SpringerLink
Log in

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients

  • Original Research
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods.

Methods

Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12 months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI).

Results

The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses.

Conclusion

Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The datasets generated and analyzed during this study can be made available upon reasonable request to the corresponding author, and decisions regarding data sharing will be made on a case-by-case basis considering data protection and other applicable regulations.

References

  1. National Cancer Institute. SEER cancer statistics review, 1975–2017. 2020. https://seer.cancer.gov/csr/1975_2017/. Accessed 20 Apr 2023.

  2. Pulte D, Jansen L, Gondos A, Katalinic A, Barnes B, Ressing M, et al. Survival of adults with acute lymphoblastic leukemia in Germany and the United States. PLoS ONE. 2014;9(1): e85554.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C, et al. Acute lymphoblastic leukaemia in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v69–82.

    Article  CAS  PubMed  Google Scholar 

  4. Paul S, Rausch CR, Nasnas PE, Kantarjian H, Jabbour EJ. Treatment of relapsed/refractory acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2019;17(3):166–75.

    PubMed  Google Scholar 

  5. Kantarjian HM, Thomas D, Ravandi F, Faderl S, Jabbour E, Garcia-Manero G, et al. Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. Cancer. 2010;116(24):5568–74.

    Article  PubMed  Google Scholar 

  6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines): acute lymphoblastic leukemia, Version 1.2023—May 31, 2023. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed 27 June 2023.

  7. ClinicalTrials.gov. Identifier NCT02614066, a study evaluating KTE-X19 in adult subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia (ZUMA-3). 2023. https://ClinicalTrials.gov/show/NCT02614066. Accessed 20 Apr 2023.

  8. Shah BD, Bishop MR, Oluwole OO, Logan AC, Baer MR, Donnellan WB, et al. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood. 2021;138(1):11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, et al. 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. J Hematol Oncol. 2022;15(1):170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Proskorovsky I, Su Y, Fahrbach K, Vandendries E, Pagé V, Onyekwere U, et al. Indirect treatment comparison of inotuzumab ozogamicin versus blinatumomab for relapsed or refractory acute lymphoblastic leukemia. Adv Ther. 2019;36(8):2147–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Song J, Ma Q, Gao W, Cong Z, **e J, Zimmerman Z, et al. Matching-adjusted indirect comparison of blinatumomab vs. inotuzumab ozogamicin for adults with relapsed/refractory acute lymphoblastic leukemia. Adv Ther. 2019;36(4):950–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet (London, England). 2021;398(10299):491–502.

    Article  CAS  PubMed  Google Scholar 

  13. Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125(14):2474–87.

    Article  CAS  PubMed  Google Scholar 

  14. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Guyot P, Ades AE, Ouwens MJ, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12:9.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Phillippo DM, Ades AE, Dias S, Palmer S, Abrams KR, Welton NJ. Methods for population-adjusted indirect comparisons in health technology appraisal. Med Decis Mak. 2018;38(2):200–11.

    Article  Google Scholar 

  17. Phillippo DM, Ades AE, Dias S, Palmer S, Abrams KR, Welton NJ. NICE DSU technical support document 18: methods for population-adjusted indirect comparisons in submission to NICE. 2016.

  18. Laetsch TW, Maude SL, Rives S, Hiramatsu H, Bittencourt H, Bader P, et al. Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA trial. J Clin Oncol. 2023;41(9):1664–9.

    Article  CAS  PubMed  Google Scholar 

  19. ClinicalTrials.gov. Identifier NCT02228096, study of efficacy and safety of CTL019 in pediatric ALL patients (ENSIGN). 2020; https://clinicaltrials.gov/ct2/show/NCT02228096. Accessed 20 Apr 2023.

Download references

Medical Writing and Editorial Assistance

Medical writing and editorial assistance were provided by Jenny MH Chen, MSc, and Sam Kee**, MSc, employees of PRECISIONheor. Support for this assistance was provided by Kite, a Gilead Company.

Authorship

All authors meet the International Committee of Medical Journal Editors (ICJME) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Funding

This study, including the Rapid Service and Open Access Fees, was sponsored by Kite, a Gilead Company.

Author information

Authors and Affiliations

  1. Moffitt Cancer Center, Tampa, FL, 33612, USA

    Bijal Shah

  2. PRECISIONheor, Vancouver, BC, Canada

    Jenny M. H. Chen, Julie E. Park & Sam Kee**

  3. Kite, a Gilead Company, Santa Monica, CA, USA

    James J. Wu, Chaoling Feng, Lang Zhou & Tsveta Hadjiivassileva

  4. Federal University of Sao Paulo and Beneficência Portuguesa de São Paulo, São Paulo, Brazil

    Fabio R. Kerbauy

  5. Wade Outcomes Research & Consulting, Salt Lake City, UT, USA

    Sally W. Wade

Authors
  1. Bijal Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jenny M. H. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James J. Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chaoling Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julie E. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tsveta Hadjiivassileva
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fabio R. Kerbauy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sally W. Wade
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sam Kee**
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Study design and conceptualization: Jenny M.H. Chen, James J. Wu, Chaoling Feng, and Sam Kee**; Data analysis: Jenny M.H. Chen, Julie E. Park, and Sam Kee**; Data interpretation: All authors; Writing – original draft preparation: Jenny M.H. Chen; Writing – review and editing: All authors. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bijal Shah.

Ethics declarations

Conflicts of Interest

Bijal Shah has received consultant and education fees from Amgen, Pfizer, Novartis, BMS/Celgene/Juno, Kite, a Gilead company, Precision Biosciences, Jazz, Beigene, Adaptive, Century Therapeutics, and Autolus; and clinical trial grants from Kite, a Gilead company, Jazz, and Servier. Jenny M.H. Chen, Julie E. Park, and Sam Kee** are employees of PRECISIONheor, funded by Kite, a Gilead Company for this study. James J. Wu is an employee of Kite, a Gilead Company; has received honoraria from the Patient-Centered Outcomes Research Institute (PCORI), both as a member of the Rare Disease Advisory Panel, and as a grants reviewer for the Improving Methods Program; has received travel/meeting support from Kite, a Gilead Company, and Amgen; owns stock in Gilead Sciences, Amgen, Abbott, AbbVie, Pfizer, Roche, Curis, Avid Biosciences, Evofem, Lensar, VBI Vaccines, and Viracta Therapeutics. Chaoling Feng is an employee of Kite, a Gilead Company and owns stock in Gilead Sciences. Lang Zhou is an employee of Kite, a Gilead Company and owns stock in AbbVie and Gilead Sciences. Tsveta Hadjiivassileva is an employee of Kite, a Gilead Company and owns stock in Gilead Sciences. Sally W. Wade has received consulting fees from Kite, a Gilead Company, Abbvie, and Johnson & Johnson. Fabio R. Kerbauy declares no competing interests.

Ethical Approval

Results presented in this article are based on a retrospective analysis of data from published studies, and therefore no institutional board review was required. Review boards at participating institutions approved the ZUMA-3, INO-VATE, and TOWER trials.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 321 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shah, B., Chen, J.M.H., Wu, J.J. et al. Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients. Adv Ther 40, 5383–5398 (2023). https://doi.org/10.1007/s12325-023-02662-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-023-02662-3

Keywords

Search

Navigation