Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma

Author(s): Michael R. Bishop, M.D., Michael Dickinson, M.B., B.S., D.M.Sci., Duncan Purtill, M.D., M.B., B.S., Pere Barba, M.D., Ph.D., Armando Santoro, M.D., Nada Hamad, M.B., B.S., Koji Kato, M.D., Ph.D., Anna Sureda, M.D., Ph.D., Richard Greil, M.D., Catherine Thieblemont, M.D., Ph.D., Franck Morschhauser, M.D., Ph.D., Martin Janz, M.D., et al.
Source: February 17, 2022 N Engl J Med 2022; 386:629-639 DOI: 10.1056/NEJMoa2116596
Lucio Gordan MD

Dr. Gordan's Thoughts

Is there a better CAR-T cell product in this setting? Are negative results of this trial due to different patient population or imbalance in 2 arms of the study? Certainly disappointing result, but further studies may define they most adequate group of patients to benefit from therapy.

ABSTRACT

BACKGROUND

Patient outcomes are poor for aggressive B-cell non-Hodgkin’s lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines.

METHODS

We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety.

RESULTS

A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P=0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events.

CONCLUSIONS

Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.)

Author Affiliations

rom the David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago (M.R.B.); Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC (M. Dickinson), Fiona Stanley Hospital, Murdoch, WA (D.P.), and the Department of Haematology, St. Vincent’s Hospital Sydney, and St. Vincent’s Clinical School, University of New South Wales, Sydney (N.H.) — all in Australia; Hospital Universitari Vall d’Hebron and Universitat Autònoma de Barcelona (P. Barba) and the Clinical Hematology Department, Institut Català d’Oncologia–Hospitalet de Llobregat (A. Sureda), Barcelona, and the Hematology Department, Hospital 12 de Octubre, Complutense University, Instituto de Investigación Hospital 12 de Octubre, Centro Nacional de Investigaciones Oncológicas, Madrid (J.M.-L.) — all in Spain; the Department of Biomedical Sciences, Humanitas University and IRCCS Humanitas Research Hospital–Humanitas Cancer Center, Milan (A. Santoro); the Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka (K.K.), and Tohoku University Hospital, Sendai (H. Harigae) — both in Japan; the Third Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute–Center for Clinical Cancer and Immunology Trials and Cancer Cluster Salzburg, Salzburg (R.G.), and Internal Medicine I, Bone Marrow Transplant Unit (W.R.), and the Clinical Division of Hematology and Hemostaseology, Department of Medicine I (U.J.), Vienna General Hospital–Medical University of Vienna, Vienna — both in Austria; Assistance Publique–Hôpitaux de Paris, Hemato-Oncology, Hôpital Saint-Louis, Paris (C.T.), Centre Hospitalier Régional Universitaire de Lille, Lille (F.M.), Hospices Civils de Lyon and Université Claude Bernard Lyon 1, Lyon (E.B.), and Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, INSERM, and Nantes Medical University, Nantes (S.L.G.) — all in France; the Department of Hematology, Oncology, and Tumorimmunology, Charité–University Hospital Berlin, Campus Benjamin Franklin, and the Experimental and Clinical Research Center of the Max Delbrück Center for Molecular Medicine and Charité Berlin, Berlin (M.J.), Medizinische Klinik III, LMU Klinikum, Munich (M. Dreyling), and Clinic I for Internal Medicine, University Hospital Cologne, Cologne (P. Borchmann) — all in Germany; Sarah Cannon Research Institute–Tennessee Oncology, Nashville (I.F., P.M.); the Department of Medicine, Queen Mary Hospital, Hong Kong (Y.-L.K.); the Department of Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam (M.J.K.), and Universitair Medisch Centrum Utrecht, Department of Medical Oncology, Utrecht (M.C.M.) — both in the Netherlands; the Department of Oncology, Oslo University Hospital, and K.G. Jebsen Center for B-Cell Malignancies — both in Oslo (H. Holte); the National University Cancer Institute Singapore, Singapore (E.H.L.C.); the Department of Medical Oncology and Hematology, University Hospital, Zurich (A.M.S.M.), and Novartis Pharma, Basel (S.N., E.D., G.A.) — both in Switzerland; the Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health and Science University, Portland (R.T.M.); the Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center, Westwood (J.P.M.); Ohio State University, Columbus (D.B.); Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco (C.A.); the Division of Hematology–Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL (M.K.-D.); Novartis Pharmaceuticals, East Hanover, NJ (R.A., C.C., A.M.); the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia (S.J.S.); and the Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston (J.R.W.).

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