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 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 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 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 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 Late Effects of CD19-Targeted CAR-T Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 223-223 ◽  
Author(s):  
Ana Cordeiro ◽  
Evandro D Bezerra ◽  
Joshua Aiden Hill ◽  
Cameron J. Turtle ◽  
David G. Maloney ◽  
...  
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

Abstract Recently two CD19-targeted CAR-T cell products were approved by the FDA for treatment of relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Excellent anti-tumor activity has been observed in patients with B cell malignancies. However, data regarding long-term effects of this therapy are very limited. Here we report long-term effects in 59 patients (pts) with R/R NHL and chronic lymphocytic leukemia (CLL) who received a total of 85 CD19-targeted CAR-T cell infusions on a clinical trial in our institution (NCT01865617), survived more than a year, and had at least one year follow-up data after their first CAR-T cell infusion. One patient who survived more than a year was excluded from this report due to incomplete data. Median follow-up was 23 months (range, 13-57) after the first CAR-T cell infusion. We report adverse events that occurred or persisted beyond 90 days after the last CAR-T cell infusion, excluding events related to disease progression. Median age at CAR-T cell infusion was 60 years (range, 34-73). There were 42 (71%) pts with NHL and 17 (29%) with CLL. The median number of prior lines of treatment was 4 (range, 1-8). 23 (39%) pts had received prior autologous (auto) hematopoietic cell transplantation (HCT), and 9 (15%) pts had received prior allogeneic (allo) HCT. 35 (59%) pts received one CAR-T cell infusion, 22 (37%) pts received 2 infusions, and 2 (3%) pts received 3 infusions. 3 (5%) pts received a maximum cell dose of 2x10(5)/kg, 40 (68%) pts received a maximum cell dose of 2x10(6)/kg, and 16 (27%) pts received a maximum cell dose of 2x10(7)/kg. 65 (76%) infusions were preceded by cyclophosphamide and fludarabine. CRS grade I/II occurred in 38 (64%) pts, and grade III in 4 (7%) pts (graded per Lee et al. Blood, 2014). No grade IV CRS was reported in this cohort. Acute neurotoxicity occurred in 20 (34%) pts. At 2 months after CAR-T cell infusion complete response (CR) was documented in 34 (58%) pts, partial response (PR) in 12 (20%) pts, and disease progression (PD) in 13 (22%) pts. During the follow-up period, another 15 (25%) pts developed PD. 29 (49%) pts received salvage therapy after CAR-T cell infusion, 8 (14%) of them received allo HCT. 5 (8%) pts received allo HCT as consolidation after CAR-T cell. 5 of 25 (20%) pts who did not receive additional therapy after last CAR-T cell infusion experienced ongoing cytopenias requiring G-CSF support, or RBC or platelet transfusions, beyond 90 days after last CAR-T cells infusion. 8 (14%) pts were diagnosed with subsequent malignancies, including 3 (5%) myelodysplasia, 4 (7%) non-melanoma skin cancer, and 1 non-invasive bladder cancer. All, but 1 patient with skin cancer, had auto or allo HCT before CAR-T cell therapy. Neuropsychiatric disorders were documented in 5 (8%) pts; including major depression, suicidal attempt, myoclonic seizures, and TIA. 5 (8%) pts experienced cardiovascular events. 4 (7%) pts developed renal dysfunction. 3 (5%) pts developed respiratory disorders. One pt had gastrointestinal bleeding. Of the 9 pts who had undergone allo HCT before CAR-T cell therapy, 1 pt (11%) developed GVHD flare. Severe hypogammaglobulinemia (IgG < 400 mg/dL) or IgG replacement beyond day 90 after last CAR-T cell infusion (and before HCT if was done) were documented in 24 (41%) pts. 54 pts were included in the infection analysis. 178 suspected infection events beyond day 90 after last CAR-T cell infusion were documented in 40 (74%) pts. Antimicrobial treatments were documented for 124 infection events. 44 (25%) of the events were microbiologically proven. The most common infections were upper (92) and lower (29) respiratory tract infections. 25 (46%) pts required hospital admission due to infections, of them 8 (15%) were admitted to the ICU. When excluding infections that occurred after salvage therapy following CAR-T cell, we identified 117 infections in 28 (52%) pts. 3 pts died of non-relapse causes (2 due to infection after allo HCT, and 1 due to duodenal ulcer and gut perforation). In conclusion, our data suggest that long-term effects of CD19-targeted CAR-T cell therapy are acceptable. Most effects identified in our cohort were not severe, and many may have been related to prior or subsequent therapies (e.g. HCT before or after CAR-T cell therapy, or subsequent salvage treatments). Our data is consistent with recent published data demonstrating excellent long-term disease outcome for this heavily pre-treated population. Disclosures Turtle: Juno/Celgene: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribu Biosciences: Membership on an entity's Board of Directors or advisory committees. Maloney:Juno Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria.

scholarly journals Comorbidities Predict Inferior Survival in Patients Receiving CAR T-Cell Therapy for Relapsed/Refractory DLBCL: A Multicenter Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 780-780 ◽  
Author(s):  
Adam S. Kittai ◽  
Max J. Gordon ◽  
Agrima Mian ◽  
Lindsey Fitzgerald ◽  
Jennifer Bishop ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Retrospective Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Introduction: CAR T-cell therapy has revolutionized treatment for patients with relapsed/refractory (r/r) diffuse large b-cell lymphoma (DLBCL). Although impressive durable responses can be achieved, this is weighted by adverse events including neurotoxicity and cytokine release syndrome (CRS). Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is a validated score that utilizes comorbidities to predict outcomes in patients receiving allogeneic stem cells transplants, but it not validated in CAR T-cell recipients. Meanwhile, the Cumulative Illness Rating Scale (CIRS) is a comprehensive tool which has been incorporated into clinical research in lymphoma. Here we report the impact of comorbidities, as measured by the HCT-CI and CIRS, on survival and tolerance of CAR T-cell therapy in patients with r/r DLBCL treated off clinical protocols. Methods: We conducted a retrospective analysis of patients with r/r DLBCL treated with commercial CART product at 4 academic medical centers after approval by the respective institutional review boards. Comorbidity data was assessed at the time of T-cell collection, and outcome data was assessed per last known follow-up. CIRS score was calculated as in Salvi et al, 2008. HCT-CI score was calculated as in Sorror et al, 2005. High comorbidity burden was defined as CIRS score ≥7, presence of severe impairment (CIRS score of 3 or 4 in ≥1 organ system; CIRS-3+), or HCT-CI ≥3. Cox proportional hazards models adjusted for age, ECOG performance status, number of prior therapies, type of product, cell of origin, MYC positivity on FISH, and comorbidities were used to assess effect on progression free survival (PFS) and overall survival (OS). Results: We analyzed 59 patients, with a median age of 63 years (range, 25-82). 80% of patients had an ECOG PS of 0 or 1. Median number of prior therapies was 3 (range, 2-6). 15 patients received tisagenlecleucel, and 44 patients received axicabtagene ciloleucel. 30 patients had germinal center B-cell (GCB) subtype DLBCL, and 29 were non-GCB as determined by Hahn's algorithm. 13 patients exhibited a MYC rearrangement by FISH, of which 9 also had BCL2 or BCL6 chromosomal translocation. Four patients did not receive CAR T-cells (3 died of disease progression; 1 died of an unrelated event). All patients (N=59) were used in the analysis. Median total CIRS was 10 (range, 1-20). 40 patients had score ≥7 and 29 had a CIRS-3+. 16 patients had neither total CIRS score ≥7 or CIRS-3+. The most common comorbidities were seen in the upper GI, endocrine and vascular/hematopoietic systems. Median HCT-CI was 2 (range, 0-13). Median follow-up was 154 days. Significant comorbidities assessed by CIRS (either total score ≥7 or CIRS-3+) were associated with inferior PFS (HR 3.65, p=0.037) and OS (OS; HR 5.31, p=0.025) compared to patients without significant comorbidities in univariate analyses. Median PFS was not reached, and OS was 305 days for patients without significant comorbidities, and was 170 and 237 for patients with significant comorbidities respectively (Figure 1,2). HCT-CI ≥3 was not predictive of PFS (HR 0.85, p=0.70) or OS (HR 1.06, p=0.90). MYC positivity was associated with inferior OS (HR 2.64, p=0.033). Presence of comorbidities assessed by CIRS and HCT-CI, were not associated with incidence of neurotoxicity or CRS. Presence of comorbidities by CIRS retained independent significance in multivariate models of PFS (HR 8.64, p=0.002) and OS (HR 15.44, p=0.042) when adjusted for all covariates. MYC also retained independent significance regarding OS (HR 3.23, p=0.032). Interestingly, older age was associated with superior PFS (HR 0.54, p=0.001) and OS (HR 0.59, p=0.007). Conclusions: In this multicenter retrospective analysis we show that CIRS has prognostic significance in patients with r/r DLBCL treated with commercial CAR T-cell therapy, as increased comorbidities, defined by presence of total CIRS score ≥7 or CIRS-3+, were associated with both a shorter PFS and OS. We did not find an association between the HCT-CI score and survival, nor did we see an association between comorbidities and incidence of neurotoxicity or CRS, however numbers were small. These findings show that evaluating comorbidities in patients eligible to receive CAR T-cell therapy should be considered. Further validation is needed to determine the extent that patient comorbidities predict survival in DLBCL patients undergoing CAR-T therapy. Disclosures Bishop: Novartis Pharmaceuticals: Consultancy. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Hill:Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria. Danilov:Seattle Genetics: Consultancy; MEI: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Bayer Oncology: Consultancy, Research Funding; Pharmacyclics: Consultancy; Aptose Biosciences: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Curis: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Takeda Oncology: Research Funding; Bristol-Meyers Squibb: Research Funding.

scholarly journals Resistance to Axicabtagene Ciloleucel Therapy in T Cell/Histiocyte-Rich Large B Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5238-5238
Author(s):  
Jonathan Trujillo ◽  
James Godfrey ◽  
Michael R. Bishop ◽  
Peter A. Riedell ◽  
Justin Kline
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

INTRODUCTION: CD19-directed chimeric antigen receptor (CAR) T cell therapy can lead to long-term remissions in a subset of patients with diffuse large B cell lymphoma (DLBCL). However, most patients fail to respond durably, and resistance mechanisms are incompletely defined. Additionally, the relative efficacy of CAR T cell therapy across DLBCL subtypes, such as T-cell/histocyte-rich large B cell lymphoma (T/HRLBCL), is not well established. T/HRLBCL is a distinct variant of large B cell lymphoma characterized histologically by rare malignant B cells scattered amongst infiltrating macrophages and reactive, yet ineffective, T cells. T/HRLBCL tumors frequently harbor genetic amplification of programmed death-ligand 1 (PD-L1) and exhibit robust infiltration by PD-L1-expressing macrophages (Chapuy et al. PMID 2971308, Griffin et al. ASH Abstract 1579, 2018). These features signify an adaptive up-regulation of the PD-L1 pathway, a negative regulator of T cell function. We hypothesized that T/HRLBCL is intrinsically resistant to CAR T cell therapy due to an immunosuppressive tumor microenvironment characterized by high expression of PD-L1 and abundant tumor-associated macrophages. Accordingly, we report 4 consecutive cases of multiply relapsed T/HRLBCL that failed to respond to CD19-directed CAR T cell therapy. METHODS: We identified 4 patients with histologically confirmed primary-refractory T/HRLBCL who were treated with axicabtagene ciloleucel (axi-cel) CAR T cell therapy at our institution according to the FDA dose and schedule. Radiographic follow up was performed by PET/CT imaging at 30 days post-treatment. Tissue specimens were obtained at the time of clinical and radiographic disease progression to confirm persistent disease and to assess the immune context of T/HRLBCL. A fluorescence in-situ hybridization (FISH) assay was used to assess for copy number gains of chromosomal region 9p24.1, containing the PD-L1 and PD-L2 genes. To characterize the tumor-microenvironment in the setting of CAR T cell therapy resistance, multiplex immunofluorescence analysis of baseline and post-progression tumor biopsies, when available, were performed to characterize the immune infiltrate and to evaluate for PD-L1 expression by tumor cells and tumor associated-macrophages. RESULTS: All the patients had primary-refractory T/HRLBCL and had received 2-4 prior lines of therapy before undergoing CAR T cell treatment (Table 1). At 30 days post-axi-cel infusion, all the patients demonstrated progressive disease. Tissue specimens obtained at the time of clinical and radiographic disease progression confirmed persistent lymphoma in all patients. In patients from whom tumor tissue is available, FISH testing for PD-L1 gene alterations, as well as, multiplex immunofluorescence analysis is ongoing and will be reported at the meeting. CONCLUSION: Though small patient numbers, our case series suggests that axi-cel therapy may have limited efficacy in T/HRLBCL. The reasons for this are not entirely clear, though, may be related to the genetic amplification of PD-L1 and robust infiltration by tumor-associated macrophages. A prospective evaluation of disease response to CAR T cell therapy in T/HRLBCL warrants further study. Disclosures Bishop: Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Riedell:Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kline:Merck: Research Funding; Merck: Honoraria.

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 T-Cell Telomere Length As a Biomarker to Predict Outcome in Patients Receiving CAR-T Immunotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4798-4798
Author(s):  
Enzo Tedone ◽  
Mohammed Sayed ◽  
Tsung-Po Lai ◽  
Aishwarya Sannareddy ◽  
Dheepthi P. Ramasamy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Telomere Length ◽  
Board Of Directors ◽  
Advisory Committees ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction: CAR T-cells remain in a quiescent or dormant state when unstimulated, showing no proliferative activity. In contrast, upon specific antigen stimulation (i.e., CD19) CAR T-cells divide both in-vitro and in-vivo, initiate immune responses and can kill their target cells in the body. However, one of the major physiological immune changes with increased age is the progressive impairment of T-cell responses. This process termed immunosenescence (which may be similar T-cell exhaustion) is associated with the shortening of telomeres, specific DNA repeated sequences that protect the end of linear chromosomes from degradation and fusion with neighbor chromosomes. We aim to investigate change in T-cell telomere length with CAR-T cell therapy and its potential impact on outcome in patients receiving CART immunotherapy. Methods: We enrolled adult patients (age range: 30-80 years old) receiving CART immunotherapy for diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), mantle cell lymphoma (MCL), or follicular lymphoma (FL). We collected peripheral blood at two time points: i) pre-lymphodepletion therapy and ii) two weeks post CAR-T cell infusion. Peripheral blood mononuclear cells were isolated from blood via density gradient and T-cells isolated from PBMC with magnetic beads (negative selection). Telomere lengths are quantified from T-cells by using a highly sensitive technique called TeSLA (Telomere Shortest Length Assay) that allows absolute quantification of both the average telomere length and the lengths of critically short telomeres, which are believed to play a major role in promoting cell cycle arrest and T-cell exhaustion. Results: We identified 7 patients receiving CAR T cell therapy for hematological malignancies at University of Texas Southwestern Medical Center. The cohort included 7 patients, 2 patients with DLBCL and 1 patient with MCL receiving CD19 CAR-T Cell therapy and 4 patients with MM receiving BCMA CAR-T cell therapy. Median age of patient was 65 yrs. Median follow up was 273 days post CAR T-cell therapy with all patients being alive at last follow-up. Two patients experienced Grade I Cytokine release syndrome (CRS), two patients with Grade 2 CRS and one patient with Grade 2 ICANS. Our initial analysis shows that patients telomere lengths changes pre and post CAR T-cell infusion. Regarding change in critically short telomere (<1.6kb); 6 out of 7 patients had reduction the shorter telomere from BL to post CAR-T. We are currently evaluating the effect of change in telomere length on outcomes. Conclusions: CAR T-cell therapy is a game-changer for hematological malignancies; however, disease still relapse. Understanding the mechanics of poor response or relapse after CAR T-cell therapy is critical in advancing the field. Initial results suggest T-cell telomere length are significantly affected during CAR T-cell manufacturing process and post infusion. These results are potentially important as telomere length can be utilized as a biomarker to predict CAR T-cell therapy outcomes. Figure 1 Figure 1. Disclosures Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan: Verastem: Consultancy; Incyte: Consultancy; Cardinal Health: Consultancy; Dava Oncology: Consultancy; BMS: Consultancy; ADCT therapeutics: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Kite pharma: Consultancy; Gilead sciences: Consultancy; Johnson and Johnson: Consultancy; Abbvie: Consultancy; Janssen: Consultancy; Astrazeneca: Consultancy; Genentech: Consultancy. Madanat: Onc Live: Honoraria; Blue Print Pharmaceutical: Honoraria; Geron Pharmaceutical: Consultancy; Stem line pharmaceutical: Honoraria. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees. Sweetenham: EMA Wellness: Membership on an entity's Board of Directors or advisory committees. Kansagra: Alynylam, Celgene/BMS, Cota Health, GSK, Janssen, Karyopharm, Oncopeptide, Pfizer, Takeda, Sanofi: Membership on an entity's Board of Directors or advisory committees.

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.

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