ZUMA-4 preliminary results: phase 1 study of KTE-C19 chimeric antigen receptor T cell therapy in pediatric and adolescent patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL)

Lee, D.W.; Wayne, Alan S.; Huynh, Van; Handgretinger, Rupert; Pieters, Rob; Michele, G. De; Baruchel, André; Feuchtinger, Tobias; Bertrand, Y.; Hemiston, M.; Brown, Patrick; Rossi, J.M.; Jiang, Yizhou; Navale, Lynn; Stout, Shanna; Aycock, Jeff; Mardiros, Armen; Wiezorek, Jeffrey S.; Jain, Rajul K.

doi:10.1093/annonc/mdx373.014

Cited by 10 publications

(12 citation statements)

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“…58,59 However, other trials suggest that tocilizumab may be associated with ablation of the cytokine milieu necessary for CAR T-cell proliferation and CAR T-cell activity, 47 and an increased risk of neurotoxicity 40,59 by increasing the levels of peripheral IL-6 that can cross the blood-brain barrier (BBB). 29,[60][61][62][63][64] ASTCT consensus recommends tocilizumab for CRS !grade 2 (8 mg/kg body weight (BW)/dose in patients !30 kg BW; IV administration over 1 h; 12 mg/kg BW in patients <30 kg BW; maximum of 800 mg/dose; administration up to four doses with 4 to 6 h between consecutive doses). 65 Preemptive use of tocilizumab has not been addressed in current CRS management algorithms and is therefore not recommended.…”

Section: Management Of Crsmentioning

confidence: 99%

Side-effect management of chimeric antigen receptor (CAR) T-cell therapy

et al. 2021

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Chimeric antigen receptor (CAR) T cells directed against the B-cell marker CD19 are currently changing the landscape for treatment of patients with refractory and/or relapsed B-cell malignancies. Due to the nature of CAR T cells as living drugs, they display a unique toxicity profile. As CAR T-cell therapy is extending towards other diseases and being more broadly employed in hematology and oncology, optimal management strategies of side-effects associated with CAR T-cell therapy are of high relevance. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias constitute challenges in the treatment of patients with CAR T cells. This review summarizes the current understanding of CAR T-cell toxicity and its management.

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Section: Management Of Crsmentioning

confidence: 99%

Side-effect management of chimeric antigen receptor (CAR) T-cell therapy

et al. 2021

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“…12 KTE-X19 was manufactured at a centralized facility, with coordinated leukapheresis and shipping from multiple centers across the United States and a fast turnaround time, which are critical for patients with rapidly proliferative disease and high tumor burden. 13,14 Here, we report phase 1 results of the phase 1/2, multicenter, single-arm, open-label ZUMA-3 study evaluating the safety and efficacy of KTE-X19 in adults with R/R B-ALL.…”

Section: Introductionmentioning

confidence: 99%

KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results

Shah

Bishop

Oluwole

et al. 2021

Blood

108

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ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-ALL. We report the phase 1 results. Following fludarabine/cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2, 1, or 0.5×106 cells/kg. The rate of dose-limiting toxicities (DLTs) within 28 days following KTE-X19 infusion was the primary endpoint. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age: 46 years [range, 18-77]). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 31% and 38% of patients, respectively. To optimize the benefit-risk ratio, revised adverse event (AE) management for CRS and NE (earlier steroid use for NE and tocilizumab only for CRS) was evaluated at 1×106 cells/kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NE, with no grade 4/5 NE. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1×106 cells/kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At 22.1 months (range, 7.1-36.1) median follow-up, the median duration of remission was 17.6 months (95% CI, 5.8-17.6) in patients treated with 1×106 cells/kg and 14.5 months (95% CI, 5.8-18.1) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1×106 cells/kg with revised AE management.

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“…50,51 The Memorial Sloan Kettering Cancer Centre (USA), National Cancer Institute (USA) and Sheba Medical Centre (Israel) have developed CD28z second generation anti-CD19 CAR-T cells generated with gamma-retrovirus. In a phase I study of KTE-C19, which contains a CD28 domain and based on the NCI CAR-T, involving 21 children and young adults, CAR-T cells were not detected beyond 68 days; 47,52,53 therefore, KTE-C19 and similarly, other CD28 CAR-T serve as a bridge to allogeneic transplantation for most patients who receive it. The CD28z CAR-T patients in all three centres were consolidated with HSCT in remission due to the recognized shorter persistence of the CD28z CAR-T.…”

Section: Clinical Trials In Car-t Therapies In Paediatric R/r B-allmentioning

confidence: 99%

A Review of CAR-T Therapy in Pediatric and Young Adult B-Lineage Acute Leukemia: Clinical Perspectives in Singapore

Seng¹,

Meierhofer²,

Lim³

et al. 2023

OTT

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Approximately 10-15% of pediatric B-cell acute lymphoblastic leukemia (B-ALL) are high risk at diagnosis or relapsed/ refractory. Prior to the availability of chimeric antigen receptor T-cell (CAR-T) in Singapore and the region, the treatment options for these paediatric and young adults are conventional salvage chemotherapy or chemo-immunotherapy regimens as a bridge to allogeneic total body irradiation-based hematopoietic stem cell transplantation (allo-HSCT). This results in significant acute and long-term toxicities, with suboptimal survival outcomes. Finding a curative salvage therapy with fewer long-term toxicities would translate to improved quality-adjusted life years in these children and young adults. In this review, we focus on the burden of relapsed/refractory pediatric B-ALL, the limitations of current strategies, the emerging paradigms for the role of CAR-T in r/r B-ALL, our local perspectives on the health economics and future direction of CAR-T therapies in pediatric patients.

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ZUMA-4 preliminary results: phase 1 study of KTE-C19 chimeric antigen receptor T cell therapy in pediatric and adolescent patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL)

Cited by 10 publications

References 0 publications

Side-effect management of chimeric antigen receptor (CAR) T-cell therapy

Side-effect management of chimeric antigen receptor (CAR) T-cell therapy

KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results

A Review of CAR-T Therapy in Pediatric and Young Adult B-Lineage Acute Leukemia: Clinical Perspectives in Singapore

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