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Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial

Nature Medicine volume 28, pages 325–332 (2022)Cite this article

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Abstract

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8–20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8–78.3) and ORR 86.2% (95% confidence interval, 77.5–92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.

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Fig. 1: CONSORT diagram for ELARA.
Fig. 2: Best response of CR according to subgroup (EAS population).
Fig. 3: Kaplan–Meier curves for patients with r/r FL who received tisagenlecleucel infusion.

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Data availability

The authors declare that all data supporting the findings of this analysis are available within the article and its appendix. Novartis is committed to sharing, with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. Availability of trial data is according to the criteria and process described at www.clinicalstudydatarequest.com.

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Acknowledgements

The study was sponsored and designed by Novartis Pharmaceuticals Corporation and was approved by the IRB at each participating institution. Data were analyzed and interpreted by the sponsor and the authors. All authors reviewed the manuscript and approved of the final version before submission. We vouch for the data and analysis and for the adherence of the study to the protocol. We thank A. A. Abozeid (former employee of Novartis) for his contributions to the analyses presented herein. Medical writing support was provided by R. Parthasarathy (Healthcare Consultancy Group) and was funded by Novartis Pharmaceuticals Corporation.

Author information

Author notes

  1. These authors jointly supervised this work: Stephen J. Schuster, Catherine Thieblemont.

Authors and Affiliations

  1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Nathan Hale Fowler & Loretta J. Nastoupil

  2. BostonGene, Waltham, MA, USA

    Nathan Hale Fowler

  3. Peter MacCallum Cancer Centre, Royal Melbourne Hospital and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

    Michael Dickinson

  4. Medizinische Klinik III, LMU Klinikum, Munich, Germany

    Martin Dreyling

  5. Hospital 12 De Octubre, Complutense University, CNIO, Madrid, Spain

    Joaquin Martinez-Lopez

  6. Oslo University Hospital, Oslo, Norway

    Arne Kolstad

  7. Royal Brisbane Hospital, Herston, Queensland, Australia

    Jason Butler

  8. Michigan Medicine University of Michigan, Ann Arbor, MI, USA

    Monalisa Ghosh

  9. City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Leslie Popplewell

  10. Moffitt Cancer Center, Tampa, FL, USA

    Julio C. Chavez

  11. Hospices Civils de Lyon and Université Claude Bernard Lyon 1, Lyon, France

    Emmanuel Bachy

  12. Kyushu University Hospital, Fukuoka, Japan

    Koji Kato

  13. Tohoku University Hospital, Sendai, Japan

    Hideo Harigae

  14. Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands

    Marie José Kersten

  15. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

    Charalambos Andreadis

  16. University of Chicago Medical Center, Chicago, IL, USA

    Peter A. Riedell

  17. Royal Prince Alfred Hospital and University of Sydney, Camperdown, New South Wales, Australia

    P. Joy Ho

  18. Department of Hematology, University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Seville, Spain

    José Antonio Pérez-Simón

  19. Oregon Health and Science University, Portland, OR, USA

    Andy I. Chen

  20. Department I of Internal Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany

    Bastian von Tresckow

  21. Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    Bastian von Tresckow

  22. Lymphoma Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Andrés José María Ferreri

  23. Hokkaido University Hospital, Sapporo, Japan

    Takanori Teshima

  24. Comprehensive Cancer Centre, King’s College London, London, UK

    Piers E. M. Patten

  25. Department of Haematology, King’s College Hospital, London, UK

    Piers E. M. Patten

  26. University of Kansas Hospital and Medical Center, Westwood, KS, USA

    Joseph P. McGuirk

  27. Internal Medicine I, Ordensklinikum Linz Barmherzige Schwestern-Elisabethinen, Linz, Austria

    Andreas L. Petzer

  28. UZ Gent, Gent, Belgium

    Fritz Offner

  29. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    Andreas Viardot

  30. IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli”, Bologna, Italy

    Pier Luigi Zinzani

  31. Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy

    Pier Luigi Zinzani

  32. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Ram Malladi

  33. Novartis Pharma AG, Basel, Switzerland

    Aiesha Zia & Oezlem Anak

  34. Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

    Rakesh Awasthi

  35. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Aisha Masood

  36. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Stephen J. Schuster

  37. Hôpital Saint-Louis, Paris, France

    Catherine Thieblemont

Authors
  1. Nathan Hale Fowler
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  2. Michael Dickinson
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  3. Martin Dreyling
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  6. Jason Butler
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Contributions

N.H.F., M.D., S.J.S. and C.T. contributed to the study design. N.H.F., M. Dickinson, M. Dreyling, J.M.-L., A.K., J.B., M.G., L.P., J.C.C., E.B., K.K., H.H., M.J.K., C.A., P.A.R., P.J.H., J.A.P.-S., A.I.C., L.J.N., B.v.T., A.J.M.F., T.T., P.E.M.P., J.P.M., A.L.P., F.O., A.V., P.L.Z., R.M., S.J.S. and C.T. enrolled and treated patients and gathered data. Data were analyzed and interpreted by all authors. All authors participated in the writing and review of this manuscript, and approved the final submitted version.

Corresponding author

Correspondence to Nathan Hale Fowler.

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Competing interests

N.H.F. is an advisor or consultant for Roche/Genentech, TG Therapeutics, Verastem, Bayer, Celgene and Novartis and reports research support from Roche, Celgene, Gilead Sciences, TG Therapeutics, Novartis, AbbVie and BeiGene. M. Dickinson is an advisor or consultant for Novartis, Bristol-Myers Squibb, Gilead Sciences, Roche and Janssen; has received honoraria from Roche, Amgen, MSD, Janssen, Bristol-Myers Squibb and Novartis; has participated in speaker bureau for Novartis; and reports research support from Novartis, Roche, Takeda, Celgene and MSD. M. Dreyling is an advisor or consultant for AstraZeneca, Bayer/Vital, BeiGene, Celgene/Jazz, Genmab, Gilead Sciences, Incyte, Janssen-Cilag, Novartis and Roche; has participated in speaker bureau for Amgen, AstraZeneca, Bayer Health, Celgene, Gilead Sciences, Janssen-Cilag and Roche Pharma AG; and reports research support from AbbVie, Bayer, Celgene, Janssen-Cilag and Roche Pharma AG and travel support from Celgene, Janssen-Cilag and Roche Pharma AG. J.M.L. is an advisor or consultant for Janssen, Novartis, BMS, Incyte, Astellas and GlaxoSmithKline; reports research support from Bristol-Myers Squibb and Roche; has participated in speaker bureau for Janssen, Novartis, BMS, Incyte, Astellas and GlaxoSmithKline; and owns stock in Altum Sequencing. A.K. is an advisor or consultant for Nordic Nanovector and reports research support from Merck and Nordic Nanovector and travel support from Nordic Nanovector. J.B. is an advisor or consultant for Novartis and has participated in speaker bureau for Novartis. M.G. declares no competing interests. L.P. reports honoraria from Pfizer and Roche and travel support from Novartis. J.C.C. is a consultant for Kite/Gilead, Novartis, Karyopharm Therapeutics, MorphoSys, TeneBio, AbbVie, ADC Therapeutics and Janssen; has participated in speaker bureau for AstraZeneca, BMS, BeiGene and MorphoSys; and reports research support from Merck, AstraZeneca and ADC Therapeutics (Inst.). E.B. is an advisor or consultant for Roche and Incyte and reports research support from Takeda and Amgen, financial support from Roche, Janssen, Celgene, Novartis and Gilead and nonfinancial support from Roche, BeiGene, Celgene and AbbVie. K.K. is an advisor or consultant for AbbVie, AstraZeneca, Celgene, Chugai, Eisai, Janssen and Novartis; has received honoraria from Celgene, Chugai, Janssen, Kyowa Kirin, Merck, Mundi, Novartis, Ono, Sumitomo Dainippon and Takeda; and reports research support from AbbVie, Celgene, Chugai, Eisai, Janssen, Kyowa Kirin, Ono, Novartis and Takeda. H.H. has received honoraria from BMS, Novartis, Chugai and Janssen and reports research support from Astellas. M.J.K. is an advisor or consultant for, and has received honoraria and travel support from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Kite/Gilead, Merck, Miltenyi Biotec, Novartis and Roche; and reports research support from Celgene, Roche and Takeda. C.A. is an advisor or consultant for Gilead Sciences, Kite Pharma, Karyopharm Therapeutics, Atara Biotherapeutics, Incyte, TG Therapeutics and Epizyme; reports research support from Novartis, GlaxoSmithKline, Amgen, Juno Therapeutics, Celgene and Merck; and reports travel support from Gilead Sciences and Kite Pharma. P.A.R. reports grants and personal fees from Kite/Gilead and Celgene/BMS; grants from MorphoSys, Xencor and Calibr; personal fees from Takeda, Verastem, Karyopharm Therapeutics, BeiGene and Bayer; and grants, personal fees and nonfinancial support from Novartis. P.J.H. reports travel support from Celgene, Janssen, La Jolla and Novartis. J.A.P.S. is an advisor or consultant for Novartis, Janssen, Roche, Jazz Pharmaceuticals, Amgen and Gilead Sciences; reports research support from Novartis, Janssen, Pfizer, Roche and Takeda; reports travel support from Roche, Gilead Sciences and Janssen; and reports patents, royalties or other intellectual property from Entourage Bioscience on cannabinoid derivatives. A.I.C. is an advisor or consultant for MorphoSys, Mesoblast and Genentech and has received clinical trial support (Inst.) from Novartis for submitted work. L.J.N. has received honoraria from Bayer, Celgene, Gilead and Novartis and reports research support from Celgene and Genentech. B.v.T. is an advisor or consultant for BMS/Celgene, Novartis, Pentixafarm, Amgen, Pfizer, Takeda, Merck Sharp & Dohme and Gilead Kite; has received honoraria from Novartis, Roche Pharma AG, Takeda and Merck Sharp & Dohme; reports research funding from Novartis (Inst), Merck Sharp & Dohme (Inst) and Takeda (Inst); and reports travel support from AbbVie, AstraZeneca, Kite-Gilead, Merck Sharp & Dohme, Takeda and Novartis. A.J.M.F. declares no competing interests. T.T. is an advisor or consultant for Merck, Novartis and Takeda; has received honoraria from Bristol-Myers Squibb, Fuji Pharma, Kyowa Kirin, Merck, Nippon Shinyaku, Pfizer, Takeda and Teijin Pharma; reports research support from Astellas, Chugai Pharma, Kyowa Kirin, Novartis and Sanofi; reports grants from the Japan Society for the Promotion of Science and Japan Science and Technology Agency; and has received assistance with manuscript preparation for Janssen and Novartis. P.E.M.P. has received grants or contracts from Roche and Gilead; has received honoraria from AbbVie, Gilead, Janssen and Novartis; has received travel support from AbbVie and Janssen; and has participated on a data safety monitoring board or advisory board for AbbVie and Novartis. J.P.M. is an advisor or consultant for Juno; has received honoraria from AlloVir, Juno and Kite; reports research support from AlloVir, Astellas, Bellicum, Fresenius Biotech, Gamida Cell, Juno, Kite, Novartis and Pluristem; has participated in speaker bureau for Kite; and has received assistance with manuscript preparation for ArticulateScience LLC. A.L.P. is an advisor or consultant for, and reports honoraria from, Novartis, BMS, Pfizer, Roche, Takeda, Celgene-BMS and Incyte and travel support from Celgene-BMS and Pfizer. F.O. declares no competing interests. A.V. is advisor or consultant for Novartis, Kite/Gilead, BMS, Amgen and Roche and reports personal fees and nonfinancial support from Roche, BMS, Novartis, Amgen, Takeda, AstraZeneca and Kite/Gilead. P.L.Z. is an advisor or consultant for Merck Sharp & Dohme, Bristol-Myers Squibb, Celgene, Gilead, Infinity, Janssen, Pfizer, Roche and Takeda. R.M. is an advisor or consultant for Roche and reports travel support from Amgen, Novartis and Gilead Sciences. A.Z., R.A., A.M. and O.A. are employees of Novartis. S.J.S. is an advisor or consultant for Acerta, AlloGene, AstraZeneca, BeiGene, Celgene/Juno, Genentech/Roche, LoxoOncology, Novartis and Tessa Therapeutics; has received honoraria from Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech/Roche, LoxoOncology, Novartis, Nordic Nanovector, Pfizer and Tessa Therapeutics; has participated in a steering committee for AbbVie, Celgene, Novartis, Juno, Nordic Nanovector and Pfizer; reports research support from AbbVie, Acerta, Celgene/Juno, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola and TG Therapeutics; and holds a patent with Novartis. C.T. has received honoraria from Celgene, AbbVie, Bayer, Janssen, Roche, Incyte, Novartis and Gilead and reports research funding from Roche and travel support from Roche, Janssen-Cilag, Kite/Gilead and Novartis.

Peer review information

Nature Medicine thanks Jeremy Abramson, Ji-Hyun Lee, Jordan Gauthier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Saheli Sadanand was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Cytokine release syndrome within 8 weeks of tisagenlecleucel infusion.

CRS=cytokine release syndrome; ICU=intensive care unit; IQR=interquartile range. Column titles are bolded for clarity.

Extended Data Fig. 2 Resolution of hematopoietic cytopenias post-tisagenlecleucel infusion.

aBased on laboratory results regardless of blood transfusion. bResolution of cytopenia is defined as achieving lab results of grade ≤2. Percent resolved probability is among subjects with cytopenia at week 4, obtained from the Kaplan-Meier survival estimates. cNumber of subjects with last value on or prior to week 4, indicating grade 3 or 4 cytopenia. dWeek 4 is defined as day 35. WBC=white blood cells. Column titles are bolded for clarity.

Extended Data Fig. 3 Neurological events within 8 weeks of tisagenlecleucel infusion.

aG4 ICANS: Onset D10, recovered – Related to tisagenlecleucel. Patient presenting with tremors, then seizures, with concomitant HHV6 positivity on CSF. The event fully recovered after high-dose MPD and GCV. CSF=cerebrospinal fluid; GCV=ganciclovir; ICANS=immune effector cell-associated neurotoxicity syndrome; HHV6, Human Herpesvirus 6; MPD=methylprednisolone. Column titles are bolded for clarity.

Extended Data Fig. 4 Summary of cellular kinetic parameters for tisagenlecleucel.

AUC0-28d=mean area under the concentration-time curve from day 0 to day 28; AUC0-84d=mean area under the concentration-time curve from day 0 to day 84; Cmax=geometric mean maximum expansion; CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease; Tmax=time to maximal expansion; Tlast=duration CAR-T cells are present in peripheral blood and tissues. Column titles are bolded for clarity.

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Fowler, N.H., Dickinson, M., Dreyling, M. et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med 28, 325–332 (2022). https://doi.org/10.1038/s41591-021-01622-0

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