11 results on '"Obstfeld A"'
Search Results
2. Cytokine release syndrome associated with chimeric-antigen receptor T-cell therapy: clinicopathological insights
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Keith Mansfield, Noelle V. Frey, J. Joseph Melenhorst, Mariusz A. Wasik, David L. Porter, Amrom E. Obstfeld, Carl H. June, and Simon F. Lacey
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0301 basic medicine ,Chimera organism ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Immunotherapy ,medicine.disease ,Biochemistry ,03 medical and health sciences ,Leukemia ,Cytokine release syndrome ,030104 developmental biology ,0302 clinical medicine ,Antigen ,030220 oncology & carcinogenesis ,medicine ,Chimeric Antigen Receptor T-Cell Therapy ,Clinical efficacy ,Receptor ,business - Abstract
To the editor: Chimeric-antigen receptor T-cell (CART-cell) immunotherapy has proven clinical efficacy,[1][1] particularly in B-cell leukemia and lymphoma.[2][2][⇓][3]-[4][4] However, it causes a unique set of toxicities, the foremost of which is cytokine release syndrome (CRS).[5][5],[6][6] The
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- 2017
3. Cytokine release syndrome associated with chimeric-antigen receptor T-cell therapy: clinicopathological insights
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Obstfeld, Amrom E., Frey, Noelle V., Mansfield, Keith, Lacey, Simon F., June, Carl H., Porter, David L., Melenhorst, Jan J., and Wasik, Mariusz A.
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- 2017
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4. Comparison of LTA Versus Wbila in Pediatric Patients with Suspected Platelet Function Disorders
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Wax, Abigail, primary, Doshi, Bhavia, additional, Arulselvan, Abinaya, additional, Obstfeld, Amrom, additional, and Lambert, Michele P., additional
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- 2018
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5. The Immature Reticulocyte Fraction As an Aid in the Diagnosis and Prognosis of Parvovirus B19 Infection in Sickle Cell Disease
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Mitrani, Robert, primary, Gollomp, Kandace, additional, Lambert, Michele P., additional, and Obstfeld, Amrom, additional
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- 2018
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6. Comparison of LTA Versus Wbila in Pediatric Patients with Suspected Platelet Function Disorders
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Bhavia Doshi, Abinaya Arulselvan, Michele P. Lambert, Abigail Wax, and Amrom E. Obstfeld
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Gold standard (test) ,Phlebotomy ,medicine.disease ,Biochemistry ,Gastroenterology ,Thrombosis ,Hemostatics ,Internal medicine ,medicine ,Medical history ,Platelet ,business ,Blood Platelet Disorders ,Whole blood - Abstract
Background Diagnosis of platelet function disorders in pediatric patients is complicated by difficulties identifying at risk patients (due to young age, fewer hemostatic challenges) (Gresele, Journal of Thrombosis and Haemostasis, 2015), large quantities of blood required for standard testing, and inability to use large gauge needles to perform phlebotomy increasing the probability of false positive results. Diagnostic testing for pediatric platelet disorders has recently shifted from Light Transmission Aggregometry (LTA) with serotonin release to Whole Blood Impedance Lumi-Aggregometry (WBILA). There is a paucity of literature comparing LTA and WBILA and few studies examining bleeding assessment tools in exclusively pediatric populations. LTA is widely studied and considered the gold standard of platelet testing. However, the newer and less validated WBILA has a lower blood volume requirement making it potentially more suitable for very young patients in need of testing. Therefore, there is a significant need to validate results from WBILA testing to be able to perform platelet testing on young patients. Aims The study purpose was to analyze lab testing results and patient characteristics for patients that have had WBILA or LTA with serotonin release and compare results across testing platforms. We also compared performance characteristics for patients with access to both methods. Further, we compared Bleeding Assessment Tool (BAT) scores, age distributions and types of testing results and their occurrences for both types of testing. Methods Medical and laboratory records of children evaluated at the Children's Hospital of Philadelphia and at the Hospital of the University of Pennsylvania that were referred for a variety of causes from 1/1/2016 until 6/30/2018 were examined. Males and females referred for concerns for bleeding who are age 2 months to 21 years at time of evaluation were included. In late 2016 the coagulation laboratory at CHOP validated WBILA. Prior to this, patients were tested using LTA. Patient history and demographic information, indication for testing, aggregometry findings and final diagnosis were compared prior to and after this transition. Medical records were used to derive a bleeding score. Approximately 300 records were reviewed. Results For LTA with serotonin release, ages were distributed bimodally with peaks at 6 years and 16 years with an average of 10.6 years (SD=5.4 years). The most frequent indications for testing were epistaxis (24%) and easy bruising (20%). For WBILA, ages were distributed bimodally with peaks at 35 months and 15 years with an average of 8.6 years (SD=5.5 years). The most frequent indications for testing were epistaxis (27%) and family history (17%). Average age of patients tested with WBILA was significantly lower than LTA with serotonin release (p=0.0013). No difference in distribution or average BAT scores was seen between patients tested with LTA and WBILA. The percent of abnormal results for cases with LTA testing was 32% versus 27% for WBILA cases, a difference that was not statistically significant. This suggests that the tests have similar diagnostic performance. Additionally, there is a trend towards an association between higher BAT scores and abnormal test results, but not significantly due to few abnormal cases. Finally, comparison of WBILA with LTA results showed that for the 9 patients with both studies, 4 had normal WBILA after borderline abnormal LTA results and 5 had congruent findings. Conclusions Our data highlight the differences in results and patient characteristics between LTA and WBILA testing. The most significant difference between the two tests was age distribution, with LTA, which requires more blood, being performed in older patients. In examining test performance, our analysis of BAT scores suggests that in our population a higher BAT score may be associated with higher probability of abnormal result, but differences in scores are small and make it hard to differentiate patients appropriate for testing based on bleeding scores alone. Our rate of abnormal results is similar to that of other populations, and highlights the difficulty of diagnosis in pediatric populations. Based on the consistent frequencies of abnormal findings across test types and the analysis of BAT scores, WBILA may be an acceptable alternative to LTA with serotonin release in young patients needing evaluation for platelet function defects. Disclosures Doshi: Bayer: Research Funding. Lambert:Rigel: Consultancy; Summus: Consultancy; Shionogi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Educational Concepts in Medicine: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy; Sysmex: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees.
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- 2018
7. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy
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Vijay Bhoj, Christoph T. Ellebrecht, Gerald Wertheim, Michael C. Milone, Dimitrios Arhontoulis, Wei-Ting Hwang, S. Grupp, Shannon L. Maude, Adam Bagg, Simon F. Lacey, Amrom E. Obstfeld, Michael Feldman, Mariusz A. Wasik, Farzana Nazimuddin, J. Joseph Melenhorst, Colleen Callahan, David L. Porter, Stephen J. Schuster, James Capobianchi, and Carl H. June
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0301 basic medicine ,Adult ,Male ,Adoptive cell transfer ,Lymphoma, B-Cell ,Adolescent ,Clinical Trials and Observations ,T-Lymphocytes ,Immunology ,Antigens, CD19 ,Plasma Cells ,Bone Marrow Cells ,Biochemistry ,Immunoglobulin G ,CD19 ,03 medical and health sciences ,Antigen ,Immunity ,Inside BLOOD Commentary ,hemic and lymphatic diseases ,medicine ,Humans ,Child ,biology ,Cell Biology ,Hematology ,Middle Aged ,Adoptive Transfer ,Immunoglobulin A ,030104 developmental biology ,medicine.anatomical_structure ,Humoral immunity ,biology.protein ,Female ,Bone marrow ,Antibody - Abstract
The mechanisms underlying the maintenance of long-lasting humoral immunity are not well understood. Studies in mice indicate that plasma cells (PCs) can survive up to a lifetime, even in the absence of regeneration by B cells, implying the presence of long-lived PCs as a mechanism for long-lasting immunity. Evidence from humans treated with anti-CD20, which depletes circulating B cells, also suggests B-cell-independent long-term survival of some PCs. On the other hand, antibody responses may be sustained solely by short-lived PCs with repopulation from clonally related memory B cells. To explore PC longevity and humoral immunity in humans, we investigated the fate of PCs and their antibodies in adult and pediatric patients who received chimeric antigen receptor-based adoptive T-cell immunotherapy targeting CD19 to treat B-cell lineage malignancies (CTL019). Treatment with CTL019 is frequently associated with B-cell aplasia that can persist for years. Serum antibody titers to vaccine-related antigens were measured, and quantitative assessment of B cells and PCs in blood and bone marrow was performed at various time points before and after CTL019 therapy. While total serum immunoglobulin concentrations decline following CTL019-induced B-cell aplasia, several vaccine/pathogen-specific serum immunoglobulin G and A (IgG and IgA) titers remain relatively stable for at least 6 and 12 months posttreatment, respectively. Analysis of bone marrow biopsies after CTL019 revealed 8 patients with persistence of antibody-secreting PCs at least 25 months post-CTL019 infusion despite absence of CD19(+)CD20(+) B cells. These results provide strong evidence for the existence of memory B-cell-independent, long-lived PCs in humans that contribute to long-lasting humoral immunity.
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- 2016
8. Incidence of Hemolytic Events after Exposure to Triggering Medications in Pediatric Patients with G6PD Deficiency
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Doshi, Bhavya, primary, Kamdar, Aditi, additional, Smith-Whitley, Kim, additional, Lambert, Michele P, additional, and Obstfeld, Amrom, additional
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- 2016
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9. Incidence of Hemolytic Events after Exposure to Triggering Medications in Pediatric Patients with G6PD Deficiency
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Amrom E. Obstfeld, Kim Smith-Whitley, Michele P. Lambert, Aditi Kamdar, and Bhavya S. Doshi
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education.field_of_study ,medicine.medical_specialty ,Primaquine ,business.industry ,Anemia ,Immunology ,Population ,Cell Biology ,Hematology ,Dapsone ,medicine.disease ,Biochemistry ,Hemolysis ,Surgery ,Tumor lysis syndrome ,Nitrofurantoin ,Internal medicine ,medicine ,Rasburicase ,education ,business ,medicine.drug - Abstract
Background: Glucose 6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder that occurs in approximately 400 million people worldwide. It is characterized by varying degrees of hemolysis most often triggered by infections, drugs, or certain foods. However, most people with G6PD deficiency do not have a clinically significant phenotype. Some medications thought to trigger hemolytic crises in patients with G6PD deficiency can be life-saving (e.g. rasburicase in severe tumor lysis syndrome). Thus, the ability to stratify patients according to risk of hemolysis may have significant clinical implications. In December 2014, our reference lab increased the lower limit of normal of the G6PD enzymatic assay from 7 units/g Hb to 9.9 units/g Hb, which increased the number of patients diagnosed with G6PD deficiency. However, it remains unknown if patients with intermediate levels (between 7 and 11 units/g Hb) experience hemolysis when exposed to triggers compared to patients with levels below 7 units/g Hb. Methods: We conducted a retrospective cohort analysis of patients with G6PD enzymatic levels between 2014 and 2016 to determine risk of hemolysis in patients with low or intermediate levels upon exposure to hemolysis-triggering medications (rasburicase, dapsone, nitrofurantoin, primaquine, cotrimoxazole, methylene blue, probenecid, phenazopyridine, moxifloxacin and aspirin). Hemolysis was defined by clinical documentation and further characterized by need for transfusion after drug exposure as well as a decrease in pre-exposure hemoglobin after exposure. Inclusion criteria were patients 0-21 years of age at time of G6PD assay, G6PD assay level less than 11 units/g Hb, exposure to one of the listed medications, and those with peri-exposure hemoglobin and transfusion data available. Patients were excluded if G6PD assay level was ≥ 11 units/g Hb, they were over 21 years of age at time of assay, or were not exposed to the listed medications. Results: We identified 704 patients who had available G6PD assays during the study period. Assay levels in this cohort ranged from 0.3 to 270 units/g Hb with 291 having G6PD assay levels less than 11 units/g Hb. Of these patients, 39 had both qualifying G6PD levels and documented exposure to one or more of the triggering medications; 5 patients had low G6PD levels ( There were two patients amongst those in the study who had significant hemolytic events associated with anemia warranting blood transfusion. One patient (a male) with a low G6PD assay level (2.4 units/g Hb) had clinically significant hemolysis in the setting of rasburicase exposure. The other patient (a female) with a high intermediate G6PD assay (10.8 units/g Hb) had clinically significant hemolysis in the setting of cotrimoxazole exposure, but had a complicated clinical course making it difficult to attribute causality of hemolysis definitively to cotrimoxazole. Of note, no patients with intermediate G6PD assay levels (between 7 and 10 units/g Hb) had significant hemolysis despite exposure to a triggering medication. Conclusions: Our results indicate that there was no clear association between G6PD assay levels above 7 units/g Hb and the incidence of hemolysis. Despite a general avoidance of cotrimoxazole exposure in patients with known G6PD deficiency, our study did not reveal a significant correlation between drug exposure and hemolytic events in this population. Importantly, the only patient with significant hemolysis in the setting of rasburicase exposure had a very low G6PD level. Further correlation with genotype and G6PD assay level may have significant clinical implications to predict one's risk of clinically significant hemolysis. Disclosures Smith-Whitley: Pfizer: Membership on an entity's Board of Directors or advisory committees. Lambert:Novartis: Consultancy.
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- 2016
10. Refractory Cytokine Release Syndrome in Recipients of Chimeric Antigen Receptor (CAR) T Cells
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Frey, Noelle V., primary, Levine, Bruce L., additional, Lacey, Simon F., additional, Grupp, Stephan A., additional, Maude, Shannon L, additional, Schuster, Stephen J., additional, Shaw, Pamela, additional, Hwang, Wei-Ting, additional, Wasik, Mariusz A., additional, Obstfeld, Amrom, additional, Leung, Mimi, additional, Shen, Angela, additional, Ericson, Solveig G., additional, Melenhorst, Jan J, additional, June, Carl H., additional, and Porter, David, additional
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- 2014
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11. Refractory Cytokine Release Syndrome in Recipients of Chimeric Antigen Receptor (CAR) T Cells
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J. Joseph Melenhorst, Mariusz A. Wasik, David L. Porter, Pamela A. Shaw, Stephen J. Schuster, Bruce L. Levine, Carl H. June, Noelle V. Frey, Wei-Ting Hwang, Shannon L. Maude, Angela Shen, Mimi Leung, Solveig G. Ericson, Stephan A. Grupp, Amrom E. Obstfeld, and Simon F. Lacey
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medicine.medical_specialty ,Chemotherapy ,Cyclophosphamide ,business.industry ,Influenzavirus B ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Siltuximab ,Etanercept ,chemistry.chemical_compound ,Cytokine release syndrome ,Tocilizumab ,chemistry ,Internal medicine ,Acute lymphocytic leukemia ,otorhinolaryngologic diseases ,Medicine ,business ,medicine.drug - Abstract
CTLO19 cells are CAR-modified T cells which recognize CD19 and produce high durable remission rates for pts with relapsed or refractory acute lymphoblastic leukemia (ALL). Cytokine Release Syndrome (CRS) has emerged as the major treatment related effect from CTL019, with symptoms that include high fevers and malaise but can progress to capillary leak, hypoxia and hypotension. CRS occurs hours to days after CTL019 infusion and correlates with rapid in vivo CTL019 expansion and marked elevation of serum IL6. In most cases, CRS is self-limited or rapidly reversed with anti-cytokine directed therapies. Here we report 3 cases of refractory CRS in adult pts with ALL. Our experience offers insight into clinical and investigational parameters describing this syndrome; highlights the variance of CRS across disease types and illustrates complexities of CRS management during concurrent infectious illness. As of 7/1/14, 97 pts (30 pediatric ALL, 12 adult ALL, 41 CLL, 14 NHL) have been treated with CTLO19. To capture clinical manifestations of CRS across protocols, we developed a novel CRS grading scale which will be described. Severe CRS (Gr 3-5) occurred in 27 (64%) of ALL pts and only 16 (29%) of CLL/NHL pts (p=0.001). 12 adults with ALL received CTL019; 8/9 evaluable pts achieved CR (MRD negative) at 1 month and 1 pt with extramedullary disease had marked reduction of PET avid disease which is maintained at 1 yr. Severe CRS occurred in 11 of 12 adult ALL pts. CRS was self-limited in 2 pts, rapidly reversed with anti-IL6 directed therapy in 6 pts and was refractory to therapy, contributing to death in 3 pts who were not evaluable for disease response. No baseline attributes differentiate these 3 pts from the 9 adult ALL pts with manageable Gr1-4 CRS. We have shown however that ALL disease burden correlates with CRS severity (in press) and all 3 pts had significant disease burden at baseline. All received lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2 q12h x 6 followed by infusion of CTLO19 cells. These 3 pts each received 6.50E+06, 6.70E+06 and 8.45E+06 CTLO19 cells/kg compared to median CTL019 dose of 3.62E+06 in the 9 adult ALL pts with manageable CRS. Pt 21413-03 developed CRS 12 hrs after infusion and tested positive for influenza B on D3. Despite broad spectrum antimicrobials (including oseltamivir) and anticytokine directed therapy with tocilizumab (4mg/kg x 2) and steroids, he died with refractory hypotension on D5. Pt 21413-06 had extensive disease after 2 prior allogeneic SCTs and developed CRS within 12 hrs of infusion. In addition to broad spectrum antibiotics, she received tocilizumab 8mg/kg (D 3, 6 and 12); intermittent high dose steroids (D 4-15) and etanercept (D14). She died D15 with hypotension, hypoxic respiratory failure and concurrent MDR pseudomonas sepsis and pneumonia. Pt 21413-11 developed CRS within 24 hrs of infusion. He received tocilizumab 8mg/kg (D3&4); siltuximab (D5&15) and intermittent high dose steroids (D 4-15). After an initial response, he developed recurrent fever, pulmonary infiltrates and blood cultures positive for stenotrophomonas. He died D15 with refractory hypoxia and hypotension. All 3 pts’ clinical CRS correlated with marked in vivo CTL019 expansion and progressive serum cytokine elevations (data to be shown). CONCLUSIONS: CRS is the major toxicity of CTL019 therapy and its clinical course varies depending on disease type (more frequent and severe in ALL) and disease burden (in ALL). The 3 refractory CRS cases described here (of 97 total pts treated) have all occurred in adult ALL pts with significant disease burden who received relatively high doses of CTL019 cells. In addition, all 3 had significant infectious complications which potentially fueled underlying CRS and/or were made more virulent due to impairment of immunity with administration of anti-cytokine directed therapies. Future protocol modifications will be made goal of limiting severity of CRS while maintaining high durable remission rates. Further exploration is planned to better correlate timing and choice of anticytokine directed therapy in relation to clinical and investigation parameters of CRS. Disclosures Frey: Novartis: Research Funding. Off Label Use: USe of CART19 cells to treat CLL. Levine:Novartis: Patents & Royalties, Research Funding. Lacey:Novartis: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Schuster:Novartis: Research Funding. Hwang:NVS: Research Funding. Leung:Novartis: Employment. Shen:Novartis: Employment. Ericson:Novartis: Employment. Melenhorst:Novartis: Research Funding. June:Novartis: Patents & Royalties, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding.
- Published
- 2014
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