Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
Sattva S Neelapu, Frederick L Locke, Nancy L Bartlett, Lazaros J Lekakis, David B Miklos, Caron A Jacobson, Ira Braunschweig, Olalekan O Oluwole, Tanya Siddiqi, Yi Lin, John M Timmerman, Patrick J Stiff, Jonathan W Friedberg, Ian W Flinn, Andre Goy, Brian T Hill, Mitchell R Smith, Abhinav Deol, Umar Farooq, Peter McSweeney, Javier Munoz, Irit Avivi, Januario E Castro, Jason R Westin, Julio C Chavez, Armin Ghobadi, Krishna V Komanduri, Ronald Levy, Eric D Jacobsen, Thomas E Witzig, Patrick Reagan, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, David Chang, Jeff Wiezorek, William Y Go, Sattva S Neelapu, Frederick L Locke, Nancy L Bartlett, Lazaros J Lekakis, David B Miklos, Caron A Jacobson, Ira Braunschweig, Olalekan O Oluwole, Tanya Siddiqi, Yi Lin, John M Timmerman, Patrick J Stiff, Jonathan W Friedberg, Ian W Flinn, Andre Goy, Brian T Hill, Mitchell R Smith, Abhinav Deol, Umar Farooq, Peter McSweeney, Javier Munoz, Irit Avivi, Januario E Castro, Jason R Westin, Julio C Chavez, Armin Ghobadi, Krishna V Komanduri, Ronald Levy, Eric D Jacobsen, Thomas E Witzig, Patrick Reagan, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, David Chang, Jeff Wiezorek, William Y Go
Abstract
Background: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.
Methods: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.
Results: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.
Conclusions: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
Conflict of interest statement
No other potential conflict of interest relevant to this article was reported.
Figures
References
- Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125:22–32.
- Dunleavy K, Wilson WH. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach? Blood. 2015;125:33–9.
- Casulo C, Burack WR, Friedberg JW. Transformed follicular non-Hodgkin lymphoma. Blood. 2015;125:40–7.
- Ardeshna KM, Kakouros N, Qian W, et al. Conventional second-line salvage chemotherapy regimens are not warranted in patients with malignant lymphomas who have progressive disease after firstline salvage therapy regimens. Br J Haematol. 2005;130:363–72.
- Hitz F, Connors JM, Gascoyne RD, et al. Outcome of patients with primary refractory diffuse large B cell lymphoma after R-CHOP treatment. Ann Hematol. 2015;94:1839–43.
- Josting A, Reiser M, Rueffer U, Salzberger B, Diehl V, Engert A. Treatment of primary progressive Hodgkin’s and aggressive non-Hodgkin’s lymphoma: is there a chance for cure? J Clin Oncol. 2000;18:332–9.
- Matasar MJ, Czuczman MS, Rodriguez MA, et al. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade Bcell lymphoma. Blood. 2013;122:499–506.
- Moskowitz CH, Bertino JR, Glassman JR, et al. Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin’s lymphoma. J Clin Oncol. 1999;17:3776–85.
- Nagle SJ, Woo K, Schuster SJ, et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after autologous stem cell transplantation in the rituximab era. Am J Hematol. 2013;88:890–4.
- Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333:1540–5.
- Seshadri T, Stakiw J, Pintilie M, Keating A, Crump M, Kuruvilla J. Utility of subsequent conventional dose chemotherapy in relapsed/refractory transplant-eligible patients with diffuse large B-cell lymphoma failing platinum-based salvage chemotherapy. Hematology. 2008;13:261–6.
- Telio D, Fernandes K, Ma C, et al. Salvage chemotherapy and autologous stem cell transplant in primary refractory diffuse large B-cell lymphoma: outcomes and prognostic factors. Leuk Lymphoma. 2012;53:836–41.
- Friedberg JW. Relapsed/refractory diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program. 2011;2011:498–505.
- Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130:1800–8.
- Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119:2709–20.
- Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33:540–9.
- Kochenderfer JN, Somerville RPT, Lu T, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther. 2017;25:2245–53.
- Schuster S, Svoboda J, Nasta S, et al. Sustained remissions following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood. 2015;126:183.
- Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8:355ra116.
- Kochenderfer JN, Feldman SA, Zhao Y, et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother. 2009;32:689–702.
- Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25:285–95.
- WHO classification of tumours of haematopoietic and lymphoid tissue. 4. Geneva: World Health Organization; 2008.
- Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.
- Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–95.
- Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35:1803–13.
- Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014;123:1214–7.
- Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat Rev Clin Oncol. 2017 Sep 19; (Epub ahead of print)
- Klyuchnikov E, Bacher U, Kroll T, et al. Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how? Bone Marrow Transplant. 2014;49:1–7.
- Kawalekar OU, O’Connor RS, Fraietta JA, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44:380–90.
- Zhao Z, Condomines M, van der Stegen SJC, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015;28:415–28.
- Park JH, Brentjens RJ. Are all chimeric antigen receptors created equal? J Clin Oncol. 2015;33:651–3.
- Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.
- Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra25.
- Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.
- Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664–79.
Source: PubMed