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In: Nature Reviews Clinical Oncology, Springer Science and Business Media LLC, Vol. 19, No. 5 ( 2022-05), p. 342-355

Type of Medium: Online Resource

ISSN: 1759-4774 , 1759-4782

URL: Article

DOI: 10.1038/s41571-022-00607-3

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2491410-1

detail.hit.zdb_id: 2491414-9

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 682-682

Abstract: Background: We have previously reported high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (CAR) targeting CD19 in adult patients with relapsed or refractory (R/R) ALL (Park et al. ASH 2014). Herein, we further report the long-term outcome of a larger cohort from our phase 1 clinical trial in adults with R/R ALL (NCT01044069) with a focused analysis on the role of post-treatment minimal residual disease (MRD) negativity as a predictive marker of survival as well as the effect of allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to or after CAR T cell infusion on safety and clinical outcome. Patients and Methods: Adult patients with R/R B-cell ALL (B-ALL) were enrolled. Eligible patients underwent leukapheresis, and T cells were transduced with a retroviral vector encoding a CAR comprising a CD19-specific scFv and CD28 and CD3ζ signaling domains (19-28z). All patients received lymphodepleting chemotherapy followed 2 days later by 1x106 - 3x106 19-28z CAR T cells/kg. The primary objective of the study was to evaluate the safety and anti-tumor activity of 19-28z CAR T cells. Post-treatment MRD was assessed at day 14-28 by multiparameter flow cytometry in bone marrow (BM) samples. Results: 44 patients have been treated to date. The median age was 45 years (range, 22-74). 14 patients (32%) had Philadelphia chromosome positive (Ph+) ALL (T315I mutation in 5 patients), 17 patients (39%) had prior allo-HSCT, and 24 patients (55%) had ≥ 3 prior lines of ALL therapy. Of the 44 patients, 43 patients were evaluable for response. At the time of 19-28z CAR T cell infusion, 22 of the 43 patients (51%) had morphologic disease (≥5% blasts in BM or measurable extramedullary disease) and the remaining 21 patients had minimal disease ( 〈 5% blasts in BM). 36 patients (84%) were in complete remission (CR) after 19-28z CAR T-cell infusion. MRD analysis was performed in 35 of 36 CR patients, and 29 of these 35 patients (83%) achieved an MRD-negative CR (MRD-CR). As of July 13, 2015, the median follow-up was 4.2 months (range 1-45), with 16 patients having at least 6 months of follow-up. Responses appear durable with 7 patients remaining disease-free beyond 1 year up to 45 months. A median overall survival (OS) of all patients and patients who achieved MRD-CR is 8.5 months and 10.8 months, respectively. Post-treatment MRD status emerged as a strong predictive marker of OS: OS at 6 months was 76% (95% CI: 51-89) in the MRD-CR cohort vs. 14% (95% CI: 8-45) in the MRD+CR cohort. In contrast, allo-HSCT after achieving CR with CAR T cell infusion did not affect the survival rate. Of the 36 patients in CR following the T cell infusion, 12 patients underwent allo-HSCT. OS at 6 months was 70% (95% CI: 33-89) in patients who underwent post-CAR allo-HSCT vs. 64% (95% CI: 36-82) in patients who did not get allo-HSCT after CAR T cells. Comparing baseline disease characteristics of patients who had prior allo-HSCT before the CAR T cell treatment vs. no prior allo-HSCT, patients who had prior allo-HSCT (n=17) were similar in age (median age 45 vs. 46), but had higher disease burden (65% with morphologic disease vs. 44%), were more heavily pretreated (59% of patients with ≥4 lines of therapy vs. 15%), and included more high-risk disease (41% with Ph+ ALL vs. 26%). However, there was no statistically significant difference in CR rates (75%, CI: 48-93 vs. 89%, CI: 71-98), incidences of severe cytokine release syndrome (24% vs. 22%), and OS at 6 months (57% vs. 60%) between these two cohorts. Fewer patients who had prior allo-HSCT underwent another allo-HSCT following CAR T cell infusion: 2 patients vs. 10 patients with no prior all-HSCT. Although no obvious case of graft-versus-host disease (GvHD) was noted, one patient experienced a grade 3 gastrointestinal toxicity that may have been related to GvHD. Conclusions: These data confirm the potent anti-tumor efficacy of 19-28z CAR T cells (JCAR015) in adult patients with R/R ALL. MRD negativity following the 19-28z CAR T cell treatment is highly predictive of survival, and allo-HSCT post-CAR T cell infusion had no significant impact on survival. Furthermore, 19-28z CAR T cells appear to be safe in patients who had prior allo-HSCT, and may represent an attractive alternative option to second allo-HSCT. These findings are being confirmed in an ongoing multi-center, pivotal phase 2 trial evaluating JCAR015 in adult patients with R/R ALL. Disclosures Park: Amgen: Consultancy; Genentech: Research Funding; Juno Therapeutics: Other: Advisory Board, Research Funding. Riviere:Juno Therapeutics: Other: Co-founder, stockholder and consultant. Curran:Juno Therapeutics: Consultancy. Sadelain:Juno Therapeutics: Consultancy, Equity Ownership, Other: Co-Founder, stockholder, Patents & Royalties: Licensed patents on CARs. Brentjens:Juno Therapeutics: Other: Co-founder, stockholder and consultant.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.682.682

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Nature Medicine, Springer Science and Business Media LLC, Vol. 29, No. 7 ( 2023-07), p. 1710-1717

Type of Medium: Online Resource

ISSN: 1078-8956 , 1546-170X

URL: Article

DOI: 10.1038/s41591-023-02404-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 1484517-9

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2507-2507

Abstract: Background: There is compelling rationale to use bridging radiotherapy (BRT) between leukapheresis and chimeric antigen receptor T-cell infusion for cytoreduction and palliation of relapsed/refractory B cell malignancies. There is also preclinical evidence suggesting possible immune synergy with the combination of BRT and CAR T. Existing BRT series are small and generally focused on diffuse large B-cell lymphoma (DLBCL). We report a large cohort of RT-bridged patients including early experience with BRT for non-DLBCL histologies. Methods: We analyzed 43 patients with DLBCL (n=35), mantle cell lymphoma (MCL; n=6), and Burkitt's lymphoma (BL; n=2). All received RT for any intent within 1 month prior to leukapheresis up until CAR T infusion. PET response was evaluated by Lugano criteria within the BRT treatment field ("in field"), outside of the BRT field ("out of field") and overall at 5 time points: pre-BRT, pre-CAR T infusion, and day +30 (n=41), +90 (n=30), and +180 (n=19). Survival analysis was per Kaplan-Meier and clincodemographic associations with survival were assessed by Cox univariate proportional hazards. Results: Patients received axicabtagene (n=20, 48%), tisagenlecleucel (n=11, 26%), lisocabtagene (n=8, 19%), brexucabtagene (n=2, 5%), and an experimental CAR T product (n=1, 2%). Overall, patients had a median of 3 prior therapies (range 1-9). Prior to BRT, most (74%) had advanced stage III/IV relapsed/refractory disease and 17 (40%) had bulky ( & gt;7.5 cm) lesions. There was heterogeneity in BRT-treatment parameters; most commonly treated sites were head/neck (n=10), pelvis/groin (n=8), and abdomen (n=7). Median BRT dose was 30 Gy (range 4-54), with 20 Gy in 5 fractions as the most common regimen (n=12). 18 (42%) received BRT to all sites of PET avid disease ("comprehensive BRT"). 16 (37%) patients also received systemic bridging therapy, including concurrently (n=10) with BRT. With a short 14d median time to restaging PET, in field overall response rate (ORR) post BRT was 82% (complete response, CR; n=9, 27% or partial response, PR; n=18, 55%) [Figure 1]. Reflective of the population referred for bridging, 21 (64%) had out of field progression post BRT and pre-CAR T. Post-CAR T, 2 patients (5%) had grade 3 cytokine release syndrome, 4 (9%) had grade 3 neurotoxicity, and no severe toxicity within the BRT field was noted. Following CAR T, ORR was 72% (CR: n=25, 60%; PR: n=5, 12%). Median post CAR T follow-up was 9 mos (range 1-40), with 44% (n=19) of patients having no evidence of disease, 44% (n=19) deceased, and 12% (n=5) alive with disease at last contact. 33 (77%) patients never progressed within the BRT field. Of the 27 (63%) patients who relapsed, 10 were CD19- and 9 (33%) had disease in the BRT field at first progression. In DLBCL patients, progression free survival (PFS) was 83%, 60%, and 51% and overall survival (OS) was 100%, 89% and 69%, respectively at Day +30, +90, and +180. Univariate analysis showed that pre-BRT ECOG performance status ≥2 (HR: 12.0, p & lt;0.005), CNS disease (HR: 7.6, p=0.006), 3 prior systemic therapies (HR: 8.1, p=0.05), and BRT dose 30 Gy (HR: 0.21, p=0.01) were significantly associated with OS. Timing of BRT relative to leukapheresis was not a significant predictor of PFS or OS. Conclusion: BRT has broad utility for aggressive B-cell malignancies and is associated with excellent pre-CAR T local control and no serious toxicity within the irradiated sites. Most patients had durable post-CAR T local control. Prospective studies are planned to clarify outcomes and evaluate mechanistic synergies. Future studies are needed to define optimal patient characteristics for systemic vs. radiotherapy bridging and elucidate the best BRT strategy for maximizing local control and potential immune augmentation. Figure 1 Figure 1. Disclosures Palomba: Kite: Consultancy; Novartis: Consultancy; Notch: Honoraria, Other: Stock; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Lygenesis: Honoraria; PCYC: Consultancy; BeiGene: Consultancy; Pluto: Honoraria; Wolters Kluwer: Patents & Royalties; Juno: Patents & Royalties; Ceramedix: Honoraria; Magenta: Honoraria; Priothera: Honoraria; Nektar: Honoraria; WindMIL: Honoraria; Rheos: Honoraria. Shouval: Medexus: Consultancy. Batlevi: Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Kite Pharma: Consultancy; Dava Oncology: Honoraria; Karyopharm: Consultancy; Juno/Celgene: Consultancy; Bayer: Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; ADC Therapeutics: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Brentjens: BMS: Consultancy, Patents & Royalties, Research Funding; Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; sanofi: Patents & Royalties; Caribou: Patents & Royalties. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Giralt: JENSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Park: Kura Oncology: Consultancy; Intellia: Consultancy; Autolus: Consultancy; Artiva: Consultancy; Novartis: Consultancy; Amgen: Consultancy; PrecisionBio: Consultancy; Curocel: Consultancy; Affyimmune: Consultancy; BMS: Consultancy; Minerva: Consultancy; Servier: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy. Scordo: i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Omeros Corporation: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding; McKinsey & Company: Consultancy. Sauter: Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Genmab: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Shah: Janssen: Research Funding; Amgen: Research Funding. Perales: NexImmune: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Bristol-Myers Squibb: Honoraria; Cidara: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Celgene: Honoraria; MorphoSys: Honoraria; Medigene: Honoraria; Omeros: Honoraria; Novartis: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Miltenyi Biotec: Honoraria, Other; Merck: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151179

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 4, No. 4 ( 2020-02-25), p. 676-686

Abstract: Various grading systems are currently used for chimeric antigen receptor (CAR) T-cell–related toxicity, cytokine release syndrome (CRS), and immune effector cell–associated neurotoxicity syndrome (ICANS). We compared the recently proposed American Society for Transplantation and Cellular Therapy (ASTCT) grading system to other grading scores in 2 populations of adults: patients (n = 53) with B-cell acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T-cells (clinicaltrials.gov #NCT01044069), and patients (n = 49) with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel after US Food and Drug Administration approval. According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas 50% of patients experienced ICANS, 55% in the B-ALL and 45% in the DLBCL groups (axi-cel: 55%, tisagenlecleucel: 15%). All grading systems agreed on CRS and ICANS diagnosis in 99% and 91% of cases, respectively. However, when analyzed grade by grade, only 25% and 54% of patients had the same grade in each system for CRS and ICANS, respectively, as different systems score symptoms differently (upgrading or downgrading their severity), leading to inconsistent final grades. Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment. Moreover, because these guidelines are based on single products and different grading systems, they cannot be universally applied. To avoid discrepancies in assessing and managing toxicities of different products, we propose that unified grading be used across clinical trials and in practice and that paired management guidelines with product-specific indications be developed.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2019000952

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 2876449-3

In: Cancer Cell, Elsevier BV, Vol. 37, No. 6 ( 2020-06), p. 761-763

Type of Medium: Online Resource

ISSN: 1535-6108

URL: Article

DOI: 10.1016/j.ccell.2020.05.015

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2074034-7

detail.hit.zdb_id: 2078448-X

SSG: 12

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4455-4455

Abstract: Background: CAR T therapy is FDA approved for specific relapsed/ refractory (R/R) B cell lymphomas and acute lymphoblastic leukemia (ALL), and clinical trials are ongoing for R/R multiple myeloma (MM). Cytopenias have been observed post-CAR T, yet there is minimal data delineating the pathobiology and trends. We report the largest series to our knowledge thus far, of hematological recovery and factors affecting count recovery after CAR T. Methods: We retrospectively reviewed adult patients who received CAR T for R/R B cell lymphomas after FDA approval and those treated for R/R B cell ALL (NCT01044069) and MM (NCT03070327) at our center. Blood counts were collected for up to 12 months or until censored for relapse, progression or initiation of chemotherapy/ conditioning for autologous or allogeneic stem cell transplantation (HCT)/ subsequent treatment with CAR T. Only patients with follow-up 〉 30 days were included. "Recovery" for the respective blood count was defined as hemoglobin 〉 8g/dL and platelets 〉 50,000/µL without transfusion support in 2 weeks and 1 week, respectively; absolute neutrophil count (ANC) 〉 1,000/µL and white cell count (WBC) 〉 3,000/µL without growth factor support in 2 weeks. "Normalization" was defined as normal range for the laboratory; hemoglobin 〉 11.2g/dL in women and 12.5g/dL in men, platelets 〉 160,000/µL, ANC 〉 1,500/µL and WBC 〉 3,000/µL without transfusion support as above. "Complete count recovery" refers to recovery per above criteria in all 4 counts. Categorical variables were compared using Fisher's exact test and continuous variables using the Wilcoxon rank-sum test. Results: Eighty three patients were included (Table 1). Using the noted nadir values, grade 1-2 and 3-4 anemia was seen in 22% and 78%, thrombocytopenia in 29% and 66%, neutropenia in 3% and 96% while leucopenia in 0% and 100%, respectively. During the follow-up, 66% patients received packed red cell transfusion, 52% received platelet transfusion and 62% received growth factor support. By 1 month (n=83), recovery of hemoglobin, platelets, ANC and WBC was noted in 61%, 51%, 33% and 28%, respectively. At 3 months (n=41), these respective percentages were 93%, 90%, 81% and 59%. All patients had recovered hemoglobin and platelet count by 4 months (n=17), and ANC by 9 months (n=14). By 3 months, normalization of hemoglobin, platelets, ANC and WBC was noted in 39%, 34%, 71%, and 39%, respectively. Upon examination of potential variables in a univariate model, lack of recovery of hemoglobin, platelets, ANC and complete counts recovery at 1 month was statistically significantly associated with type of CAR construct, higher grade (grade 3-4 vs grade 1-2 vs none) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) as well as a higher peak CRP and ferritin (data for complete count recovery in Table 2). Additionally, lack of hemoglobin recovery at 1 month was associated with lymphodepletion using high dose cyclophosphamide (recovered vs no recovery in 58% vs 42%, p=0.01) and diagnosis of ALL (65% vs 35%, p = 〈 0.001). Similarly, inability to recover platelets at 1 month was significantly associated with prior HCT (63% vs 36%, p =0.04); while ANC was associated with prior HCT (87% vs 13%, p = 0.004) and 〉 3 prior lines of therapy (78% vs 22%, p = 0.04). At 3 months, absence of complete count recovery was associated only with the CAR T construct utilized. A multivariate logistic regression model resulted in wide confidence intervals due to small size of subgroups, hence leading to unreliable point estimates (data not shown). Conclusions: Our study shows that blood counts recover in most patients who have not progressed or received additional therapy by 3 months post-CAR T. The association of count recovery with severity of CRS, ICANS as well as inflammatory marker levels indicates that inflammatory response post-CAR T influences hematological recovery in these patients. The association of count recovery and CAR construct can be influenced by underlying diagnosis as specific CAR constructs were used for specific diagnosis. Since patients with no disease response were excluded and were censored at progression, these effects are less likely to be affected by disease response; however the association of depth of response could not be evaluated in this study. These results warrant future studies to understand underlying mechanisms of inadequate recovery. Disclosures Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy. Sauter:Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Celgene: Consultancy; GSK: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy. Santomasso:Novartis: Consultancy; Kite/Gilead: Consultancy; Juno/Celgene: Consultancy. Palomba:Noble Insights: Consultancy; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen: Research Funding; Janssen: Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Brentjens:Celgene: Consultancy; JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding. Park:Takeda: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Incyte: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy. Perales:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mailankody:Celgene: Research Funding; Juno: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-127480

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 5, No. 17 ( 2021-09-14), p. 3397-3406

Abstract: Patients who develop chimeric antigen receptor (CAR) T-cell–related severe cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase [LDH; U/L] × creatinine [mg/dL] /platelets [PLTs; 109 cells/L]) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX [m-EASIX] , which replaces creatinine with CRP [mg/dL]), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve [AUC] at lymphodepletion, 80.4%; at day −1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell–related toxicities.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2020003885

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1947-1947

Abstract: Introduction Chimeric Antigen Receptor (CAR) T cells are associated with unique toxicities, including cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS). Patients (pts) with severe CRS and ICANS exhibit hemodynamic instability and coagulopathy with evidence of endothelial activation and increased blood brain barrier permeability. Increases in inflammatory cytokines and biomarkers of endothelial activation in serum and CSF have been associated with severe CRS and ICANS. The EASIX (Endothelial Activation and Stress Index) score [lactate dehydrogenase (LDH) (U/L) × creatinine (mg/dl) / platelets (PLT) (109 cells/L)] correlates with severe fluid overload and survival in allogeneic transplant pts. Elevated LDH and low PLT levels have been associated with severe ICANS development, and high IL-6 levels are seen in severe CRS and ICANS. We hypothesized that the EASIX and a newly proposed version of it, the modified-EASIX (mEASIX), in which creatinine is replaced by CRP (mg/dL) as an easily available surrogate for IL6, would be associated with CRS and ICANS in CAR T cells pts. Methods We analyzed 2 different populations of adult CAR T cells pts treated at our institution: 1) B-cell acute lymphoblastic leukemia (B-ALL) pts treated with CD1928z CAR T cells from 2010 to 2016 (NCT01044069), and 2) aggressive diffuse large B-cell lymphoma (DLBCL) pts treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after FDA approval starting from 2018. EASIX and mEASIX scores were calculated for each patient daily from start of lymphodepletion conditioning to day +14. A log transformation using base 2 (log2) was applied to all EASIX/mEASIX variables to reduce skew. CRS and ICANS were graded according to the ASTCT grading system. Results 87 pts, B-ALL (n=53) and DLBCL (n=34), were analyzed. According to ASTCT grading, 83% (72/87) experienced CRS and 54% (47/87) developed ICANS, grade ≥3 in 23% (20/87) and 40% (35/87) of pts, respectively. When analyzed by disease, CRS and ICANS rates were 87% (46/53) and 55% (29/53) for B-ALL and 76% (26/34) and 53% (18/34) for DLBCL, respectively. CRS and ICANS were grade ≥3 in 28% (15/53) and 45% (24/53) of B-ALL pts and in 15% (5/34) and 32% (11/34) of DLBCL pts, respectively. Median time of onset of CRS after CAR T cell infusion was day +2 and median onset of ICANS was day +6 for the overall population and the subgroups. High EASIX and mEASIX scores at start of conditioning were both associated with development of any grade CRS [OR=1.81 (95% CI 1.09-3.36) p=0.038 and OR=1.94 (95% CI 1.32-3.38) p=0.005] and grade ≥3 CRS [OR=1.47 (95% CI 1.05-2.29) p=0.049 and OR=1.34 (95% CI 1.07-1.80) p=0.024] , respectively (Table). Following CAR T cell infusion, high scores of both EASIX [OR=1.60 (95% CI 1.12-2.43) p=0.017] and mEASIX [OR=1.32 (95% CI 1.07-1.69) p=0.014] on day +1 were associated with development of grade ≥3 CRS. Moreover, both high EASIX [OR=1.43 (95% CI 1.08-1.96) p=0.018] and mEASIX [OR=1.29 (95% CI 1.07-1.60) p=0.010] scores on day +3 were associated with grade ≥3 ICANS. When analyzed by disease, results were confirmed for severe CRS and ICANS in B-ALL patients, while in the DLBCL group only mEASIX at start of conditioning and at day +1 was associated with development of any grade CRS. EASIX and mEASIX scores were not associated with response rates to CAR T cells therapy. Conclusions EASIX and mEASIX scores calculated at baseline (before lymphodepletion) are associated with development of CRS and severe CRS. Moreover, both high EASIX and mEASIX scores on day +1 and day +3 are associated with occurrence of grade ≥3 CRS and grade ≥3 ICANS, respectively. We conclude that EASIX and mEASIX, as markers of endothelial damage and inflammation, could be useful as early predictors in guiding treatment decisions before the onset of severe symptoms. Table Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brentjens:JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy. Giralt:Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Kite: Consultancy. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy. Santomasso:Kite/Gilead: Consultancy; Juno/Celgene: Consultancy; Novartis: Consultancy. Sauter:GSK: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Perales:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-126208

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4458-4458

Abstract: Introduction Cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS) are commonly associated with Chimeric Antigen Receptor (CAR) T cells therapy. To assess CAR T cell safety, various grading systems were developed and used in clinical trials: Lee, Penn, Memorial Sloan Kettering Cancer Center (MSKCC), CARTOX and CTCAEv5.0 for CRS; and CTCAEv4.03 and CARTOX for ICANS. While these grading systems evaluate mostly uniform symptoms, their intensity gradings differ. The American Society for Transplantation and Cellular Therapy (ASTCT) recently developed a simplified consensus grading system for CRS and ICANS. To validate the ASTCT grading, we compared it to the aforementioned gradings. Methods We included 2 populations of adult patients (pts) treated at our center: 1) B-cell acute lymphoblastic leukemia (B-ALL) treated with CD1928z CAR T cells from 2010 to 2016 (NCT01044069), and 2) diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after FDA approval from 2018. Upon chart review, one expert clinician re-graded all CRS and ICANS. For validation, another expert independently graded a randomly selected sample (20%). A neurologist and an intensivist supervised the review process. CRS/ICANS rates and concordance rates were assessed for all grading systems. In pts with DLBCL (treated with axi-cel or tisa-cel), we used ASTCT grades to predict treatment according to currently available guidelines (axi-cel and tisa-cel FDA insert packages, CARTOX and NCCN guidelines) and compare it to the actual treatment received at our institution. Results We analyzed 102 pts: 53 B-ALL and 49 DLBCL (axi-cel: 36, tisa-cel: 13). According to ASTCT grading, 82% pts had CRS, 87% in B-ALL and 77% in DLBCL pts (axi-cel: 86%, tisa-cel: 54%). The concordance rate on diagnosis of CRS (yes vs no) across all scores was 99%. Concordance rate grade by grade, instead, was 27%, with major discordance in grades 1 to 3 (figure a-b). The Penn score upgraded 91% pts from gr 1 to 2 (neutropenic fever requiring inpatient antibiotics), and 93% from gr 2 to 3 (fluid responsive hypotension or low-dose oxygen). Grading concordance increased to 78% when Penn was excluded, with other differences due to: 1) CARTOX downgraded 15% of gr 2 pts with hypotension, for systolic blood pressure 〉 90; and 2) CARTOX and Lee upgraded 8% pts for organ damage. By ASTCT, 50% pts experienced ICANS, 55% in B-ALL and 45% in DLBCL pts (axi-cel: 55%, tisa-cel: 15%). By CTCAEv4.03, ICANS incidence was 55% because 5 pts with headache and slurred speech with trouble word finding didn't meet criteria for ICANS by ASTCT (due to normal ICE score), leading to a 91% global concordance rate. Concordance grade by grade was 57%, mainly due to gr 1 and gr 3-4 ICANS (figure c). CARTOX upgraded 42% of gr 3 pts to gr 4 because of brief generalized seizures which, notably, where mostly seen in B-ALL pts compared to DLBCL (30% vs 6%). Another pt was upgraded from gr 2 to 4 for asymptomatic intracranial pressure 〉 20 mmHg without cerebral edema. We then looked at implications on management in the DLBCL group (Table 1). For CRS, only 4 pts with gr 3-4 CRS would receive tocilizumab according to tisa-cel's label (doesn't include tocilizumab for gr 2 CRS) compared to 24, 19, 25 pts according to axi-cel's label, CARTOX and NCCN, respectively. In our practice, 22 patients received tocilizumab. For ICANS, steroids use was consistent across all guidelines (16 pts, 5 with gr 2 ICANS and 11 with gr ≥3 ICANS) and almost comparable to our practice (19 pts treated). Conversely, only a few pts at our institution received tocilizumab for ICANS with concurrent CRS (2 pts vs 7, 11, 11 for axi-cel, CARTOX and NCCN, respectively). Conclusions Over or under attribution of symptoms due to CAR T cells results in inconsistent scores across different grading systems. Current guidelines for CRS and ICANS management are based on the experience derived from single products and various grading systems, which may result in either overtreating or delaying treatment. As such, they cannot be universally applied. To avoid discrepancies in assessing safety and in managing different product toxicities, we conclude that a unified grading system should be utilized across clinical trials and in clinical practice, and that similar consensus management guidelines be developed and adopted. Disclosures Santomasso: Juno/Celgene: Consultancy; Kite/Gilead: Consultancy; Novartis: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brentjens:Celgene: Consultancy; JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding. Giralt:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Novartis: Consultancy; Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy. Palomba:MSK (IP for Juno and Seres): Patents & Royalties; Evelo: Equity Ownership; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees. Sauter:Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; GSK: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Incyte: Consultancy. Perales:Miltenyi: Research Funding; Kyte/Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-126022

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7