scholarly journals Do PROs Tell the Whole Story? Differential Outcomes Based on Patient-Reported Outcomes (PROs) Versus Performance-Based Metrics (PBM) on Cognition for Patients Receiving Chimeric Antigen Receptor (CAR)-T Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3043-3043
Author(s):  
Irena Tan ◽  
Rachel Cusatis ◽  
Emma Crawford ◽  
Aline Thiengmany ◽  
Claire Piehowski ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Physical Function ◽  
Board Of Directors ◽  
Research Funding ◽  
Composite Score ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
T Score ◽  
Patient Reported ◽  
Car T

Abstract Introduction: As the use of CAR-T cell therapy grows, there is an increased need to understand its impact on the patient experience, especially symptom burden and cognitive function. While the immediate side-effects of CAR-T therapy have been reported, our study aims to describe the longitudinal impact of CAR-T therapy on patients' quality of life (QoL), including patient-reported cognitive function and performance-based cognition, which are not well understood. Methods: Patients with hematologic malignancies undergoing CAR-T therapy were prospectively recruited from two academic centers. The primary endpoint was feasibility of completing longitudinal PRO assessments and PBM of cognition. NIH PROMIS measures assessed physical, mental, cognitive, and social health. PROMIS measures use the t-score metric, where 50 is the average in the U.S. population and a 5 point (0.5 SD) change was considered clinically meaningful. The NIH Toolbox Cognition Battery measured 6 constructs of cognition, scored on the t-score metric (10 point = 1SD, change considered clinically meaningful). Exploratory analyses described change from baseline. PROMIS measures were completed at baseline, 7 and 14 days, 1, 3, 6, and 12 months (mo) after CAR-T. The Toolbox was assessed at baseline, 1 month, and 12 months. Due to COVID restrictions on in person research, the Toolbox could not be assessed for the first 13 patients. Results: From 8/2020 to 6/2021, 28 patients have been enrolled. Baseline, day 7, day 14, 1 mo, 3 mo, and 6 mo data were available in 27, 20, 21, 23, 15 (10 not yet reached), and 9 (16 not yet reached) patients, respectively. The mean age was 57 years (range 27-78); 44% were female. Race distribution was: Caucasian 75%, Asian 8%, Hawaiian/Pacific Islander 4% and other race 8%; 21% were Hispanic ethnicity. Patients received CAR-T for diagnoses of NHL (75%), MM (17%), and ALL (13%). CRS was seen in 86% (all grade 1-2), neurotoxicity (ICANS) in 34% (grade 1-2: N=5 and grade > 3: N=5). PROMIS questionnaires were completed in >70% of patients across all timepoints with current follow-up; thus it was feasible to collect these data at frequent intervals after CAR-T. Mean baseline PROMIS t-scores (N=27) were similar to the average US population in all domains (fatigue: 53, sleep: 52, pain: 52, anxiety: 53, depression: 49) except for decreased physical function (44) among patients (Fig 1a-b). Physical function, fatigue, and pain interference worsened during the first month but returned to baseline by month 3 (Fig 1a-b). PBM of cognition (NIH Toolbox) were assessed at baseline in 15 pts and 1 mo in 8 patients (4 incomplete, 3 not reached timepoint). The toolbox requires in-person administration and takes 35 minutes, but has been completed in 75% of evaluable patients. At baseline, the mean total composite score was 65 th percentile and t-score was 57; mean fluid composite score was 50 th percentile and t-score was 50; mean crystallized composite score was 69 th percentile and t-score was 58 (fluid composite score measures ability to reason, crystallized composite score measures accrual of knowledge over time, Weintraub et al Neurology 2013). Little change in scores was seen in language domains and some increase (not clinically significant) was seen in constructs on attention, executive function, and episodic memory. While not significant, a trend towards worsening working memory and processing speed and a trend towards worsening t-scores for all composite scores was seen (Figure 1c). 2 patients with neurotoxicity grade 3 and available baseline and 1-mo Toolboxes were noted to have decreases in all composite scores (clinically significant in 1). Patients did not self-report changes in cognitive function over 6 months (Fig 1d). Conclusion: This study reports early data from longitudinal neurocognitive assessments and PROs in patients undergoing CAR-T. It is feasible for patients undergoing CAR-T to complete PROMIS surveys (PROs) and NIH cognitive Toolboxes (performance-based test). Early and frequent PRO surveys captured initial worsening in physical function, fatigue, and pain interference that returned to baseline by month 3. There was no change in patient-reported cognitive function over time, but using PBM cognition testing, we noted a trend towards worsening cognition in some domains. Continued patient accrual and longer follow up will allow assessment of degree and persistence of worsened PBM cognition associated with CAR-T. Figure 1 Figure 1. Disclosures Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Shah: Lily: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Legend: Consultancy; Kite: Consultancy; Incyte: Consultancy; Umoja: Consultancy. D'Souza: Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Janssen, Prothena: Consultancy; Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding. Miklos: Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding; Astellas, Jasper, Adaptive, Baxalta: Research Funding. Sidana: Janssen: Consultancy, Research Funding; Magenta Therapeutics: Consultancy, Research Funding; Allogene: Research Funding; BMS: Consultancy.

scholarly journals Profiling T-Cell Receptor Diversity and Dynamics during Lymphoma Immunotherapy Using Cell-Free DNA (cfDNA)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 49-50
Author(s):  
Navika D Shukla ◽  
Alexander F. M. Craig ◽  
Brian Sworder ◽  
David M. Kurtz ◽  
Charles Macaulay ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T ◽  
Tcr Repertoire ◽  
Support Research

Background: Characterization of T-cell receptor (TCR) diversity and dynamics is increasingly critical to understanding therapeutic immune responses targeting tumors. Current TCR profiling methods generally require invasive tissue biopsies that capture a single snapshot of immune activity or are limited by the sheer diversity of the circulating TCR repertoire. In theory, T-cells with the greatest turnover could best reflect pivotal immune dynamics from both circulating and tissue-derived compartments, including non-circulating tissue-resident memory T-cells (Trm). To noninvasively capture such responses in the blood, we developed and benchmarked a high-throughput TCR profiling approach using plasma, optimized for the fragmented nature of cfDNA and the non-templated nature of rearranged TCRs. We then applied this method for residual disease monitoring in mature T-cell lymphomas (TCL) without circulating disease and for characterizing immune dynamics after anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy of B-cell lymphomas with axicabtagene ciloleucel. Methods: We developed SABER (Sequence Affinity capture & analysis By Enumeration of cell-free Receptors) as a technique for TCR enrichment and analysis of fragmented rearrangements shed in cfDNA and applied this method using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). We used SABER to profile a total of 381 samples (300 cfDNA and 81 PBMC samples) from 75 lymphoma patients and 18 healthy controls. After mapping sequencing reads (hg38) to identify candidate rearrangements within TCR loci, unique cfDNA fragments were resolved by a novel strategy to define consensus of unique molecular identifiers clustered by Levenshtein distances, followed by CDR3-anchoring for enumeration of final receptor clonotypes. SABER thus leverages information from fragmented TCRs, a critical requirement for cfDNA, to make V gene, CDR3, and J gene assignments after deduplication-mediated error-correction. We benchmarked SABER against established amplicon-based TCR-β targeted sequencing (LymphoTrack, Invivoscribe) and repertoire analysis methods (MiXCR; Bolotin et al, 2015 Nature Methods) when considering both cfDNA and PBMC samples from healthy adults and TCL patients. We assessed SABER performance for tracking clonal molecular disease in patients with mature TCLs from both cellular and cell-free circulating compartments (n=9). Malignant TCL clonotypes were identified in tumor specimens using clonoSEQ (Adaptive Biotechnologies). Finally, we evaluated TCR repertoire dynamics over time in 66 DLBCL patients after CAR19 T-cell therapy. Results: SABER demonstrated superior recovery of TCR clonotypes from cfDNA compared to both amplicon sequencing (LymphoTrack, Invivoscribe) and hybrid-capture methods when enumerating receptors using MiXCR (Fig. 1A). When applied to blood samples from TCL patients, SABER identified the malignant clonal TCR-β rearrangement in 8/9 (88.9%) cases, with significantly improved detection in cfDNA (p=0.015, Fig. 1B). Specifically, tumoral TCR clonotype was detectable only in cfDNA in 6 cases (75%), cfDNA-enriched in 1 case (12.5%), and detectable only in PBMCs in 1 case (12.5%). We applied SABER to monitor TCR repertoire dynamics in cfDNA after CAR T-cell therapy of patients with relapsed/refractory DLBCL and observed increased T-cell turnover and repertoire expansion (greater total TCR-β clonotypes) (Fig. 1C). As early as 1-week after CAR19 infusion, TCR repertoire size was significantly correlated both with cellular CAR19 T-cell levels by flow cytometry (p=0.008) as well as with retroviral CAR19 levels in cfDNA (p=2.20e-07) suggesting faithful monitoring of CAR T-cell activity (Fig. 1D). TCR repertoire size one month after infusion was significantly associated with longer progression-free survival (HR 0.246, 95% CI 0.080-0.754, p=0.014). Conclusions: SABER has a favorable profile for cfDNA TCR repertoire capture when compared to existing methods and could thus have potential broad applicability to diverse disease contexts. Given the higher abundance of lymphoma-derived TCRs in cfDNA than intact circulating leukocytes, SABER holds promise for monitoring minimal residual disease in T-cell lymphomas. This approach also holds promise for monitoring T-cell repertoire changes including after CAR T-cell therapy and for predicting therapeutic responses. Disclosures Kurtz: Genentech: Consultancy; Foresight Diagnostics: Other: Ownership; Roche: Consultancy. Kim:Corvus: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin Pharma: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Solingenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding. Mackall:Lyell Immunopharma: Consultancy, Current equity holder in private company; BMS: Consultancy; Allogene: Current equity holder in publicly-traded company; Apricity Health: Consultancy, Current equity holder in private company; Nektar Therapeutics: Consultancy; NeoImmune Tech: Consultancy. Miklos:Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Diehn:Varian Medical Systems: Research Funding; Illumina: Research Funding; Roche: Consultancy; AstraZeneca: Consultancy; RefleXion: Consultancy; BioNTech: Consultancy. Khodadoust:Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Alizadeh:Janssen: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy; Pfizer: Research Funding.

scholarly journals Evaluating Hematologist's Knowledge of CAR T-Cell Therapy in Hematologic Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2269-2269
Author(s):  
Lauren Willis ◽  
Sara R. Fagerlie ◽  
Sattva S. Neelapu
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background: The objective of this study was to assess current clinical practices of hematologist/oncologist (hem/onc) specialists related to chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies, in order to identify knowledge, competency, and practice gaps and barriers to optimal care. Methods: A continuing medical education (CME)-certified clinical practice assessment consisting of 25 multiple choice questions was developed to measure knowledge, skills, attitudes, and competence of hem/onc specialists regarding CAR T-cell therapy. The survey instrument was made available online to physicians without monetary compensation or charge. Respondent confidentiality was maintained, and responses were de-identified and aggregated prior to analyses. The activity launched on December 22, 2017 with global distribution, and participant responses are still being collected at the time of abstract submission. Results: At the time of this report there are 192 hem/onc activity participants, collection is on-going. Demographics are listed in Table 1 and levels of confidence and barriers to incorporating CAR T-cell therapy are listed in Table 2.Foundational KnowledgeSub-optimal knowledge was demonstrated in the area of CAR components, dosing, and FDA-approved indications.Over half (61%) could not correctly identify the components of a CAR construct (antigen-specific domain and the signaling domain).Almost half (45%) of the participants did not recognize that currently approved CAR T-cell therapies are dosed as a single infusion.25% demonstrated inaccurate knowledge by recommending patients wait 4 weeks after CAR T-cell infusion before driving.Over half (62%) of participants could not identify the FDA-approved indication for axicabtagene ciloleucel.Knowledge of Clinical Trial DataVery low awareness of efficacy data seen with various CAR T-cell products used to treat R/R B-cell ALL (ELIANA trial), R/R DLBCL (ZUMA-1, JULIET, TRANSCEND trials).Only 32% identified the correct CR/CRi rate seen with tisagenlecleucel in the ELIANA trial.Only 25% correctly identified the CR rate seen with axicabtagene ciloleucel in the ZUMA-1 trial.Only 32% demonstrated knowledge of the 6-month DFS rate for patients in the JULIET trial that had a CR at 3 months.Only 25% identified the association between the dose of JCAR017 and response rates from the TRANSCEND trial.Knowledge and Competence Managing Adverse EventsLack of competence recognizing and treating CAR T-cell associated adverse events such as cytokine release syndrome (CRS) and neurotoxicity.Almost half (44%) could not identify signs of CRS associated with CAR T-cell therapy and 43% lack knowledge that elevated serum C-reactive protein (CRP) is associated with the highest level of CRS (in patients with lymphoma receiving axicabtagene ciloleucel).41% could not identify that the mechanism of tocilizumab is to block IL-6 signaling.Over a third (35%) were unable to identify signs/symptoms/causes of neurotoxicity associated with CAR T-cell therapy.More than half of the learners (54%) could not identify the appropriate role of corticosteroid therapy after CAR T-cell administration in managing CRS and neurotoxicity. Conclusions: This activity found knowledge and competence deficits for hem/onc practitioners related to using CAR T-cell therapy for the treatment of patients with hematologic malignancies. Additionally, the activity demonstrated large gaps in confidence discussing CAR T-cell therapy with patients/families and managing adverse events. There is sub-optimal awareness of CAR T-cell foundational knowledge, clinical trial data, and recognition of common therapy related adverse events and management strategies. Additional education is needed to improve the knowledge, competence, and confidence of academic and community hem/onc specialists who care for patients with hematologic malignancies receiving CAR T-cell therapy as well as strategies for integrating novel agents into clinical practice. Disclosures Neelapu: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Hospitalization Patterns with Commercial CAR T-Cell Therapy: A Single Institution Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3240-3240 ◽  
Author(s):  
Sunita Dwivedy Nasta ◽  
Esin C. Namoglu ◽  
Mitchell E. Hughes ◽  
Elise A. Chong ◽  
Jakub Svoboda ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Mental Status ◽  
Research Funding ◽  
Altered Mental Status ◽  
Outpatient Setting ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, there are substantial costs associated with CAR-T therapy. The current practice of admission for tisa-cel infusion and subsequent monitoring may contribute to these costs. Generally, our institution administers tisa-cel in the outpatient setting (Schuster NEJM 2017), and we now report our clinical approach and analyze the frequency of hospitalization post outpatient tisa-cel infusion with in the first 30 days of infusion. Patients and Methods: We conducted a single institution, retrospective study investigating hospitalization after CAR-T of adult lymphoma patients treated with commercial tisa-cel at the University of Pennsylvania between 6/2018 and 7/2019. Data collected included number and timing of hospitalizations, symptoms leading to hospitalization, diagnosis during hospitalization, and length of stay. Patients were eligible for inclusion if they had at least 30 days of follow-up after tisa-cel or hospitalization within the first 30 days after tisa-cel. Patients were followed for hospitalization events until progression of lymphoma. Admissions for elective surgical procedures were not included in hospitalization count. Patients received lymphodepleting therapy as an outpatient, followed by evaluation in clinic and outpatient infusion of tisa-cel. Indications for hospitalization at our institution included bulky disease, suboptimal organ function at time of tisa-cel infusion, or progressive lymphoma symptoms requiring inpatient management. After infusion, patients returned for follow-up on day 2 and day 4, then weekly starting day 8 through day 30 for physical examination, labs, and assessment for cytokine release syndrome (CRS) and neurotoxicity. Patients were instructed to contact our clinic with fever > 100.4F, any change in mental status, or for malaise. Patients were also required to stay within 1 hour driving distance of our clinic and have identified a caregiver who will remain with them for the first 28 days. Results: 30 patients with relapsed/refractory non-Hodgkin lymphoma who received commercial tisa-cel were identified; 28 (93%) patients received outpatient tisa-cel; two pts were admitted at the time of T-cell infusion due to progressive lymphoma symptoms requiring urgent management. The length of stay for the two patients who received inpatient tisa-cel was 17.5 days (17-18). Nine of 28 patients were admitted after tisa-cel infusion a median of 5 days after tisa-cel infusion (range: day +1 to +7). No patient required a second admission within 30 days. In most instances, 8/9 (89%) patients were referred for fever (fever range: 99.6F-102.0F) and one patient was referred for altered mental status. Of those hospitalized with fever, 5/8 (63%) patients had CRS and 3/8 (37%) patients had an infection. The patient with altered mental status was diagnosed with grade 3 neurotoxicity. One of the admitted patients died during hospitalization; however, this was due to progression of lymphoma after initial admission for an infection. There were no deaths due to tisa-cel related toxicity. Conclusion: Our experience suggests that treatment with tisa-cel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, most admissions within the first 30 days were triggered by fever and the etiology of fever was either CRS or infection. Admission diagnoses matched prior experience with tisa-cel as previously reported. Disclosures Dwivedy Nasta: Millenium/Takeda: Research Funding; Aileron: Research Funding; Pharmacyclics: Research Funding; Rafael: Research Funding; Celgene: Honoraria; Merck: Membership on an entity's Board of Directors or advisory committees; ATARA: Research Funding; Debiopharm: Research Funding; Roche: Research Funding; 47 (Forty Seven): Research Funding. Hughes:Acerta Pharna/HOPA: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chong:Novartis: Consultancy; Tessa: Consultancy; Merck: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Barta:Celgene: Research Funding; Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Takeda: Research Funding; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding. Gerson:Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy. Ruella:Nanostring: Consultancy, Speakers Bureau; Novartis: Patents & Royalties: CART for cancer; AbClon: Membership on an entity's Board of Directors or advisory committees. Frey:Novartis: Research Funding. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Porter:Wiley and Sons: Honoraria; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Kite: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Fever Characteristics Associated with Toxicity and Outcome after Anti-CD19 CAR T-Cell Therapy for Aggressive Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1612-1612 ◽  
Author(s):  
Hamza Hashmi ◽  
Alicia Darwin ◽  
Christina A Bachmeier ◽  
Julio Chavez ◽  
Bijal Shah ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Background: Fever is a cardinal symptom of cytokine release syndrome (CRS) after CAR T-cell therapy with 84% of patients experiencing fever on the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel). Knowledge of the patterns of fever and associated symptoms may inform the clinical management of these patients. Methods: We performed a single center retrospective study in 78 patients receiving axi-cel for large B cell lymphoma (LBCL) as of 12/31/2018. We evaluated all the patients who developed fever during lymphodepleting chemotherapy with fludarabine (Flu) and cyclophosphamide (Cy), after CAR T-cell infusion, and after administration of tocilizumab (toci); and analyzed the association of fever with toxicity rates (grade 3+ CRS and neurotoxicity) and efficacy [overall response rates (ORR) and complete response (CR) rate 6 months post CAR T-cell infusion]. Fever was defined per the Lee criteria [equal to or greater than 38 °C], CRS used the modified Lee criteria and neurotoxicity used the CARTOX grading system. Results: Fever occurred in 71/78 (91%) of patients. Rates of grade 3+ CRS and neurotoxicity were 9% (7/78) and 26% (20/78) respectively. The CR rate at 6 months was 41% (32/78). Toxicities and outcomes in patients with the described fever characteristics are shown in the Table. During lymphodepletion with Flu/Cy, fever was observed in 11% (9/78) of patients. Fever occurred within 24 hours of axi-cel infusion in 47% (37/78) and within 72 hours of axi-cel infusion in 71% (55/78) of the patients. In total, 41% (32/78) of patients were treated with anti-IL6R therapy (tocilizumab; toci) for CAR T toxicity. After the first dose of toci, fever recurred in 69% of patients (22/32), of which 34% (11/32) experienced fever recurrence within 24 hours of toci infusion. Conclusions: This is the first study to our knowledge that describes in detail the characteristics of fever after CAR T-cell therapy with axi-cel. Fever was common and occurred in 71% of the patients within 72 hours of axi-cel infusion. When toci was used, fever recurred in a majority of patients (69%) and in 1/3 of patients the fever recurred within 24 hours of toci infusion. These descriptive data may be used by clinicians to inform their expectations of fever occurring after treatment with axi-cel and/or toci. Table Disclosures Bachmeier: Kite/Gilead: Speakers Bureau. Chavez:Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Lazaryan:Kadmon: Consultancy. Davila:Bellicum: Consultancy; Anixa: Consultancy; GlaxoSmithKline: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; Adaptive: Consultancy; Celgene: Research Funding; Atara: Research Funding. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Jain:Kite/Gilead: Consultancy.

scholarly journals Infectious Complications in Patients Treated with Idecabtagene Vicleucel for Relapsed and Refractory Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3839-3839
Author(s):  
Jessica S. Little ◽  
Parth Shah ◽  
Adam S. Sperling ◽  
Andrew R. Branagan ◽  
Omar Nadeem ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Bacterial Infections ◽  
Infectious Complications ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a novel adoptive immunotherapy utilizing autologous T cells expressing synthetic fusion proteins that target specific antitumor antigens. Over recent years, novel CAR T-cell constructs have shown efficacy for the treatment of hematologic malignancies. The B-cell maturation antigen (BCMA)-directed CAR T-cell product idecabtagene vicleucel (ide-cel) is the first approved CAR T-cell therapy for the treatment of multiple myeloma (MM). While ide-cel represents an important advance in MM treatment, it is critical to better characterize the risk of infectious diseases following this novel therapy. Methods: We investigated infectious complications in 27 (CRB-401, n/62; KarMMa, n/128) adult patients who received ide-cel for relapsed and refractory MM at two institutions. Patients were enrolled in an open label, multi-site Phase 1 or 2 clinical trial (NCT02658929; NCT03361748) evaluating the safety and efficacy of ide-cel. All participants received a 3-day cycle of lymphodepleting chemotherapy with fludarabine and cyclophosphamide 5 days prior to infusion and ide-cel was administered at target doses of 150×10 6 to 450×10 6 CAR-positive T cells. All patients but one received antiviral prophylaxis with val/acyclovir or famciclovir. Seventeen patients received pneumocystis prophylaxis with atovaquone or trimethoprim-sulfamethoxazole. Only 2 patients received antibacterial prophylaxis with levofloxacin and no patients received antifungal prophylaxis. Infections were retrospectively identified from day of cell infusion (day 0) up to day 100 after infusion. Infections were reported if patients experienced symptoms with a microbiologic or histopathologic diagnosis, or for symptomatic site-specific infections in conjunction with radiographic or exam findings and treatment with systemic antimicrobials. Infection severity was determined using the Blood and Marrow Transplant Clinical Trials Network criteria. Cytokine release syndrome (CRS) events were graded according to the Lee criteria. Patients were censored on date of disease relapse, the last day of the study period, or death. Results: Median age was 59 (range 41 - 79), 56% were males. Patients had received a median of 6 previous antimyeloma regimens (range 3 - 10); and 74% had undergone prior autologous hematopoietic cell transplantation. Following infusion of cells, 24 patients (89%) developed CRS with 54% of those receiving ≥ 1 dose of tocilizumab and 17% receiving ≥ 1 dose of corticosteroid. Only two patients (7%) developed CAR T cell associated neurotoxicity (ICANS) and one of those patients received treatment with corticosteroids. Eight patients experienced 19 infection-related events over the first 100 days after ide-cel infusion. To determine infection density, we evaluated 27 patients contributing 667 days at risk between d0 and d30 and 1777 days at risk between d0 and d100. Median time to first infection was 22 days (range 0 - 85). The estimated infection density was 1.8 infections per 100 patient days over the first 30 days, and decreased to 1.1 infections per 100 patient days from day 30 to d100. Among the infection events, bacterial infections were the most common (74%) with 6 bloodstream infections (32%) observed. Viral infections were less frequent (21% of events) and only one fungal infection (5% of events) was observed during the at-risk period. Four infections were of moderate severity; 10 were severe; and 5 were life-threatening. Eleven of the 27 patients (41%) had persistent neutropenia (absolute neutrophil count <1000) after day 30. Conclusions: Our study in this cohort of patients provides clarity on specific infectious complications in a unique population, and is of particular relevance given the recent FDA approval of ide-cel. Of note, these results represent a cross study single institution subgroup analysis that may not reflect the complete trial data. The overall incidence of infection was similar to what has previously been reported in patients receiving CD-19 directed CAR T-cell therapy, even with persistent neutropenia after one month documented in 41% of patients. Bacterial infections were the most common, and there were 5 life-threatening bacterial infections within the first 30 days after infusion. Notably, patients in this group experienced only 1 fungal infection, despite no patients receiving antifungal prophylaxis. Figure 1 Figure 1. Disclosures Sperling: Adaptive: Consultancy. Branagan: Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; Sanofi Genzyme: Consultancy. Nadeem: Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Amgen: Consultancy. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Munshi: Abbvie: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Legend: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy. Hammond: Merck: Research Funding; F2G: Research Funding; Synexis: Research Funding; Biointelect: Consultancy.

scholarly journals Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 556-556 ◽  
Author(s):  
Amanda M. Li ◽  
George E Hucks ◽  
Amanda M. Dinofia ◽  
Alix E. Seif ◽  
David T Teachey ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Abstract CAR T cell therapy in relapsed B-ALL can result in complete response (CR) rates of 80-90%, but relapse-free survival declines to 60% within the first 12-months due to both CD19-positive and negative relapses. CD19-positive relapses that occur during this time are largely due to early CAR T cell loss. We hypothesize that inhibiting the PD-1:PD-L1 (programmed cell death 1) checkpoint axis may decrease T cell exhaustion, thereby improving CAR T cell function and persistence. We report our single institution experience of the use of PD-1 inhibitors in patients with relapsed or refractory B lymphoblastic malignancies treated with CD19-directed CAR T cell therapy. Methods: Patients treated with CD19-directed CAR T cell therapy (murine CTL019 or humanized CTL119) at the Children's Hospital of Philadelphia who demonstrated repeated early CAR T cell loss or partial/no response to CAR T cell therapy received a PD-1 inhibitor starting no sooner than 14 days after CAR T cell infusion and after resolution of cytokine release syndrome (CRS) symptoms, with the possibility of repeated doses up to every 3 weeks. Results: Fourteen patients, ages 4-17 years, with heavily pretreated, relapsed B-ALL (n=13) or B lymphoblastic lymphoma (n=1), were treated with CD19-directed CAR T cell therapy (CTL019, n=4; or CTL119, n=10) in combination with pembrolizumab (n=13) or nivolumab (n=1). Three of 6 patients treated with CD19 CAR T cells in combination with a PD-1 inhibitor for early B cell recovery re-established B cell aplasia (a reflection of CAR T cell function) for 5-15 months, 2 of whom have persistent B cell aplasia with ongoing pembrolizumab therapy. Four patients started pembrolizumab for bulky extramedullary disease unresponsive to or relapsed after CAR T cells, with 2 partial and 2 complete responses seen. In one patient, significant CAR T cell proliferation was measured within days of starting pembrolizumab and in temporal correlation to radiographic disease response. In 4 patients who failed to achieve disease remission with initial CAR T cell infusion, no CRs were achieved with the addition of pembrolizumab, although partial responses were seen, and one patient progressed with CD19-dim/negative disease. CRS symptoms and fever typical of CAR T cell proliferative responses were observed in 3/14 patients within 2 days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1 inhibition were tolerable or reversible upon discontinuation, and including 1 case each of acute pancreatitis, hypothyroidism, arthralgias, urticaria, as well as 4 patients with grade 3-4 cytopenias. No grade 5 toxicities or graft-versus-host disease flares occurred. Two patients discontinued pembrolizumab for delayed adverse effects after multiple doses; both patients relapsed/progressed with CD19+ disease a few weeks after discontinuation. Discussion: T cell exhaustion or activation induced CAR T death (AICD) has been suspected to contribute to poor persistence of CAR T cells. We hypothesized that the PD-1 checkpoint pathway may be involved in CAR T cell exhaustion in some cases, which may be overcome by checkpoint inhibition. Here, promising responses were specifically seen in those with early B-cell recovery and bulky extramedullary disease. In contrast, PD-1 inhibition had partial, but no durable, effect in the four B-ALL patients with poor initial marrow response to CAR T cell therapy alone, suggesting a different mechanism such as AICD may be responsible for poor initial responses. No unexpected or fatal toxicities were seen. This cohort shows initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T cell therapy in children with relapsed B-ALL, and that this strategy may augment CAR T cell effect and persistence. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Callahan:Novartis Pharmaceuticals Corporation: Consultancy. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Consensus Grading of Cytokine Release Syndrome (CRS) in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) Treated with Tisagenlecleucel on the JULIET Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4190-4190 ◽  
Author(s):  
Stephen J. Schuster ◽  
Richard T. Maziarz ◽  
Solveig G. Ericson ◽  
Elisha S. Rusch ◽  
James Signorovitch ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Introduction: Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy achieves rapid and durable responses in patients with r/r DLBCL, although unique potential toxicities require specialized management. Cytokine release syndrome (CRS) is the most commonly observed adverse event of special interest associated with CAR T-cell therapy. Two CRS grading scales have been used in different clinical trials of CAR T-cell therapy: the Penn scale (Porter, Sci Transl Med, 2015; Porter, J Hematol & Oncol, 2018) and the Lee scale (Lee, Blood, 2014; Neelapu, Nat Rev Clin Oncol, 2017). To better inform management of CRS and develop best practices, we assessed concordance and differences between the two scales by using the Lee scale to regrade observed CRS events in r/r DLBCL patients treated with tisagenlecleucel, who were previously graded per protocol using the Penn scale. Methods: Individual patient level data from the JULIET trial, a single-arm, open-label, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248), were used in this study. Four medical experts who had managed DLBCL patients using different CAR T-cell therapy protocols and products independently reviewed the data, while blinded to the original Penn grading, and re-graded CRS for JULIET patients using the Lee scale. Re-grading assessments and disagreements in the assigned Lee grade were discussed and reconciled among reviewers during a live meeting. As per the investigational charter, the most conservative final assessment of any expert reviewer determined the final grading for any individual case. For example, if an event was graded as 2, 3, 3 and 4, then grade 4 would be the final grading. Results: As of December. 8, 2017, 111 patients with r/r DLBCL were infused with tisagenlecleucel in the JULIET trial. Sixty-four (58%) patients had CRS graded according to the Penn scale and each case was re-graded using the Lee scale based on JULIET data collected prospectively (e.g., CRS-related symptoms, oxygen supplementation, intervention for hypotension, and organ toxicities). Using the Lee scale, 63 (57%) patients were considered to have any grade CRS by investigators, including grade 1 events in 26 (23%), grade 2 in 18 (16%), grade 3 in 10 (9%), and grade 4 in 9 (8%) (Figure 1). One patient with grade 1 per Penn scale was re-graded to grade 0 due to absence of documented fever or symptoms requiring intervention. Compared to Penn grades, the Lee scale provided the same grade for 39 patients, a lower grade for 20 patients, and a higher grade for 5 patients. Among 64 patients re-graded, 59 (92%) had fever, 27 (42%) had oxygen supplementation (3 with grade 1, 6 grade 2, 9 grade 3, and 9 grade 4 per Lee scale) and 7 (11%) had concurrent infections. Of 29 (45%) patients requiring intervention for hypotension (13 with grade 2, 7 grade 3, and 9 grade 4 per Lee scale), 28 had fluid resuscitation and 10 received high dose/combination vasopressors. In addition, 8 of 9 patients re-graded as Lee grade 4 were intubated. As for anti-cytokine therapy, only 17 patients received tocilizumab (1 for grade 1, 2 for grade 2, 5 for grade 3, and 9 for grade 4 CRS per Lee scale) and 12 patients received corticosteroids (2 for grade 2, 1 for grade 3, and 9 for grade 4 CRS per Lee scale). Conclusions: Different CAR-T studies in DLBCL patients have used different approaches (Lee and Penn scales) for grading CRS and had different thresholds for tocilizumab treatment of CRS. Harmonization of grading CRS between studies permits a more accurate comparison of observations and outcomes. In this analysis, patients with r/r DLBCL receiving tisagenlecleucel in the JULIET trial, which used the Penn scale to grade CRS, were re-graded by expert consensus using the Lee scale. Using the Lee scale, more patients were categorized as grade 1 (Lee vs. Penn: 26 vs. 17), fewer patients as grades 2 and 3 (18 vs. 23, and 10 vs. 15, respectively), and the same number of patients as grade 4 (9 vs. 9) compared to the Penn scale. The re-grading of the JULIET CRS data using the Lee scale makes it possible to perform comparative analyses of CRS outcomes from clinical trials using different CAR-T products and could be used to develop best practice guidelines. Disclosures Schuster: Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physician's Education Source, LLC: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maziarz:Athersys, Inc.: Patents & Royalties; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ericson:Novartis Pharmaceuticals Corporation: Employment. Rusch:Novartis Pharmaceuticals Corporation: Employment. Romanov:Novartis Pharmaceuticals Corporation: Employment. Locke:Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor. Maloney:Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding.

scholarly journals Management of CAR T-Cell Toxicities: Concordance and Divergence between Healthcare Providers and Expert Consensus Recommendations

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2199-2199
Author(s):  
Matthew Frigault ◽  
Megan Cartwright ◽  
Krista Marcello ◽  
Timothy A Quill ◽  
Daniel J. DeAngelo ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Expert Recommendations

Background: Chimeric antigen receptor (CAR) T-cell therapy has been a major innovative breakthrough for hematologic malignancies with 2 currently FDA approved CAR T-cell products (tisagenlecleucel and axicabtagene ciloleucel) and several others in different stages of clinical investigation. However, these therapies are associated with unique safety profiles and potentially serious toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), that require vigilant monitoring and prompt recognition and management to ensure patient safety and optimal therapeutic benefit. We developed an online interactive decision support tool at www.clinicaloptions.com/carttool to give healthcare providers (HCPs) case-specific, evidence-based guidance from experts on the management of adverse events (AEs) due to CAR T-cell therapy. Here, we report a comparison of CAR T-cell toxicity management among HCPs using the tool vs the expert consensus recommendations in the tool. Methods: In March 2019, a panel of 5 experts provided consensus guidance for the screening, prophylaxis, monitoring, and management of CRS and ICANS in patients for which CAR T-cell therapy was either planned or started. This information was used to build the interactive online tool. To use the online tool, HCPs enter the AE that the patient is experiencing, either CRS or ICANS; the grade or severity of the event, per the American Society for Transplantation and Cellular Therapy consensus grading for CRS and ICANS (Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638); and their planned management approach. The HCPs were then shown the expert management recommendation for that specific AE scenario. After viewing the expert management recommendation, HCPs were asked if it impacted their intended management approach. Results: Between May and July 2019, 115 HCPs entered 166 unique case scenarios into the tool. The majority of cases (58%) entered were for patients who were planned for CAR T-cell therapy or who had started therapy without yet experiencing an AE, for which users received expert recommendations on pretreatment screening along with AE prophylaxis and monitoring. Of the 69 cases entered for patients who had received CAR T-cell therapy and were experiencing an AE, 71% were CRS and 29% were neurotoxicity/ICANS. The majority of CRS cases (67%) were intermediate grade (2/3) whereas the ICANS cases were evenly distributed across all grades (1-4). Overall the planned toxicity management strategy of HCPs matched the expert recommendations in 45% of cases, with the greatest discordance for CRS management, where the rate of agreement was 37% (Figure). The proportion of cases in which the planned management strategies of HCPs matched expert recommendations also varied by syndrome grade/severity between US and non-US HCPs. There was no concordance (0%) among US HCPs compared with non-US HCPs (60%) for grade 1 AEs, whereas greater concordance was found in the management of grade 2 and grade 3 AEs among US HCPs (67% and 57%, respectively) compared with non-US HCPs (43% and 44%, respectively; Figure). Of the 15 grade 1 AEs entered by users, only 5 came from US HCPs. Among the 48% of HCPs who answered the optional survey on the impact of the tool on their intended management plan, 48% indicated that the expert recommendations changed their approach, and 80% reported practicing at a treatment center authorized to administer CAR T-cell therapy. Conclusions: These data suggest that many HCPs are challenged to optimally manage toxicities related to CAR T-cell therapy and are not managing their patients in concordance with expert recommendations. Use of an online tool providing easy access to evidence-based consensus expert recommendations may improve patient care and safety in patients treated with CAR T-cell therapy. A detailed analysis of the tool, including case entries and planned management vs expert consensus recommendations for each toxicity and grade, will be presented. Figure. Planned Management of HCPs Compared With Expert Recommendations Figure Disclosures Frigault: Novartis: Patents & Royalties: Royalty; Arcellx, Celgene, Foundation Medicine, Kite/Gilead, Nkarta, Novartis, and Xenetic: Consultancy. DeAngelo:GlycoMimetics: Research Funding; Abbvie: Research Funding; Blue Print Medicines: Consultancy, Research Funding; Novartis: Consultancy, Patents & Royalties: Royalty, Research Funding; Celgene: Consultancy; Amgen: Consultancy; Shire: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy. Galinsky:Pfizer Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merus Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ABIM: Other: Member on specialty oncology board; AbbVie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Paul:Agios: Consultancy; Pfizer: Consultancy. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

scholarly journals HESTER: A Phase II Study Evaluating Efficacy and Safety of Tisagenlecleucel Reinfusion in Pediatric and Young Adult Patients with Acute Lymphoblastic Leukemia Experiencing Loss of B-Cell Aplasia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Michael W Boyer ◽  
Sonali Chaudhury ◽  
Kara L Davis ◽  
Timothy Alan Driscoll ◽  
Stephan A Grupp ◽  
...  
Keyword(s):  
T Cell ◽  
Young Adult ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Adult Patients ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T

Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy approved for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma. The ELIANA trial showed efficacy (81% overall remission rate [ORR]; 60% complete remission [CR]) and safety of tisagenlecleucel in r/r B-ALL (Maude et al. N Engl J Med. 2018). In the ELIANA trial, sustained remissions were associated with B-cell aplasia, an expected on-target effect of tisagenlecleucel and a pharmacodynamic marker for tisagenlecleucel persistence. In some patients who demonstrated short CAR-T cell persistence, reinfusion with 1 or more additional doses of tisagenlecleucel has restored B-cell aplasia and produced a 60% CR rate in patients who were reinfused with humanized CD19-targeted CAR-T cell therapy (Maude et al. J Clin Oncol. 2016). This prolongs the period of tisagenlecleucel activity and immunosurveillance and may therefore prolong durable remission. We introduce a trial in progress investigating the efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with B-ALL experiencing a loss of B-cell aplasia. Study Design and Methods: HESTER (NCT04225676) is a phase II, open-label, multicenter trial to determine the efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with B-ALL experiencing loss of B-cell aplasia. Eligible patients must be ≤25 years of age with a confirmed diagnosis of CD19(+) leukemia. Patients must have been previously infused with commercial tisagenlecleucel and have at least 1 additional dose of commercial tisagenlecleucel prescribed to them in the course of medical practice. Commercial tisagenlecleucel must be given for reinfusion within 9 months of the initial manufacturing date. Patients must have loss of B-cell aplasia defined as peripheral blood (PB) absolute B lymphocyte count ≥50/μL or PB B lymphocyte ≥10% of the total lymphocytes; patients are not required to be minimal residual disease negative (MRD)(-). Karnofsky (age ≥16 years) or Lansky (age <16 years) performance status must be ≥50 at screening. Patients treated with prior gene/adoptive T-cell therapy other than tisagenlecleucel and patients with active central nervous system involvement by malignancy are excluded. The primary efficacy endpoint is the proportion of patients who reestablish B-cell aplasia within 12 months of reinfusion as measured by circulating B lymphocytes (<50/μL) and presence of tisagenlecleucel cells by quantitative polymerase chain reaction (qPCR) in the PB. Secondary outcomes include the ORR (CR + CR with incomplete blood count recovery) during the 12 months post reinfusion, event-free survival, overall survival, MRD status, and safety; immunogenicity and tisagenlecleucel persistence (by qPCR) are exploratory endpoints. Subgroup analysis of efficacy outcomes will include patients with a loss of B-cell aplasia within 9 months of first infusion who are MRD(+) at time of enrollment, as well as patients with very early (<3 mo), early (≤3 to <6 mo), and later (≥6 mo) loss of B-cell aplasia following first infusion. Safety will be assessed throughout the trial. For the primary analysis, a minimum of 10% of patients reestablishing B-cell aplasia within 12 months after reinfusion is expected with an estimated true rate of 25%. All secondary and exploratory variables will be summarized descriptively. Estimated enrollment is about 54 patients in the United States. Clinical Trial Information: NCT04225676 Disclosures Boyer: Thunder Biotech Inc: Consultancy. Grupp:Servier: Research Funding; Cellectis: Other; Roche: Consultancy; Adaptimmune: Other: SAB; Jazz: Other: SSC; TCR2: Other: SAB; GlaxoSmithKline: Consultancy; CRISPR Therapeutics/Vertex Pharmaceuticals: Other; Juno/BMS: Other; Janssen/JnJ: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Kite/Gilead: Research Funding; Allogene: Other; Novartis: Consultancy, Other: SSC, Research Funding. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Kovacs:Novartis: Current Employment. Magley:Novartis: Current Employment. Myers:Novartis: Consultancy, Honoraria, Other: ELIANA trial Steering Committee, Speakers Bureau. Phillips:Novartis: Membership on an entity's Board of Directors or advisory committees. Pulsipher:Bellicum: Honoraria; Mesoblast: Honoraria; Miltenyi: Honoraria, Research Funding; Adaptive: Research Funding; Novartis: Honoraria; Jasper: Honoraria. Purkayastha:Novartis: Current Employment. Willert:Novartis: Current Employment.

scholarly journals Seroconversion Rates after COVID-19 Vaccination Amongst Patients with Hematologic Malignancies: Results of a Rapid Vaccination and Evaluation Program in a Minority Rich, Ethnically Diverse Inner City Cohort

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2537-2537
Author(s):  
Lauren C Shapiro ◽  
Radhika Gali ◽  
Astha Thakkar ◽  
Jesus D Gonzalez-Lugo ◽  
Abdul Hamid Bazarbachi ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Publicly Traded ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract It is well established that COVID-19 carries a higher risk of morbidity and mortality in patients (pts) with hematologic malignancies. Emerging data suggests that despite the 3 COVID-19 vaccines with emergency use authorization (EUA) by the FDA inducing high levels of immunity in the general population, pts with hematologic malignancies have lower rates of seroconversion for the SARS-CoV-2 Spike antibody (Spike IgG) and thus possibly lower protection against severe COVID-19. We established a program of rapid vaccination and evaluation of response in an inner city minority population to help determine the factors that contribute to the poor seroconversion to COVID-19 vaccination in pts with hematologic malignancies. We conducted a cross-sectional cohort study of pts with hematologic malignancies seen at Montefiore Medical Center between March 29, 2021 and July 8, 2021 who completed their vaccination series with 1 of the 3 FDA EUA COVID-19 vaccines, Moderna, Pfizer, or Johnson & Johnson (J&J). We qualitatively measured Spike IgG production in all pts using the AdviseDx Spike IgG assay and performed quantitative analysis on pts who completed their vaccination series with at least 14 days (d) after the 2 nd dose of the Moderna or Pfizer vaccines or 28d after the single J&J vaccine. Safety data was collected via questionnaires or as part of the electronic medical record. We analyzed the characteristics of these pts using standard descriptive statistics and associations between pts characteristics, cancer subtypes, treatments, and vaccine response using a Fisher Exact test, Kruskal-Wallis Rank Sum test, or Kendall Tau-b test. A total of 121 pts with hematologic malignancies were enrolled and another 10 pts were included by retrospective chart review. Five pts did not have a Spike IgG performed after consent and excluded. Ten patients had Spike IgG testing before completion of their vaccination series and excluded from quantitative analyses. A total of 116 pts were included in immunogenicity analysis and 106 pts in quantitative analysis. Baseline characteristics and representative malignancies are listed in Table 1. Seventy pts (60%) received Pfizer, 36 pts (31%) Moderna, and 10 pts (9%) J&J. Median time from vaccination completion to Spike IgG was 40d. We observed a high-rate of seropositivity (86%) with 16 pts (14%) having a negative Spike IgG. Percent positivity was not statistically significant between vaccine types (p=0.50). We observed significantly lower seroconversion rates in pts with Non-Hodgkin lymphoma (p=0.005) and pts who received: cytotoxic chemotherapy (p=0.002), IVIG (p=0.01), CAR-T cell therapy (p=0.00002), and CD20 monoclonal antibodies (Ab) (p=0.0000008) especially within 6 mo of Spike Ab evaluation (p=0.01). All pts who received anti-CD19 (Axi-cel) CAR-T therapy (0/6) were seronegative, and 1 pt that received BCMA directed CAR-T (Cilta-cel) was seropositive with no association between timing CAR-T cell infusion and seroconversion/titer. Use of BCL2 inhibitors (p=0.04), CD20 monoclonal Ab (p=0.0009), CAR-T cell therapy (p=0.01), BTK inhibitors (p=0.04), current steroid use (p=0.002), and IVIG (p=0.003) also correlated with significantly lower Ab titers with a trend toward lower Ab titers in pts on any active cancer therapy at time of vaccination (p=0.051). Immunomodulatory drugs (p=0.01) and proteasome inhibitors (p=0.01) had significantly higher seroconversion rates, and pts with history prior COVID-19 (12/106) had significantly higher Ab titers (p=0.0003). Of 47 pts who received stem cell transplant, 43 received an autologous (37 seropositive, 6 seronegative) and 4 an allogeneic transplant (3 seropositive, 1 seronegative), with no significant association with seroconversion, Ab titer, or time since transplant (greater or less than 1 year). The majority of pts, 64% and 53%, reported no adverse effects (AE) to the 1 st and 2 nd dose respectively. The most common AE were mild in severity and included sore arm, muscle aches, fatigue, and fever. No life-threatening AE were observed. Our findings indicate that vaccination is safe, effective, and well tolerated in the majority of pts with hematologic malignancies. We observed that pts receiving B-cell depleting therapies are unable to mount an effective serological response to COVID-19 vaccines and remain vulnerable to the disease. Novel immunization strategies (active or passive) are urgently needed in this population. Figure 1 Figure 1. Disclosures Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; Kymera Therapeutics: Research Funding; Guidepoint: Consultancy; GLC: Consultancy. Halmos: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mirati: Research Funding; Elevation: Research Funding; Blueprint: Research Funding; Advaxis: Research Funding; Eli-Lilly: Research Funding; TPT: Membership on an entity's Board of Directors or advisory committees; Apollomics: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees. Verma: BMS: Research Funding; GSK: Research Funding; Novartis: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; Acceleron: Consultancy; Stelexis: Current equity holder in publicly-traded company; Celgene: Consultancy; Throws Exception: Current equity holder in publicly-traded company.

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