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CAR T-cell therapy in diffuse large B-cell lymphoma

CAR T-cell therapy in diffuse large B-cell lymphoma short review memo (2020) 13:32–35 https://doi.org/10.1007/s12254-019-00558-z Georg Hopfinger · Nina Worel Received: 1 September 2019 / Accepted: 10 December 2019 / Published online: 24 January 2020 © The Author(s) 2020 Summary Diffuse large B-cell lymphoma (DLBCL) Unfortunately, 30–40% of patients eventually re- comprises 30–40% of non-Hodgkin’s lymphoma. Clin- lapse and 10% are primary refractory. Despite inten- ical factorssuch asa high International Prognostic In- sive salvage immunochemotherapy and autologous dex (IPI) or molecular factors as cell of origin (COO) stem cell transplantation (ASCT), outcome in these have an influence on the clinical outcome after con- patients is poor with an ORR of 27–63% and long- ventional immunochemotherapy. Patients with re- term survival in up to 48% [2]. With the introduc- sistant or relapsed (r/r) DLBCL have a poor prog- tion of (mostly autologous) chimeric antigen receptor nosis with a median overall survival of 6,3 months T-cell (CAR-T) therapy, very encouraging results with and low complete response rates (CR 7%) to salvage CR rates up to 50% in r/r DLBCL have been demon- chemoimmunotherapy. Currently, therapy with autol- strated leading to approval of two products by the ogous chimeric antigen receptor T-cells (CAR T-cells) US FDA (Food and Drug Administration) and EMA provide encouraging complete responses (CR) of up (European Medicines Agency). to 50%. However, high costs for approved products and elaborate logistics have to be encountered. Chimeric antigen receptor T-cells Keywords Tisagenlecleucel · Axicabtagene A CAR is commonly composed of a specificity-confer- ciloleucel · Cytokine Release Syndrome · Autologous ring extracellular antibody single chain variable frag- chimeric antigen receptor T-cells · Diffuse large ment (scFv), a hinge region transmembrane domain, B-cell lymphoma one or more intracellular costimulatory domains (e.g., CD28 or 4-1BB [CD137]), and a T-cell receptor signal- ing domain (CD3 ζ). Several generations of CARs can Introduction be distinguished, differing by co-stimulating signaling With standard immunochemotherapy, e.g., R-CHOP domains (CD28, 4–1 BB) being responsible for T-cell (rituximab+ cyclophosphamide, doxorubicin, vin- activation and expansion [3]. cristine, and prednisone), patients with diffuse large B-cell lymphoma (DLBCL) can achieve an overall re- Approved CAR T-cells in hematological disease sponse rate (ORR) of 60% resulting in a long-term event-free survival of 50% [1]. At present two CAR-T products against CD19 are ap- proved: Axicabtagen–ciloleucel (Yescarta )for thetreat- ment of adult patients with relapsed or refractory PD Dr. G. Hopfinger () Department of Internal Medicine I, Bone Marrow diffuse large B-cell lymphoma (DLBCL) and pri- Transplantation Unit, Medical University of Vienna, mary mediastinal large B-cell lymphoma (PMBCL), Waehringer Guertel 18-20, 1090 Vienna, Austria after two or more lines of systemic therapy. georg.hopfinger@meduniwien.ac.at Tisagenlecleucel (Kymriah ) for the treatment of Univ.Prof.Dr.N.Worel pediatric and young adult patients up to 25 years of Department of Blood Group Serology and Transfusion age with B-cell acute lymphoblastic leukemia (ALL) Medicine, Medical University of Vienna, Vienna, Austria that is refractory, in relapse posttransplant or in 32 CAR T-cell therapy in diffuse large B-cell lymphoma K short review second or later relapse and adult patients with re- (95% CI, 41–62) including 40% CR. Those patients lapsed or refractory diffuse large B-cell lymphoma that had obtained CR at 3 months were also more (DLBCL) after two or more lines of systemic therapy likely to remain in remission at 6 months after CAR- T infusion. Median duration of response was not reached at the time of analysis. For patients achieving CAR T-cells in non-Hodgkin’s lymphoma a CR, the 12-month relapse-free survival rate was 79% With the introduction of CAR T-cells targeting CD19- with an OS of 95%. The OS probability at 12-months positive lymphoid malignancies, encouraging re- for all infused patients was 49% [8]. More recently, sponse rates have been observed in heavily pretreated “real-word data” for tisagenlecleucel clearly support patients. clinical activity with an ORR of 66% (CR 42%) [9]. The ZUMA1 trial (NCT02348216) was the piv- A third CD19-directed CAR T-cell product, not yet otal trial for axicabtagene ciloleucel incorporating approved, is currently investigated in the JCAR017- a CD28 costimulatory domain (Axi-cel; Yescarta ). TRANSCEND trial (NCT02631044) using lisocabtagene The trial included two cohorts with r/r lymphoma: maraleucel (Liso-cel) (incorporating a 4-1BB costim- cohort 1 which included 77 patients with r/r DL- ulatory domain). During manufacturing, T-cells are BCL and cohort 2 which included 24 patients with selected in CD4+ and CD8+ cells and then further pro- primarily mediastinal B-cell lymphoma (PMBCL) or cessed to CAR-T separately. The product is prepared transformed follicular NHL (tFL). After lymphode- in two tubes consisting of CD4+ and CD8+ CAR-T cells pleting chemotherapy with fludarabine 30 mg/m /day in a precise 1:1 ratio. Patients were treated in two and cyclophosphamide 500 mg/m /day (FC 30/500) cohorts, including 73 patients DLBCL NOS and high for 3 days, 91% patients received a target dose of grade B cell lymphoma and 102 patients with DLBCL 2.0 × 10 CAR T-cells/kg body weight. Patients had NOS, PMBCLortFL.Median ofprior therapies was median of 3 pretreatments (range 1–7), including au- 3(range, 2–8, ASCT in 38%). A CRS occurred in 37% tologous stem cell transplantation (ASCT) in 21%. (grade ≥3: 1%) and NT in 23% (grade ≥3: 13%), the Bridging therapy between enrollment in the study ORR was 80% including 55% CR [10]. Based on en- and lymphodepleting chemotherapy was not allowed. couraging data, a submission to FDA for approval is Observed specific toxicity was a cytokine release syn- expected next year. More recently, a subset of pa- drome (CRS) in 93% (grade ≥3: 13%) and neurological tients with secondary central nervous system (CNS) toxicity (NT) in 64% (grade ≥3: 28%). More recently, manifestation showed response in 4/9 patients cases an up-date with median follow-up of 15.4 months [10, 11]. was published, confirming durable ORR of 83% and a CR of 58%. The COO had no impact on clinical out- Assessment and management of adverse events come. Median duration of response was 11.1 months in CAR T-cell therapy (4.2–not estimable), OS was not reached, progression- free survival (PFS) was 5.9 months (95% confidence CAR T-cell therapy is associated with significant acute interval [CI] 3.3–15.0). [4]. Furthermore, analysis of toxicities, which can be severe or even fatal [12]. The “real-world data” from different centers utilizing the following symptoms can be observed: cytokine release approved, commercial available product, confirmed syndrome (CRS), neurotoxicity (CAR-T cell related en- high activity in r/r DLBCL treated outside of clinical cephalopathy syndrome [CRES] or immune effector trial, while 50% of the patients did not meet inclu- cell associated neurotoxicity syndrome [iCANS]), cy- sion criteria for different comorbidities [5, 6]. Despite topenia, prolonged B cell aplasia, hypo-gammaglob- higher comorbidity, slightly higher median age and ulinemia resulting in increased risk for infections and higher proportion of patients receiving Axci-cel after rarely hemophagocytic lymphohistiocytosis (HLH). relapse ASCT (27% and 33 % for “real-world data” compared to 23% in the ZUMA1 trial), the ORR was Cytokine release syndrome similar (71% and 81% for “real-world data” and 83% in the ZUMA1 trial) [6, 7]. Virtually all patients experience at least a mild cy- Tisagenlecleucel (Tisa-cel) (Kymriah ), incorpo- tokine release syndrome (CRS) presenting with fever rating a 4-1BB costimulatory domain, was approved >38.5 °C. The therapy of mild, i.e., grade I CRS, is based on the JULIET trial (NCT02445248) for r/r DL- symptomatic. Grade ≥2 CRS, which can include sys- BCL, including patients with a median of 3 prior tolic blood pressure ≤90 mm Hg and/or hypoxia (FiO2 therapies (range 1–8) including ASCT in 49%. Af- ≤40%) needs prompt interventions with IV fluids or ter lymphodepleting chemotherapy with FC (25/250) non-invasive oxygen supply through breathing mask. or bendamustine 90 mg/m /day for 2 days, 93% of If conditions deteriorate, CRS 3 is diagnosed and mul- patients received a median single dose of 3.0 × 10 tiple pressor/resuscitator or respirator might become (range, 0.1–6.0 × 10 ) CAR-T cells. In 102/111 (92%) necessary; a CRS 4 means life-threating conditions. patients bridging therapy was given between leuko- For monitoring of CRS proinflammatory parameters, cyte collection and CAR T-cell infusion. There was no e.g., CRP, ferritin or IL-6 can be used. As the time treatment-related death observed. Best ORR was 52% pointofCRS mayvarybetween day1to day14(me- K CAR T-cell therapy in diffuse large B-cell lymphoma 33 short review dian 5), patients will be observed in hospital for 14 Hemophagocytic lymphohistiocytosis/ days in most centers. As a side effect of lymphodeple- macrophage-activation syndrome tion and CAR T infusion, B-cell aplasia and leukopenia can occur and therefore infection has to be ruled out Hemophagocytic lymphohistiocytosis/macrophage- in febrile patients, despite low incidence of infections activation syndrome (HLH/MAS) rarely occurs and during CAR T-cell therapy [13]. is characterized by similar clinical manifestations as In moderate to severe symptoms, i.e., CRS ≥2not CRS as high fever, multiorgan dysfunction or CNS responding to supportive therapy, tocilizumab, an disturbances. interleukin-6 receptor antibody, is recommended. Tocilizumab inhibits direct binding of IL-6 or IL-6/ Conclusion and perspective soluble IL-6 receptor complex to cell membranes. Tocilizumab can be given at a dose of 8 mg/kg CAR T-cell therapy is “en vogue” due to very promis- IV (max. 800 mg), every 8 h with a maximum of ing response data in relapsed and refractory DLBCL three doses within 24 h and a total of four doses. In and 50–70% of patients will be alive after 12 month case of CRS grade ≥3 or patients not responding to trials. This has been confirmed in “real-world” data tocilizumab within 24 h, corticosteroids (methylpred- including patients not eligible for trials due to several nisolone 1 g/kg or dexamethasone 10 mg twice daily) comorbidities [5, 6, 9]. Despite the high efficacy of should be considered. So far, corticosteroids were not CAR T-cell therapy with CR rate up to 50%, which is in recommended as first-line for CRS due a possible in- contrast to poor outcome after conventional salvage teraction with T-cell expansion. However, a recently immune-chemotherapy, results have to be interpreted proposed regimen showed no negative impact on with caution [17]. So far, only data of single-arm phase T-cell expansion [14]. Comparison of clinical data are II trials with highly selected patients and short ob- difficult between trials, as different scoring systems servation times are available. Even “real-world” data and algorithms for CRS treatment were used. More do not really improve the information quality, as data recently, a simplified scoring system was introduced were provided by only a few highly experienced cen- [15]. ters. No randomized data comparing ASCT or allo- HSCT are available so far. Therefore, no recommen- dation can be given in patients relapsing or refractory Immune effector cell associated neurotoxicity to first line therapy if transplant eligible. Clinical trials syndrome (iCANS) comparing ASCT with CAR T-cell therapy are currently Immune effector cell associated neurotoxicity syn- being initiated. drome (iCANS) is another major complication of CAR As CAR T-cell therapy is associated with specific T-cell therapy which can occur with or independently toxicity as described above, has to be established of CRS, mostly within 28 days after CAR T-cell infu- a dedicated and well-trained team in specific cen- sion. As CAR T-cells can cross the blood–brain barrier ters. Finally, financial burden of CAR T-cell therapy (BBB), endothelial cell activation might play a role is significant. Therefore, new funding systems are in the development of iCANS and cerebral edema necessary. Furthermore, a significant proportion of [16]. Clinical symptoms, e.g., diminished attention, patients are refractory to CAR-T cells. Pathomechims confusion, word-finding difficulties, disorientation, are only partially explained by a loss of the target aphasia, somnolence, seizures or cerebral edema may structure (CD19) at the tumor cell or receptor mu- occur. Tocilizumab is not expected to cross the BBB tations [18] or expression of checkpoint proteins by and could theoretically increase the amount of cir- the tumor [19]. Administration of checkpoint in- culating IL-6 in the brain. Dexamethasone 10 mg hibitors along with CAR-T cells are currently being IV every 6 h or methylprednisolone 1 mg/kg IV ev- tested: ZUMA-6 trial, axicabtagen-ciloleucel +anti- ery 12 h is considered as rescue therapy of iCANS in PD-L1 antibody atezolizumab or PORTIA trial using patients without signs of CRS. In addition to seizure tisagenlecleucel +pembrolizumab. Combining differ- prophylaxis or treatment, brain imaging (CT-scan ent epitopes to improve activity of CAR T-cell therapy or MRI) should be considered to rule out cerebral was recently applied in r/r leukemia providing CR of edema. A vigilant observation and close monitor- 73% in ALL using an anti-CD19/CD22 CAR-T [20]. ing using a neurological assessment score is strongly Novel CAR-T constructs are directed against CD79b recommended. alone or in combination with CD19 in cell line- and patient-derived xenograft models and should be clin- ically tested in B-cell lymphoma [21]. A CD30 CAR B-cell aplasia T-cell therapy demonstrated activity in patients with As off target toxicity B-cell aplasia can occur; there- Hodgkin lymphoma and anaplastic large cell lym- fore some patients are in need of immunoglobulin phoma [22]. Ongoing concepts use CAR T-cell ther- infusion in the case of recurrent infections or even apy in earlier lines, as randomized trials (ZUMA prophylactically, depending to local guidelines. 7-NCT03391466; BELINDA-NCT03570892) compare CAR T-cell therapy versus ASCT in first relapse. 34 CAR T-cell therapy in diffuse large B-cell lymphoma K short review 8. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in CAR-T cells have demonstrated significant clinical adult relapsed or refractory diffuse large B-cell lymphoma. benefit in all studies published so far. Although Ad- NEnglJMed. 2019;380(1):45–56. verse Events (AEs) such as CRS, neurological toxic- 9. Pasquini M, Hu Z-H, Zhang Y, et al. Real world experi- ity, and B-cell aplasia are common, the majority of ence of tisagenlecleucel chimeric antigen receptor (CAR) events are manageable when treated by an appropri- T-cells targeting CD19 in patients with acutelymphoblastic ately trained multidisciplinary team. leukemia(ALL)anddiffuselargeB-celllymphoma(DLBCL) using the center for international blood and marrow trans- Funding Open access funding providedby Medical University plantresearch(CIBMTR)cellulartherapy(CT)registry. Clin of Vienna. LymphomaMyelomaLeuk. 2019;19:S267. 10. Abramson JS, Gordon LI, Palomba ML, Lunning MA, Ar- Conflict of interest G. Hopfinger has received honoraria nason JE, Forero-Torres A. Updated safety and long term from Celgene, Gilead, GlaxoSmithKline, Janssen, Novartis, clinical outcomes in TRANSCEND NHL 001, pivotal trial Roche, Takeda, and received research funding from Gilead. of lisocabtagene maraleucel (JCAR017) in R/R aggressive N. Worel has received honoraria from AOP Orphan, Celgene, NHL.JClinOncol. 2018;36:abstr7505. Gilead, Jazz, Novartis, Therakos Mallinckrodt Pharmaceuti- 11. Abramson J, Palomba M, Arnason J, et al. Lisocabta- cals, Sanofi Genzyme, and received research funding from gene maraleucel (liso-cel) treatment of patients (pts) with Therakos Mallinckrodt Pharmaceuticals, and Sanofi Gen- relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma zyme. (NHL) and secondary CNS lymphoma: Initial results from Open Access This article is licensed under a Creative Com- TRANSCEND NHL 001. J Clin Oncol. 2019;37(suppl):abstr mons Attribution 4.0 International License, which permits 7515–2019. use, sharing, adaptation, distribution and reproduction in 12. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen any medium or format, as long as you give appropriate credit receptor T-cell therapy—assessment and management of to the original author(s) and the source, provide a link to toxicities. NatRevClinOncol. 2018;15(1):47–62. the Creative Commons licence, and indicate if changes were 13. Di Blasi R, Aguinaga L, Paillassa J, et al. Infectious compli- made. The images or other third party material in this article cations in patients receiving anti-CD-19 chimeric antigen are included in the article’s Creative Commons licence, unless receptors T-cells (CAR-T) for diffuse large cell B-cell lym- indicated otherwise in a credit line to the material. If material phoma (DLBCL). A monocentric preliminary experience. is not included in the article’s Creative Commons licence and S1641. HemaSphere. 2019;3:759. your intended use is not permitted by statutory regulation or 14. Topp M, van Meerten T, Wermke M, et al. Axicabtagene exceeds the permitted use, you will need to obtain permis- ciloleucel(axi-cel)inpatientswithrelapsed/refractorylarge sion directly from the copyright holder. To view a copy of this b cell lymphoma: preliminary results of earlier steroid use. licence, visit http://creativecommons.org/licenses/by/4.0/. PS1067. HemaSphere. 2019;3:483. 15. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consen- sus grading for cytokine release syndrome and neurologic References toxicity associated with immune effector cells. Biol Blood MarrowTransplant. 2019;25(4):625–38. 1. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long- 16. Gust J, Hay KA, Hanafi LA, et al. Endothelial activation term outcome of patients in the LNH-98.5 trial, the first and blood-brain barrier disruption in neurotoxicity after randomizedstudycomparingrituximab-CHOPtostandard adoptive immunotherapy with CD19 CAR-T cells. Cancer CHOP chemotherapy in DLBCL patients: a study by the Discov. 2017;7(12):1404–19. Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 17. VanDenNesteE,SchmitzN,MounierN,etal. Outcomesof 2010;116(12):2040–5. diffuse large B-cell lymphoma patients relapsing after au- 2. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regi- tologous stem cell transplantation: an analysis of patients mens with autologous transplantation for relapsed large included in the CORAL study. Bone Marrow Transplant. B-cell lymphoma in the rituximab era. J Clin Oncol. 2017;52(2):216–21. 2010;28(27):4184–90. 18. OrlandoEJ,HanX,TribouleyC,etal. Geneticmechanismsof 3. Wohlfarth P, Worel N, Hopfinger G. Chimeric antigen recep- target antigen loss in CAR19 therapy of acutelymphoblastic tor Tcell therapy—a hematological success story. memo. leukemia. NatMed. 2018;24(10):1504–6. 2018;11(2):116–21. 19. Cherkassky L, Morello A, Villena-Vargas J, et al. Human 4. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety CAR T cells with cell-intrinsic PD-1 checkpoint block- and activity of axicabtagene ciloleucel in refractory large ade resist tumor-mediated inhibition. J Clin Invest. B-cell lymphoma (ZUMA-1): a single-arm, multicentre, 2016;126(8):3130–44. phase1–2trial. LancetOncol. 2019;20(1):31–42. 20. FryTJ,ShahNN,OrentasRJ,etal. CD22-targetedCARTcells 5. Jacobson CA, Hunter B,Armand P,et al. Axicabtagene induceremissioninB-ALLthatisnaiveorresistanttoCD19- ciloleucel in the real world: outcomes and predictors of targetedCARimmunotherapy. NatMed. 2018;24(1):20–8. response, resistance and toxicity. Blood. 2018;132(Suppl 21. Ormhoj M, Scarfo I, Cabral ML, et al. Chimeric antigen 1):92. receptorTcellstargetingCD79bshowefficacyinlymphoma 6. NastoupilLJ,JainMD,SpiegelJY,etal. AxicabtageneCiloleu- with or without co-targeting CD19. Clin Cancer Res. cel (Axi-cel) CD19 chimeric antigen receptor (CAR) T-cell 2019;25(23):7046–57. therapyforrelapsed/refractorylargeB-cellLymphoma: real 22. Ramos CA, Ballard B, Zhang H, et al. Clinical and worldexperience. Blood. 2018;132(Suppl1):91. immunological responses after CD30-specific chimeric 7. Jacobson CA, Locke FL, Miklos DB, et al. End of phase antigen receptor-redirected lymphocytes. J Clin Invest. 1 results from Zuma-6: Axicabtagene ciloleucel (Axi-Cel) 2017;127(9):3462–71. in combination with atezolizumab for the treatment of Publisher’s Note Springer Nature remains neutral with regard patients with refractory diffuse large B cell Lymphoma. to jurisdictional claims in published maps and institutional Blood. 2018;132(Suppl1):4192. affiliations. K CAR T-cell therapy in diffuse large B-cell lymphoma 35 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

CAR T-cell therapy in diffuse large B-cell lymphoma

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short review memo (2020) 13:32–35 https://doi.org/10.1007/s12254-019-00558-z Georg Hopfinger · Nina Worel Received: 1 September 2019 / Accepted: 10 December 2019 / Published online: 24 January 2020 © The Author(s) 2020 Summary Diffuse large B-cell lymphoma (DLBCL) Unfortunately, 30–40% of patients eventually re- comprises 30–40% of non-Hodgkin’s lymphoma. Clin- lapse and 10% are primary refractory. Despite inten- ical factorssuch asa high International Prognostic In- sive salvage immunochemotherapy and autologous dex (IPI) or molecular factors as cell of origin (COO) stem cell transplantation (ASCT), outcome in these have an influence on the clinical outcome after con- patients is poor with an ORR of 27–63% and long- ventional immunochemotherapy. Patients with re- term survival in up to 48% [2]. With the introduc- sistant or relapsed (r/r) DLBCL have a poor prog- tion of (mostly autologous) chimeric antigen receptor nosis with a median overall survival of 6,3 months T-cell (CAR-T) therapy, very encouraging results with and low complete response rates (CR 7%) to salvage CR rates up to 50% in r/r DLBCL have been demon- chemoimmunotherapy. Currently, therapy with autol- strated leading to approval of two products by the ogous chimeric antigen receptor T-cells (CAR T-cells) US FDA (Food and Drug Administration) and EMA provide encouraging complete responses (CR) of up (European Medicines Agency). to 50%. However, high costs for approved products and elaborate logistics have to be encountered. Chimeric antigen receptor T-cells Keywords Tisagenlecleucel · Axicabtagene A CAR is commonly composed of a specificity-confer- ciloleucel · Cytokine Release Syndrome · Autologous ring extracellular antibody single chain variable frag- chimeric antigen receptor T-cells · Diffuse large ment (scFv), a hinge region transmembrane domain, B-cell lymphoma one or more intracellular costimulatory domains (e.g., CD28 or 4-1BB [CD137]), and a T-cell receptor signal- ing domain (CD3 ζ). Several generations of CARs can Introduction be distinguished, differing by co-stimulating signaling With standard immunochemotherapy, e.g., R-CHOP domains (CD28, 4–1 BB) being responsible for T-cell (rituximab+ cyclophosphamide, doxorubicin, vin- activation and expansion [3]. cristine, and prednisone), patients with diffuse large B-cell lymphoma (DLBCL) can achieve an overall re- Approved CAR T-cells in hematological disease sponse rate (ORR) of 60% resulting in a long-term event-free survival of 50% [1]. At present two CAR-T products against CD19 are ap- proved: Axicabtagen–ciloleucel (Yescarta )for thetreat- ment of adult patients with relapsed or refractory PD Dr. G. Hopfinger () Department of Internal Medicine I, Bone Marrow diffuse large B-cell lymphoma (DLBCL) and pri- Transplantation Unit, Medical University of Vienna, mary mediastinal large B-cell lymphoma (PMBCL), Waehringer Guertel 18-20, 1090 Vienna, Austria after two or more lines of systemic therapy. georg.hopfinger@meduniwien.ac.at Tisagenlecleucel (Kymriah ) for the treatment of Univ.Prof.Dr.N.Worel pediatric and young adult patients up to 25 years of Department of Blood Group Serology and Transfusion age with B-cell acute lymphoblastic leukemia (ALL) Medicine, Medical University of Vienna, Vienna, Austria that is refractory, in relapse posttransplant or in 32 CAR T-cell therapy in diffuse large B-cell lymphoma K short review second or later relapse and adult patients with re- (95% CI, 41–62) including 40% CR. Those patients lapsed or refractory diffuse large B-cell lymphoma that had obtained CR at 3 months were also more (DLBCL) after two or more lines of systemic therapy likely to remain in remission at 6 months after CAR- T infusion. Median duration of response was not reached at the time of analysis. For patients achieving CAR T-cells in non-Hodgkin’s lymphoma a CR, the 12-month relapse-free survival rate was 79% With the introduction of CAR T-cells targeting CD19- with an OS of 95%. The OS probability at 12-months positive lymphoid malignancies, encouraging re- for all infused patients was 49% [8]. More recently, sponse rates have been observed in heavily pretreated “real-word data” for tisagenlecleucel clearly support patients. clinical activity with an ORR of 66% (CR 42%) [9]. The ZUMA1 trial (NCT02348216) was the piv- A third CD19-directed CAR T-cell product, not yet otal trial for axicabtagene ciloleucel incorporating approved, is currently investigated in the JCAR017- a CD28 costimulatory domain (Axi-cel; Yescarta ). TRANSCEND trial (NCT02631044) using lisocabtagene The trial included two cohorts with r/r lymphoma: maraleucel (Liso-cel) (incorporating a 4-1BB costim- cohort 1 which included 77 patients with r/r DL- ulatory domain). During manufacturing, T-cells are BCL and cohort 2 which included 24 patients with selected in CD4+ and CD8+ cells and then further pro- primarily mediastinal B-cell lymphoma (PMBCL) or cessed to CAR-T separately. The product is prepared transformed follicular NHL (tFL). After lymphode- in two tubes consisting of CD4+ and CD8+ CAR-T cells pleting chemotherapy with fludarabine 30 mg/m /day in a precise 1:1 ratio. Patients were treated in two and cyclophosphamide 500 mg/m /day (FC 30/500) cohorts, including 73 patients DLBCL NOS and high for 3 days, 91% patients received a target dose of grade B cell lymphoma and 102 patients with DLBCL 2.0 × 10 CAR T-cells/kg body weight. Patients had NOS, PMBCLortFL.Median ofprior therapies was median of 3 pretreatments (range 1–7), including au- 3(range, 2–8, ASCT in 38%). A CRS occurred in 37% tologous stem cell transplantation (ASCT) in 21%. (grade ≥3: 1%) and NT in 23% (grade ≥3: 13%), the Bridging therapy between enrollment in the study ORR was 80% including 55% CR [10]. Based on en- and lymphodepleting chemotherapy was not allowed. couraging data, a submission to FDA for approval is Observed specific toxicity was a cytokine release syn- expected next year. More recently, a subset of pa- drome (CRS) in 93% (grade ≥3: 13%) and neurological tients with secondary central nervous system (CNS) toxicity (NT) in 64% (grade ≥3: 28%). More recently, manifestation showed response in 4/9 patients cases an up-date with median follow-up of 15.4 months [10, 11]. was published, confirming durable ORR of 83% and a CR of 58%. The COO had no impact on clinical out- Assessment and management of adverse events come. Median duration of response was 11.1 months in CAR T-cell therapy (4.2–not estimable), OS was not reached, progression- free survival (PFS) was 5.9 months (95% confidence CAR T-cell therapy is associated with significant acute interval [CI] 3.3–15.0). [4]. Furthermore, analysis of toxicities, which can be severe or even fatal [12]. The “real-world data” from different centers utilizing the following symptoms can be observed: cytokine release approved, commercial available product, confirmed syndrome (CRS), neurotoxicity (CAR-T cell related en- high activity in r/r DLBCL treated outside of clinical cephalopathy syndrome [CRES] or immune effector trial, while 50% of the patients did not meet inclu- cell associated neurotoxicity syndrome [iCANS]), cy- sion criteria for different comorbidities [5, 6]. Despite topenia, prolonged B cell aplasia, hypo-gammaglob- higher comorbidity, slightly higher median age and ulinemia resulting in increased risk for infections and higher proportion of patients receiving Axci-cel after rarely hemophagocytic lymphohistiocytosis (HLH). relapse ASCT (27% and 33 % for “real-world data” compared to 23% in the ZUMA1 trial), the ORR was Cytokine release syndrome similar (71% and 81% for “real-world data” and 83% in the ZUMA1 trial) [6, 7]. Virtually all patients experience at least a mild cy- Tisagenlecleucel (Tisa-cel) (Kymriah ), incorpo- tokine release syndrome (CRS) presenting with fever rating a 4-1BB costimulatory domain, was approved >38.5 °C. The therapy of mild, i.e., grade I CRS, is based on the JULIET trial (NCT02445248) for r/r DL- symptomatic. Grade ≥2 CRS, which can include sys- BCL, including patients with a median of 3 prior tolic blood pressure ≤90 mm Hg and/or hypoxia (FiO2 therapies (range 1–8) including ASCT in 49%. Af- ≤40%) needs prompt interventions with IV fluids or ter lymphodepleting chemotherapy with FC (25/250) non-invasive oxygen supply through breathing mask. or bendamustine 90 mg/m /day for 2 days, 93% of If conditions deteriorate, CRS 3 is diagnosed and mul- patients received a median single dose of 3.0 × 10 tiple pressor/resuscitator or respirator might become (range, 0.1–6.0 × 10 ) CAR-T cells. In 102/111 (92%) necessary; a CRS 4 means life-threating conditions. patients bridging therapy was given between leuko- For monitoring of CRS proinflammatory parameters, cyte collection and CAR T-cell infusion. There was no e.g., CRP, ferritin or IL-6 can be used. As the time treatment-related death observed. Best ORR was 52% pointofCRS mayvarybetween day1to day14(me- K CAR T-cell therapy in diffuse large B-cell lymphoma 33 short review dian 5), patients will be observed in hospital for 14 Hemophagocytic lymphohistiocytosis/ days in most centers. As a side effect of lymphodeple- macrophage-activation syndrome tion and CAR T infusion, B-cell aplasia and leukopenia can occur and therefore infection has to be ruled out Hemophagocytic lymphohistiocytosis/macrophage- in febrile patients, despite low incidence of infections activation syndrome (HLH/MAS) rarely occurs and during CAR T-cell therapy [13]. is characterized by similar clinical manifestations as In moderate to severe symptoms, i.e., CRS ≥2not CRS as high fever, multiorgan dysfunction or CNS responding to supportive therapy, tocilizumab, an disturbances. interleukin-6 receptor antibody, is recommended. Tocilizumab inhibits direct binding of IL-6 or IL-6/ Conclusion and perspective soluble IL-6 receptor complex to cell membranes. Tocilizumab can be given at a dose of 8 mg/kg CAR T-cell therapy is “en vogue” due to very promis- IV (max. 800 mg), every 8 h with a maximum of ing response data in relapsed and refractory DLBCL three doses within 24 h and a total of four doses. In and 50–70% of patients will be alive after 12 month case of CRS grade ≥3 or patients not responding to trials. This has been confirmed in “real-world” data tocilizumab within 24 h, corticosteroids (methylpred- including patients not eligible for trials due to several nisolone 1 g/kg or dexamethasone 10 mg twice daily) comorbidities [5, 6, 9]. Despite the high efficacy of should be considered. So far, corticosteroids were not CAR T-cell therapy with CR rate up to 50%, which is in recommended as first-line for CRS due a possible in- contrast to poor outcome after conventional salvage teraction with T-cell expansion. However, a recently immune-chemotherapy, results have to be interpreted proposed regimen showed no negative impact on with caution [17]. So far, only data of single-arm phase T-cell expansion [14]. Comparison of clinical data are II trials with highly selected patients and short ob- difficult between trials, as different scoring systems servation times are available. Even “real-world” data and algorithms for CRS treatment were used. More do not really improve the information quality, as data recently, a simplified scoring system was introduced were provided by only a few highly experienced cen- [15]. ters. No randomized data comparing ASCT or allo- HSCT are available so far. Therefore, no recommen- dation can be given in patients relapsing or refractory Immune effector cell associated neurotoxicity to first line therapy if transplant eligible. Clinical trials syndrome (iCANS) comparing ASCT with CAR T-cell therapy are currently Immune effector cell associated neurotoxicity syn- being initiated. drome (iCANS) is another major complication of CAR As CAR T-cell therapy is associated with specific T-cell therapy which can occur with or independently toxicity as described above, has to be established of CRS, mostly within 28 days after CAR T-cell infu- a dedicated and well-trained team in specific cen- sion. As CAR T-cells can cross the blood–brain barrier ters. Finally, financial burden of CAR T-cell therapy (BBB), endothelial cell activation might play a role is significant. Therefore, new funding systems are in the development of iCANS and cerebral edema necessary. Furthermore, a significant proportion of [16]. Clinical symptoms, e.g., diminished attention, patients are refractory to CAR-T cells. Pathomechims confusion, word-finding difficulties, disorientation, are only partially explained by a loss of the target aphasia, somnolence, seizures or cerebral edema may structure (CD19) at the tumor cell or receptor mu- occur. Tocilizumab is not expected to cross the BBB tations [18] or expression of checkpoint proteins by and could theoretically increase the amount of cir- the tumor [19]. Administration of checkpoint in- culating IL-6 in the brain. Dexamethasone 10 mg hibitors along with CAR-T cells are currently being IV every 6 h or methylprednisolone 1 mg/kg IV ev- tested: ZUMA-6 trial, axicabtagen-ciloleucel +anti- ery 12 h is considered as rescue therapy of iCANS in PD-L1 antibody atezolizumab or PORTIA trial using patients without signs of CRS. In addition to seizure tisagenlecleucel +pembrolizumab. Combining differ- prophylaxis or treatment, brain imaging (CT-scan ent epitopes to improve activity of CAR T-cell therapy or MRI) should be considered to rule out cerebral was recently applied in r/r leukemia providing CR of edema. A vigilant observation and close monitor- 73% in ALL using an anti-CD19/CD22 CAR-T [20]. ing using a neurological assessment score is strongly Novel CAR-T constructs are directed against CD79b recommended. alone or in combination with CD19 in cell line- and patient-derived xenograft models and should be clin- ically tested in B-cell lymphoma [21]. A CD30 CAR B-cell aplasia T-cell therapy demonstrated activity in patients with As off target toxicity B-cell aplasia can occur; there- Hodgkin lymphoma and anaplastic large cell lym- fore some patients are in need of immunoglobulin phoma [22]. Ongoing concepts use CAR T-cell ther- infusion in the case of recurrent infections or even apy in earlier lines, as randomized trials (ZUMA prophylactically, depending to local guidelines. 7-NCT03391466; BELINDA-NCT03570892) compare CAR T-cell therapy versus ASCT in first relapse. 34 CAR T-cell therapy in diffuse large B-cell lymphoma K short review 8. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in CAR-T cells have demonstrated significant clinical adult relapsed or refractory diffuse large B-cell lymphoma. benefit in all studies published so far. Although Ad- NEnglJMed. 2019;380(1):45–56. verse Events (AEs) such as CRS, neurological toxic- 9. Pasquini M, Hu Z-H, Zhang Y, et al. Real world experi- ity, and B-cell aplasia are common, the majority of ence of tisagenlecleucel chimeric antigen receptor (CAR) events are manageable when treated by an appropri- T-cells targeting CD19 in patients with acutelymphoblastic ately trained multidisciplinary team. leukemia(ALL)anddiffuselargeB-celllymphoma(DLBCL) using the center for international blood and marrow trans- Funding Open access funding providedby Medical University plantresearch(CIBMTR)cellulartherapy(CT)registry. Clin of Vienna. LymphomaMyelomaLeuk. 2019;19:S267. 10. Abramson JS, Gordon LI, Palomba ML, Lunning MA, Ar- Conflict of interest G. Hopfinger has received honoraria nason JE, Forero-Torres A. Updated safety and long term from Celgene, Gilead, GlaxoSmithKline, Janssen, Novartis, clinical outcomes in TRANSCEND NHL 001, pivotal trial Roche, Takeda, and received research funding from Gilead. of lisocabtagene maraleucel (JCAR017) in R/R aggressive N. Worel has received honoraria from AOP Orphan, Celgene, NHL.JClinOncol. 2018;36:abstr7505. Gilead, Jazz, Novartis, Therakos Mallinckrodt Pharmaceuti- 11. Abramson J, Palomba M, Arnason J, et al. Lisocabta- cals, Sanofi Genzyme, and received research funding from gene maraleucel (liso-cel) treatment of patients (pts) with Therakos Mallinckrodt Pharmaceuticals, and Sanofi Gen- relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma zyme. (NHL) and secondary CNS lymphoma: Initial results from Open Access This article is licensed under a Creative Com- TRANSCEND NHL 001. J Clin Oncol. 2019;37(suppl):abstr mons Attribution 4.0 International License, which permits 7515–2019. use, sharing, adaptation, distribution and reproduction in 12. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen any medium or format, as long as you give appropriate credit receptor T-cell therapy—assessment and management of to the original author(s) and the source, provide a link to toxicities. NatRevClinOncol. 2018;15(1):47–62. the Creative Commons licence, and indicate if changes were 13. Di Blasi R, Aguinaga L, Paillassa J, et al. Infectious compli- made. The images or other third party material in this article cations in patients receiving anti-CD-19 chimeric antigen are included in the article’s Creative Commons licence, unless receptors T-cells (CAR-T) for diffuse large cell B-cell lym- indicated otherwise in a credit line to the material. If material phoma (DLBCL). A monocentric preliminary experience. is not included in the article’s Creative Commons licence and S1641. HemaSphere. 2019;3:759. your intended use is not permitted by statutory regulation or 14. Topp M, van Meerten T, Wermke M, et al. Axicabtagene exceeds the permitted use, you will need to obtain permis- ciloleucel(axi-cel)inpatientswithrelapsed/refractorylarge sion directly from the copyright holder. 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Published: Mar 24, 2020

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