9, and 12 months after JCAR014 infusion and the best anti-tumor response was reported according to the Lugano criteria (Cheson, JCO 2014). Results Patient characteristics are shown in Table 1. Fifteen pts have been treated, including 6 in group 1 who received post-JCAR014 durvalumab doses of 225 mg (n = 3) and 750 mg (n = 3), and 9 in group 2 who received pre-JCAR014 durvalumab doses of 7.5 mg (n = 1), 22.5 mg (n = 1), 75 mg (n = 3), or 225 mg (n = 4). Durvalumab dose escalation is ongoing. JCAR014 manufacturing was successful for all pts. All pts received 2 x 106 JCAR014 CAR-T cells/kg, except the first 2 pts treated on the study who received 7 x 105 CAR-T cells/kg. Of the 13 pts who received JCAR014 at 2 x 106 CAR-T cells/kg, 5 pts (38%) developed CRS (2 grade 1, 2 grade 2, and 1 grade 4) and one (8%) developed grade 1 neurotoxicity. CRS and/or neurotoxicity occurred within 4 weeks of JCAR014 infusion, and were not observed when durvalumab was administered after JCAR014. With the exception of B cell aplasia, no autoimmune adverse events were observed. Twelve of 13 pts who received 2 x 106 CAR-T cells/kg were evaluable for response. One patient, who had grade 4 CRS and biopsy evidence of extensive CAR-T cell infiltration into persistent sites of disease, elected to receive hospice care and died on day 32 after JCAR014 infusion without full response evaluation. The overall response rate was 50% (5 CR, 42%; 1 PR, 8%). Of the 5 pts who achieved CR, 3 were in CR at the first restaging after JCAR014 and 2 subsequently converted to CR after the first post-JCAR014 durvalumab infusion. Only one patient who achieved CR has relapsed (median follow-up 10.6 months, range 3.7-11.8). Continued stable disease or evidence of regression was seen in 4 of 6 (67%) initially non-responding pts who continued durvalumab therapy (median 5 doses, range 1-6). CAR-T cell counts expanded in the peripheral blood within 14 days of JCAR014 infusion in all pts. Higher peak and day 28 CAR-T cell copy numbers in blood by qPCR were observed in responding pts. CAR-T cells were detected for a median of 5.1 months (range, 1.7 to 9.1 months) in responding pts. In vivo re-accumulation of CAR-T cells after the first post-JCAR014 durvalumab dose was observed in the blood of two patients in group 2. Conclusion The combination of JCAR014 with durvalumab for the treatment of adult pts with aggressive B-cell NHL appears safe; however, dose escalation is ongoing. Complete responses were observed both at initial restaging after JCAR014 infusion, and also subsequently in pts continuing durvalumab therapy after initially failing to achieve CR. Disclosures Hirayama: DAVA Oncology: Honoraria. Hay:DAVA Oncology: Honoraria. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Homology Medicine: Consultancy; Magenta: Consultancy; Rocket Pharmaceuticals: Consultancy. Shadman:Verastem: Consultancy; Beigene: Research Funding; Mustang Biopharma: Research Funding; Gilead Sciences: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Research Funding. Cassaday:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Research Funding; Incyte: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Riddell:Cell Medica: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; NOHLA: Consultancy. Maloney:Roche/Genentech: Honoraria; Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; GlaxoSmithKline: Research Funding; Seattle Genetics: Honoraria. Turtle:Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; Bluebird Bio: Consultancy; Gilead: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Caribou Biosciences: Consultancy; Aptevo: Consultancy.
- Published
- 2018
42. Factors Impacting Progression-Free Survival after CD19-Specific CAR-T Cell Therapy for Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma
- Author
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Jordan Gauthier, Sindhu Cherian, Kevin A. Hay, Utkarsh Acharya, Daniel Li, Barbara S. Pender, Ryan C. Lynch, Aesha Vakil, Ryan D. Cassaday, Jorge Ramos, Alexandre V. Hirayama, Qian Wu, David G. Maloney, Aude G. Chapuis, Brian G. Till, Janaki Purushe, Rachel N. Steinmetz, Cameron J. Turtle, Tinh-Doan Phi, Alyssa Sheih, Hans-Peter Kiem, Stanley R. Riddell, Jenna M. Voutsinas, Ted Gooley, Mazyar Shadman, Xueyan Chen, and Reed M. Hawkins
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Chemotherapy ,Cyclophosphamide ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,Immunology ,Aggressive lymphoma ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Fludarabine ,Lymphoma ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,Internal medicine ,medicine ,Progression-free survival ,business ,medicine.drug - Abstract
Introduction Lymphodepletion chemotherapy followed by infusion of T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) has shown remarkable efficacy in patients (pts) with relapsed/refractory (R/R) CD19+ B-cell malignancies, with high response rates reported in non-Hodgkin lymphoma (NHL). Durable responses have been observed in a subset of pts, but the factors associated with these long-term remissions have not been identified. We studied adults with R/R CD19+ B-cell NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by infusion of 2 x 106 CD19 CAR-T cells/kg, and identified factors before and after CAR-T cell infusion that are associated with progression-free survival (PFS). Methods We conducted a phase 1/2 open-label clinical trial (NCT01865617) with the primary objective of evaluating the feasibility and safety of infusing a defined composition of CD4+ and CD8+ CD19 CAR-T cells after lymphodepletion chemotherapy in pts with R/R CD19+ B-cell malignancies. Best responses are reported according to the Lugano criteria (Cheson, JCO 2014). PFS was defined as the time from CAR-T cell infusion until disease progression or death, without censoring for new therapy. Logistic regression and penalized Cox regression multivariable modeling using elastic net were performed for analysis of response and PFS, respectively. Results Characteristics of the 57 pts in the study are shown in Table 1. One patient with incomplete response assessment was excluded. For the 56 remaining pts, the best overall response rate (ORR) without additional therapy was 57% (95% confidence interval [CI], 43-70%), with 48% achieving complete remission (CR; 95% CI, 35-62%). Most pts with partial response (PR) or stable disease (SD) after initial restaging at 4 weeks after CAR-T cell infusion received new therapy (11 of 15, 73%). All pts with PR/SD on initial restaging who did not receive additional therapy after CAR-T cells (n = 4) subsequently achieved CR. The duration of persistence of CAR-T cells was longer in pts who did not receive new therapy (15.7 vs. 5.3 months; P = .06). Eight of 9 pts with indolent histology achieved CR (89%; 95% CI, 51-99%). For the 47 pts with aggressive NHL, the best ORR was 51% (95% CI, 36-66%), with 40% (95% CI, 27-56%) achieving CR. Among aggressive NHL subtypes, pts with DLBCL (n = 28) had best ORR and CR rates of 50% (95% CI, 33-67%) and 43% (95% CI, 25-63%), respectively. In pts with aggressive lymphoma, multivariable analysis showed that the probability of achieving CR was independently associated with a lower pre-lymphodepletion serum LDH concentration (P = .003) and greater increase in serum MCP-1 concentration from a pre-lymphodepletion timepoint to immediately before CAR-T cell infusion (P = .01). Analysis of pts with all histologic subtypes showed that those achieving CR had better PFS and overall survival (OS) compared to those who did not achieve CR (median PFS: CR, not reached; non-CR, 1.35 month; Figure 1). In pts achieving CR, after a median follow-up of 20.2 months (range 2.5-32.4 months), the 24-month probabilities of PFS and OS were 59% (95% CI, 41-84%) and 79% (95% CI, 64-97%), respectively. No pts with indolent NHL who achieved CR (n = 8) have relapsed with a median follow-up of 14.5 months (range, 10.7-30.1 months). For pts with aggressive lymphoma who achieved CR, after a median follow-up of 26.9 months (range, 2.5-32.4 months), the median PFS was 20.0 months (95% CI, 9.2-not reached), and 24-month probabilities of PFS and OS were 46% (95% CI, 28-76%) and 72% (95% CI, 54-96%), respectively. In aggressive NHL, multivariable analysis suggested that, in addition to being associated with the probability of achieving CR, serum LDH and MCP-1 concentration also impacted the probability of longer PFS. The model found that lower pre-lymphodepletion serum LDH (P = .0004) and higher serum MCP-1 peak after CAR-T cell infusion (P = .05), along with higher serum IL-7 (P = .02) and lower serum IL-18 (P = .02) concentrations before lymphodepletion were independently associated with better PFS. Similar findings were obtained after multivariable analysis was performed only in those who had achieved CR. Conclusion CR after CD19 CAR-T cell therapy appears to be a strong predictor of PFS in adult pts with B-cell NHL. Identification of additional factors associated with better PFS might guide future management strategies for pts achieving CR after CD19 CAR-T cell therapy. Disclosures Hirayama: DAVA Oncology: Honoraria. Hay:DAVA Oncology: Honoraria. Li:Juno Therapeutics: Employment, Equity Ownership. Lynch:Incyte: Research Funding; Johnson Graffe Keay Moniz and Wick LLP: Consultancy; Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals: Research Funding; Takeda: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Homology Medicine: Consultancy; Rocket Pharmaceuticals: Consultancy; Magenta: Consultancy. Ramos:Seattle Genetics: Employment, Equity Ownership. Shadman:Gilead Sciences: Research Funding; Genentech: Consultancy; Pharmacyclics: Research Funding; Celgene: Research Funding; Mustang Biopharma: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Beigene: Research Funding; AstraZeneca: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy. Cassaday:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Kite Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; Merck: Research Funding; Pfizer: Consultancy, Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Riddell:Cell Medica: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; NOHLA: Consultancy; Adaptive Biotechnologies: Consultancy. Maloney:GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; Janssen Scientific Affairs: Honoraria. Turtle:Bluebird Bio: Consultancy; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Nektar Therapeutics: Consultancy, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Consultancy; Gilead: Consultancy; Adaptive Biotechnologies: Consultancy; Aptevo: Consultancy.
- Published
- 2018
43. Comparative analysis of flow cytometry and morphology for the detection of acute myeloid leukaemia cells in cerebrospinal fluid
- Author
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Frederick R. Appelbaum, Elihu H. Estey, Janis L. Abkowitz, Brent L. Wood, John M. Pagel, Sindhu Cherian, Pamela S. Becker, Roland B. Walter, and Keith R. Loeb
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pathology ,Hematology ,medicine.diagnostic_test ,business.industry ,Flow cytometry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cerebrospinal fluid ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Cytology ,Internal medicine ,Immunology ,medicine ,Myeloid leukaemia ,business ,human activities - Abstract
Keywords: acute myeloid leukaemia; cerebrospinal fluid; flow cytometry; diagnostic haematology; cytology
- Published
- 2015
44. Immunotherapy of non-Hodgkin lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells
- Author
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Xueyan Chen, Lorinda Soma, Carolina Berger, Reed M. Hawkins, Colette Chaney, Sindhu Cherian, Cameron J. Turtle, Laila-Aicha Hanafi, Brent L. Wood, David G. Maloney, Barbara S. Pender, Stanley R. Riddell, Michael Hudecek, Daniel Li, Shelly Heimfeld, and Emily Robinson
- Subjects
0301 basic medicine ,Adult ,CD4-Positive T-Lymphocytes ,Male ,T cell ,medicine.medical_treatment ,Receptors, Antigen, T-Cell ,CD8-Positive T-Lymphocytes ,Article ,Lymphocyte Depletion ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,medicine ,Biomarkers, Tumor ,Humans ,Transgenes ,Cyclophosphamide ,B cell ,Aged ,Cell Proliferation ,business.industry ,Lymphoma, Non-Hodgkin ,General Medicine ,Immunotherapy ,Syndrome ,Middle Aged ,medicine.disease ,Chimeric antigen receptor ,Lymphocyte Subsets ,Non-Hodgkin's lymphoma ,Cytokine release syndrome ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunology ,Chimeric Antigen Receptor T-Cell Therapy ,Female ,business ,CD8 ,Vidarabine - Abstract
CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that impact toxicity and efficacy have been difficult to define because of differences in lymphodepletion regimens and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4+:CD8+ ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had markedly increased CAR-T cell expansion and persistence, and higher response rates (50% CR, 72% ORR, n=20) than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR, n=12). The complete response (CR) rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR, n=11). Cy/Flu minimized the effects of an immune response to the murine scFv component of the CAR, which limited CAR-T cell expansion, persistence, and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥ 3 neurotoxicity were observed in 13% and 28% of all patients, respectively. Serum biomarkers one day after CAR-T cell infusion correlated with subsequent development of sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4+:CD8+ ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of a lymphodepletion regimen that improved disease response and overall and progression-free survival.
- Published
- 2016
45. A novel flow cytometric assay for detection of residual disease in patients with B-lymphoblastic leukemia/lymphoma post anti-CD19 therapy
- Author
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Sindhu, Cherian, Valerie, Miller, Vivian, McCullouch, Katy, Dougherty, Jonathan R, Fromm, and Brent L, Wood
- Subjects
Neoplasm, Residual ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Antigens, CD19 ,Humans ,Flow Cytometry ,Prognosis ,Antibodies - Abstract
Residual disease detection following therapy is an important prognostic variable in B-lymphoblastic leukemia (B-LL). Most flow cytometric strategies for detecting B cell malignancy utilize CD19 to identify B cells. With growing use of anti-CD19 targeted therapies, alternative strategies are needed for residual disease detection. We describe an approach for residual disease detection in this setting.A novel combination was designed using expression of CD22 or CD24 (without CD66b) for B cell detection in combination with markers aberrantly expressed in B-LL (CD10, CD20, CD34, CD38, and CD45). The performance characteristics of this combination were evaluated and compared to a standard, validated B-LL MRD assay using 10 known negative samples, 10 overtly positive samples, and 11 post-therapy samples (prior therapy other than anti-CD19 therapy). Subsequently, results from the first 100 samples on which the new tube was performed were reviewed.The described combination performed well in the initial analysis of 31 samples with all negative and positive samples correctly classified. In positive samples, the percentage of abnormal cells correlated well between the standard and new assay. Evaluation of the first 100 samples demonstrated good performance with adequate detection of CD19-positive and CD19-negative B-LL. Additionally, it was observed that patients receiving anti-CD19 therapies demonstrate an increased proportion of CD19-negative progenitors.These preliminary findings describe a strategy that performs well for residual disease detection in B-LL post anti-CD19 therapy. Such alternative strategies will become more important as the use of targeted immunotherapies becomes more common. © 2016 International Clinical Cytometry Society.
- Published
- 2016
46. The Myeloproliferative Neoplasms
- Author
-
Sindhu Cherian and Brent L. Wood
- Subjects
Polycythemia vera ,business.industry ,Essential thrombocythemia ,Cancer research ,medicine ,medicine.disease ,business ,JAK2 V617F ,Chronic myelogenous leukemia - Published
- 2012
47. Frequency of additional clonal populations detected by high sensitivity flow cytometry in patients with hairy cell leukemia
- Author
-
Sindhu Cherian and Mikhail Roshal
- Subjects
education.field_of_study ,Histology ,Lymphocytosis ,Population ,Clone (cell biology) ,Hematology ,Plasma cell ,Plasma cell neoplasm ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,medicine.anatomical_structure ,Monoclonal ,Immunology ,medicine ,Hairy cell leukemia ,medicine.symptom ,education ,Monoclonal gammopathy of undetermined significance - Abstract
Samples from 115 patients with hairy cell leukemia (HCL) were analyzed by high sensitivity flow cytometry for evidence of an additional B cell or plasma cell clone. We found that 10.4% of HCL patients harbored an additional clonal population in either peripheral blood or bone marrow. Among the patients with additional clones, 58% had the second population present at the time of HCL diagnosis and 42% developed the second clone in a subsequent sample. Half of the clonal populations identified represented true disease entities rather than a monoclonal B lymphocytosis (MBL) or monoclonal gammopathy of undetermined significance (MGUS). The frequency of MBL and MGUS was similar to that reported in the general population, but the frequency of B cell-derived malignancies appears increased in the HCL cohort. Compared to patients without additional clones, the patients with second clones were older (median age 66 vs. 55 years old). Patients over age 60 were at higher risk for a second clone (18.2% vs. 5.6%, OR 3.7, P
- Published
- 2012
48. In-vivo purging of the circulating clonal T-cells with Alemtuzumab prior to autologous peripheral blood hematopoietic cell mobilization and transplantation
- Author
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Ajay K. Gopal, Toni Ann Lupinacci, Andrei R. Shustov, David G. Maloney, Allison Shaw, Leona Holmberg, and Sindhu Cherian
- Subjects
Mobilization ,business.industry ,medicine.medical_treatment ,Hematology ,Immunotherapy ,medicine.disease ,Bone marrow purging ,Transplantation ,In vivo ,medicine ,Cancer research ,Alemtuzumab ,T-cell lymphoma ,business ,Hematopoietic Stem Cell Mobilization ,medicine.drug - Published
- 2011
49. Factors associated with duration of response after CD19-specific CAR-T cell therapy for refractory/relapsed B-cell non-Hodgkin lymphoma
- Author
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Xueyan Chen, Jordan Gauthier, Sindhu Cherian, Kevin A. Hay, Daniel Li, Alyssa Sheih, Reed M. Hawkins, David G. Maloney, Jenna M. Voutsinas, Alexandre V. Hirayama, Cameron J. Turtle, Vicky Wu, Stanley R. Riddell, Tinh-Doan Phi, Barbara S. Pender, Aesha Vakil, and Rachel N. Steinmetz
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,chemical and pharmacologic phenomena ,CD19 ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Antigen ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,biology ,business.industry ,Complete remission ,hemic and immune systems ,medicine.disease ,Lymphoma ,030220 oncology & carcinogenesis ,B-Cell Non-Hodgkin Lymphoma ,biology.protein ,CAR T-cell therapy ,business ,030215 immunology - Abstract
7567Background: CD19-specific chimeric antigen receptor-modified T (CD19 CAR-T) cells achieve high complete remission (CR) rates in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), yet factor...
- Published
- 2018
50. Factors impacting disease-free survival in adult B cell B-ALL patients achieving MRD-negative CR after CD19 CAR-T cells
- Author
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Rachel N. Steinmetz, Tinh-Doan Phi, Cameron J. Turtle, David G. Maloney, Alexandre V. Hirayama, Daniel Li, Kevin A. Hay, Jordan Gauthier, Sindhu Cherian, Stanley R. Riddell, Xueyan Chen, Alyssa Sheih, Aesha Vakil, Barbara S. Pender, Reed M. Hawkins, Vicky Wu, and Jenna M. Voutsinas
- Subjects
Cancer Research ,Disease free survival ,biology ,business.industry ,Complete remission ,MRD Negative ,CD19 ,Autologous T-cells ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,biology.protein ,Car t cells ,business ,human activities ,B cell ,030215 immunology - Abstract
7005Background: Autologous T cells engineered to express a CD19-targeting 4-1BB-costimulated CAR (CAR-T cells) have produced high complete remission (CR) rates in adult B-ALL patients (pts; NCT 018...
- Published
- 2018
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