A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma
Emmanuel Bachy, Steven Le Gouill, Roberta Di Blasi, Pierre Sesques, Guillaume Manson, Guillaume Cartron, David Beauvais, Louise Roulin, François Xavier Gros, Marie Thérèse Rubio, Pierre Bories, Jacques Olivier Bay, Cristina Castilla Llorente, Sylvain Choquet, René-Olivier Casasnovas, Mohamad Mohty, Stéphanie Guidez, Magalie Joris, Michaël Loschi, Sylvain Carras, Julie Abraham, Adrien Chauchet, Laurianne Drieu La Rochelle, Bénédicte Deau-Fischer, Olivier Hermine, Thomas Gastinne, Jean Jacques Tudesq, Elodie Gat, Florence Broussais, Catherine Thieblemont, Roch Houot, Franck Morschhauser, Emmanuel Bachy, Steven Le Gouill, Roberta Di Blasi, Pierre Sesques, Guillaume Manson, Guillaume Cartron, David Beauvais, Louise Roulin, François Xavier Gros, Marie Thérèse Rubio, Pierre Bories, Jacques Olivier Bay, Cristina Castilla Llorente, Sylvain Choquet, René-Olivier Casasnovas, Mohamad Mohty, Stéphanie Guidez, Magalie Joris, Michaël Loschi, Sylvain Carras, Julie Abraham, Adrien Chauchet, Laurianne Drieu La Rochelle, Bénédicte Deau-Fischer, Olivier Hermine, Thomas Gastinne, Jean Jacques Tudesq, Elodie Gat, Florence Broussais, Catherine Thieblemont, Roch Houot, Franck Morschhauser
Abstract
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study ( NCT04328298 ). After 1:1 propensity score matching (n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively (P < 0.001 for both ORR and CRR comparisons). After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axi-cel and 33.2% for tisa-cel (hazard ratio (HR) = 0.61; 95% confidence interval (CI), 0.46-0.79; P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45-0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1-2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1-2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL.
Conflict of interest statement
The authors report the following competing interests: E.B.: consulting fees or honoraria from Novartis, Kite/Gilead, Roche, Takeda and Incyte; research funding (paid to institution) from Amgen; and travel and personal fees from Roche and Incyte. S.L.G.: honoraria from Janssen-Cilag, Kite/Gilead and Novartis. P.S.: honoraria or consultancy form Chugaï, Bristol Myers Squibb, Novartis and Kite/Gilead. T.G.: honoraria from Kite/Gilead, Pfizer and Takeda. S.G.: honoraria from Kite/Gilead, Incyte, Takeda and Janssen. P.B.: honoraria from Bristol Myers Squibb, Kite/Gilead, Novartis and Abbvie. R.H.: honoraria from Bristol Myers Squibb, Kite/Gilead, Incyte, Janssen, Merck Sharp & Dohme, Takeda, Novartis and Roche. F.M.: consulting fees or honoraria from Genmab, Novartis, Kite/Gilead, Bristol Myers Squibb, AstraZeneca, Epizyme, Roche, Abbvie, Chugaï, Janssen, Incyte, Kymera, Miltenyi and Roche; and expert testimony for Roche. O.H.: consultancy for AB Science and Inatherys; and research funding (paid to institution) from Bristol Myers Squibb and Alexion. G.C.: consulting fees and honoraria from Roche, Bristol Myers Squibb, Onwards Therapeutics, MedxCell, EmerCell, MabQ, Sanofi, Abbvie, Takeda, Roche, Janssen, Roche, Novartis and Myltenyi. M.L.: honoraria or travel grants from Pfizer, Novartis, Gilead and Bristol Myers Squibb. R.O.C.: consultancy and honoraria from Roche, Takeda, Bristol Myers Squibb, Merck, Kite/Gilead, Abbvie and ADC Therapeutics; and research funding from Roche, Takeda and Kite/Gilead. J.A.: consulting fees and honoraria from Roche and Janssen-Cilag; S.C.: consulting fees and honoraria from Abbvie, AstraZeneca, Novartis, Janssen, Takeda, Atara, Pierre Fabre, Kite/Gilead and Viatris. C.C.L.: honoraria from Kite/Gilead; D.B.: honoraria from Kite/Gilead. J.J.T.: consulting fees and honoraria from Bristol Myers Squibb and Kite/Gilead. M.M.: consulting fees and honoraria from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Janssen, Takeda, Novartis and Sanofi; and research funding from Bristol Myers Squibb, Janssen and Sanofi; F.X.G.: honoraria from Bristol Myers Squibb, Novartis and Kite/Gilead; L.D.L.R.: honoraria from Kite/Gilead; M.T.R.: honoraria from Novartis and Kite/Gilead. C.T.: consulting fees and honoraria from Novartis, Bristol Myers Squibb, Bayer, Abbvie, Gilead Sciences, Roche, Janssen, Kite, Incyte and Amgen; and educational activities for Janssen, Roche, Bristol Myers Squibb and Novartis. R.D.B.: honoraria, consulting and personal fees from Janssen, Pfizer, Bristol Myers Squibb, Kite/Gilead and Novartis.
© 2022. The Author(s).
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References
- World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues (eds Swerdlow, S. et al) (IARC Publications, 2008).
- Wang M, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 2020;382:1331–1342. doi: 10.1056/NEJMoa1914347.
- Fowler NH, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat. Med. 2022;28:325–332. doi: 10.1038/s41591-021-01622-0.
- Jacobson CA, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23:91–103. doi: 10.1016/S1470-2045(21)00591-X.
- Neelapu SS, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 2017;377:2531–2544. doi: 10.1056/NEJMoa1707447.
- Schuster SJ, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 2019;380:45–56. doi: 10.1056/NEJMoa1804980.
- Abramson JS, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396:839–852. doi: 10.1016/S0140-6736(20)31366-0.
- Locke FL, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20:31–42. doi: 10.1016/S1470-2045(18)30864-7.
- Schuster SJ, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22:1403–1415. doi: 10.1016/S1470-2045(21)00375-2.
- Jacobson C, et al. Long-term (≥4 year and ≥5 year) overall survival (OS) by 12- and 24-month event-free survival (EFS): an updated analysis of ZUMA-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma (LBCL) Blood. 2021;138:1764–1764. doi: 10.1182/blood-2021-148078.
- Jacobson CA, et al. Axicabtagene ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J. Clin. Oncol. 2020;38:3095–3106. doi: 10.1200/JCO.19.02103.
- Nastoupil, L. J. et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J. Clin. Oncol. 38, 3119–3128 (2020).
- Pasquini MC, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4:5414–5424. doi: 10.1182/bloodadvances.2020003092.
- Sesques P, et al. Commercial anti-CD19 CAR T cell therapy for patients with relapsed/refractory aggressive B cell lymphoma in a European center. Am. J. Hematol. 2020;95:1324–1333. doi: 10.1002/ajh.25951.
- Vercellino L, et al. Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 2020;4:5607–5615. doi: 10.1182/bloodadvances.2020003001.
- Neelapu SS, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat. Rev. Clin. Oncol. 2018;15:47–62. doi: 10.1038/nrclinonc.2017.148.
- Oluwole OO, et al. Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma. Br. J. Haematol. 2021;194:690–700. doi: 10.1111/bjh.17527.
- Locke FL, et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4:4898–4911. doi: 10.1182/bloodadvances.2020002394.
- Pinnix CC, et al. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. Blood Adv. 2020;4:2871–2883. doi: 10.1182/bloodadvances.2020001837.
- Oluwole OO, et al. Comparing efficacy, safety, and preinfusion period of axicabtagene ciloleucel versus tisagenlecleucel in relapsed/refractory large B cell lymphoma. Biol. Blood Marrow Transplant. 2020;26:1581–1588. doi: 10.1016/j.bbmt.2020.06.008.
- Maloney DG, et al. Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma. J. Hematol. Oncol. 2021;14:140. doi: 10.1186/s13045-021-01144-9.
- Zhang J, et al. Letter to the editor regarding ‘Comparing efficacy, safety, and preinfusion period of axicabtagene ciloleucel versus tisagenlecleucel in relapsed/refractory large B cell lymphoma’. Biol. Blood Marrow Transplant. 2020;26:e333–e334. doi: 10.1016/j.bbmt.2020.08.032.
- Zhang J, et al. A review of two regulatory approved anti-CD19 CAR T-cell therapies in diffuse large B-cell lymphoma: why are indirect treatment comparisons not feasible? Adv. Ther. 2020;37:3040–3058. doi: 10.1007/s12325-020-01397-9.
- Signorovitch JE, et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health. 2012;15:940–947. doi: 10.1016/j.jval.2012.05.004.
- Allan V, et al. Propensity score matching and inverse probability of treatment weighting to address confounding by indication in comparative effectiveness research of oral anticoagulants. J. Comp. Eff. Res. 2020;9:603–614. doi: 10.2217/cer-2020-0013.
- Topp MS, et al. Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma. Br. J. Haematol. 2021;195:388–398. doi: 10.1111/bjh.17673.
- Bethge, W. A. et al. GLA/DRST real-world outcome analysis of CAR-T cell therapies for large B-cell lymphoma in Germany. Blood. 140, 349–358 (2022).
- Cappell KM, Kochenderfer JN. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat. Rev. Clin. Oncol. 2021;18:715–727. doi: 10.1038/s41571-021-00530-z.
- Kawalekar OU, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44:380–390. doi: 10.1016/j.immuni.2016.01.021.
- Bishop MR, et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N. Engl. J. Med. 2022;386:629–639. doi: 10.1056/NEJMoa2116596.
- Locke FL, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N. Engl. J. Med. 2022;386:640–654. doi: 10.1056/NEJMoa2116133.
- Gauthier, J. et al. Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL. Blood. 139, 3722–3731 (2022).
- Cheson BD, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J. Clin. Oncol. 2014;32:3059–3068. doi: 10.1200/JCO.2013.54.8800.
- Lee DW, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 2019;25:625–638. doi: 10.1016/j.bbmt.2018.12.758.
- Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat. Med. 2014;33:1242–1258. doi: 10.1002/sim.5984.
- VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann. Intern Med. 2017;167:268–274. doi: 10.7326/M16-2607.
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