Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study

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Abstract

Background

Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care.

Methods

Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 10 ⁶ CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3.

Results

After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients ( N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients ( N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 ( N = 49) and matched historical controls ( N = 40) was 25.4 and 5.5 months, respectively.

Conclusions

These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population.

Trial Registration: NCT02614066.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13045-022-01379-0.

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Most cited references 9

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Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial

Frederick L Locke, Armin Ghobadi, Caron Jacobson … (2018)

Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study.

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KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma

Michael Wang, Javier Munoz, Andre Goy … (2020)

Background Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton’s tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma. Methods In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×10 6 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months. Results A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression- free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred. Conclusions KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313 .)

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Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

Hagop Kantarjian, Anthony Stein, Nicola Gökbuget … (2017)

Background Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects. Methods In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival. Results Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Conclusions Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).

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Author and article information

Contributors

Bijal D. Shah: bijal.shah@moffitt.org

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 10 December 2022

Publication date PMC-release: 10 December 2022

Publication date Collection: 2022

Volume: 15

Electronic Location Identifier: 170

Affiliations

[1 ]GRID grid.468198.a, ISNI 0000 0000 9891 5233, Moffitt Cancer Center, ; Tampa, FL 33612 USA

[2 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Washington University School of Medicine, ; St Louis, MO USA

[3 ]GRID grid.152326.1, ISNI 0000 0001 2264 7217, Vanderbilt University Cancer Center, ; Nashville, TN USA

[4 ]GRID grid.413077.6, ISNI 0000 0004 0434 9023, UCSF Medical Center, ; San Francisco, CA USA

[5 ]GRID grid.413328.f, ISNI 0000 0001 2300 6614, Hôpital Saint-Louis, ; Paris, France

[6 ]GRID grid.34477.33, ISNI 0000000122986657, University of Washington, ; Fred Hutchinson Cancer Center, Seattle, WA USA

[7 ]GRID grid.42399.35, ISNI 0000 0004 0593 7118, Service d’hématologie Clinique Et Thérapie Cellulaire, , Hopital du Haut-Leveque CHU de Bordeaux, ; Bordeaux, France

[8 ]GRID grid.170205.1, ISNI 0000 0004 1936 7822, The University of Chicago Medicine, ; Chicago, IL USA

[9 ]GRID grid.411760.5, ISNI 0000 0001 1378 7891, Medizinische Klinik Und Poliklinik II, , Universitätsklinikum Würzburg, ; Würzburg, Germany

[10 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, University of California San Diego, ; San Diego, CA USA

[11 ]GRID grid.16416.34, ISNI 0000 0004 1936 9174, Wilmot Cancer Institute of University of Rochester, ; Rochester, NY USA

[12 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Winship Cancer Institute of Emory University, ; Atlanta, GA USA

[13 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Mayo Clinic, ; Rochester, MN USA

[14 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, ; Baltimore, MD USA

[15 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, David Geffen School of Medicine at UCLA, ; Los Angeles, CA USA

[16 ]GRID grid.51462.34, ISNI 0000 0001 2171 9952, Memorial Sloan Kettering Cancer Center, ; New York, NY USA

[17 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Ludwig-Maximilians-Universität München, ; Munich, Germany

[18 ]GRID grid.27860.3b, ISNI 0000 0004 1936 9684, University of California Davis Comprehensive Cancer Center, ; Sacramento, CA USA

[19 ]GRID grid.7692.a, ISNI 0000000090126352, University Medical Center Utrecht (on behalf of HOVON/LLPC), ; Utrecht, The Netherlands

[20 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, The University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[21 ]GRID grid.65499.37, ISNI 0000 0001 2106 9910, Dana-Farber Cancer Institute, ; Boston, MA USA

[22 ]GRID grid.164971.c, ISNI 0000 0001 1089 6558, Loyola University Chicago Stritch School of Medicine, ; Maywood, IL USA

[23 ]GRID grid.417319.9, ISNI 0000 0004 0434 883X, University of California Irvine Medical Center, ; Orange, CA USA

[24 ]GRID grid.504964.a, Kite, a Gilead Company, ; Santa Monica, CA USA

[25 ]GRID grid.411154.4, ISNI 0000 0001 2175 0984, CHU Rennes, Univ Rennes, Inserm & EFS, ; Rennes, France

Article

Publisher ID: 1379

DOI: 10.1186/s13045-022-01379-0

PMC ID: 9734710

PubMed ID: 36494725

SO-VID: a11faeeb-556b-4458-968a-30257c8554b6

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 4 August 2022

Date accepted : 5 October 2022

Funding

Funded by: Kite, a Gilead Company

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: b-precursor acute lymphoblastic leukemia,brexucabtagene autoleucel,car t-cell therapy,kte-x19,scholar-3,zuma-3

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: b-precursor acute lymphoblastic leukemia, brexucabtagene autoleucel, car t-cell therapy, kte-x19, scholar-3, zuma-3

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study

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Abstract

Background

Methods

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Supplementary Information

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Karger: Oncology

Most cited references 9

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial

KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

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