- 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Received: 3 March 2022 Accepted: 7 April 2022 DOI: 10.1002/hon.3013 REVIEW Targeting CD19 in diffuse large B‐cell lymphoma: An expert opinion paper Sarah Bailly1 | Guillaume Cartron2 | Sridhar Chaganti3 | Raul Córdoba4 | 5 6 7 8 Paolo Corradini | Johannes Düll | Isacco Ferrarini | Wendy Osborne | 9 10 Andreas Rosenwald | Juan‐Manuel Sancho | Hervé Tilly11 | 1 12 7 Eric Van Den Neste | Andreas Viardot | Carlo Visco 1 Département d’Hématologie, Cliniques Universitaires Saint‐Luc, Brussels, Belgium 2 Department of Haematology, Centre Hospitalier Universitaire de Montpellier, UMR‐CNRS 5535, Montpellier, France 3 Department of Haematology, Queen Elizabeth Hospital, Birmingham, UK 4 Department of Hematology, Fundación Jiménez Díaz University Hospital, Health Research Institute IIS‐FJD, Madrid, Spain 5 Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milan, Italy 6 Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany 7 Department of Medicine, Section of Hematology, University of Verona, Verona, Italy 8 Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK 9 Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany 10 ICO‐IJC‐Hospital Germans Trias I Pujol, Barcelona, Spain 11 Department of Hematology and U1245, Centre Henri Becquerel and University of Rouen, Rouen, France 12 Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany Correspondence Eric Van Den Neste, Département Abstract d’Hématologie, Cliniques Universitaires Saint‐ The ubiquitous, early‐stage expression, efficient internalization, limited off‐target Luc, Brussels, 1200, Belgium Email: eric.vandenneste@uclouvain.be effects, and high disease specificity of CD19 make it an attractive therapeutic target. Currently available anti‐CD19 therapies have demonstrated particular Funding information promise in patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma. Se- Incyte Biosciences International Sàrl lection of the most appropriate treatment strategy should be based on individual patient characteristics and the goal of therapy. However, evidence and knowledge about the sequencing of anti‐CD19 therapies are limited. Here, we review the current evidence for CD19 as a target in diffuse large B‐cell lymphoma and consider approaches to the use of anti‐CD19 therapy. KEYWORDS CD19, diffuse large B‐cell lymphoma, non‐Hodgkin lymphoma, relapsed/refractory - This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd. Hematological Oncology. 2022;40:505–517. wileyonlinelibrary.com/journal/hon 505 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 506 - BAILLY ET AL. 1 | INTRODUCTION these, CD19 shows particular promise, since it is constantly and strongly expressed in the vast majority of B‐cell lymphoprolifer- Diffuse large B‐cell lymphoma (DLBCL) is the most common type of ative diseases, is highly disease‐specific, and has a limited number non‐Hodgkin lymphoma (NHL), constituting around 25%–40% of of off‐target effects.19,20 1,2 cases worldwide. The annual incidence of DLBCL is three to four In this paper, we examine the role of CD19 in the patho- per 100,000 persons in Europe and 7 per 100,000 persons in the physiology of DLBCL, review the evidence for CD19 as a target in United States,3,4 with diagnosed incident cases predicted to increase DLBCL, and consider approaches to the use of anti‐CD19 therapy. steadily over the coming years.5 The introduction of the anti‐CD20 monoclonal antibody rit- uximab in 1997 revolutionized the treatment of DLBCL.6 2 | NATURAL ROLE OF CD19 AND ROLE IN B‐ Rituximab‐mediated cell death is thought to occur through several LYMPHOMAGENESIS different mechanisms including natural killer (NK)‐cell–mediated antibody‐dependent cellular cytotoxicity (ADCC), antibody‐ CD19 is a type 1 transmembrane glycoprotein that belongs to the dependent cellular phagocytosis (ADCP), complement‐dependent immunoglobulin (Ig) superfamily.21,22 It consists of a single trans- cytotoxicity (CDC), and direct antitumor effects via apoptosis or membrane domain, a cytoplasmic C‐terminus, and extracellular N‐ other cell death pathways.7,8 Rituximab given in combination with terminus (Figure 1).22 CD19 is the main signaling component of a cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐ multimolecular complex located on the surface of mature B cells CHOP) was approved in 2006 as first‐line treatment for patients together with tetraspanin membrane protein CD81, complement re- with DLBCL and remains the standard therapy for previously ceptor CD21, and CD225.22‐25 CD81 is required for the transfer of untreated patients, achieving complete and sustained remission in CD19 to the cell surface and for CD19 surface expression.26‐30 CD19 9‐11 approximately 60% of this population. However, around 30%– is expressed ubiquitously on the surface of B cells from the early to 40% of patients relapse following an initial response to therapy or mature stages of development,31 and is subsequently downmodulated are unable to achieve remission with first‐line treatment.1 Among at the plasma cell stage.23,32 CD19 is not shed from the surface of B patients with relapsed/refractory (R/R) DLBCL, 30%–40% have a cells into the circulation.33 The expression profile of CD19 is broader response to salvage chemotherapy and up to 50% of these pa- than that of CD2034 and CD19 is expressed at an earlier pre‐B stage tients subsequently undergo autologous stem‐cell transplantation than CD20.35 In normal cells, CD19 plays a key role in many B‐cell (ASCT), with around half ultimately relapsing after functions, including development and differentiation, proliferation, 1,3 transplantation. and signaling.23,36 Patients with R/R DLBCL currently have few treatment op- CD19 also modulates B‐cell receptor signaling at several stages tions, and outcomes are poor due to a lack of durable response to of B‐cell development, and effects antigen‐independent and salvage chemotherapy.12 Rituximab‐containing regimens are immunoglobulin‐induced B‐cell activation through various protein 2 frequently used, despite limited evidence supporting their use. kinases.22,37 Various mechanisms of resistance to rituximab have been pro- B‐cell receptors consist of a surface‐expressed immunoglobulin posed,13 with CD20‐negative change after rituximab‐containing joined to CD79A and CD79B heterodimers, which are necessary for therapy believed to be one of the main resistance mechanisms in signal transduction, plasma membrane expression, and intracellular B‐cell NHLs. This is thought to occur as a result of epigenetic trafficking.38,39 In DLBCL, B‐cell receptor expression is retained, and downregulation of CD20 messenger ribonucleic acid expression, these receptors play a pivotal role in lymphoma pathogenesis and homozygous deletion of the CD20 gene, and selection of CD20‐ proliferation.38,39 The activated B‐cell–like DLBCL subtype is char- negative clones.14 Research suggests that many patients with acterized by chronic active B‐cell receptor signaling and activation DLBCL may have a low peripheral blood NK cell count, and this of the Nuclear Factor Kappa B signaling pathway, and mainly ex- may be associated with poorer outcomes with anti‐CD20–based presses immunoglobulin M (IgM)‐B‐cell receptors.38,39 The germinal therapy, including shorter progression‐free survival (PFS), versus center B‐cell–like subtype expresses IgG‐B‐cell receptors.39 IgM‐B‐ 15 patients who have higher NK cell counts. cell receptor signaling preferentially induces pro‐survival and mito- A considerable focus has been placed on improving outcomes genic signals, while IgG‐B‐cell signaling favors plasma cell 39 of first‐line treatment and increasing cure rates in newly diagnosed differentiation. DLBCL,16 although there is limited evidence demonstrating a The B‐cell–specific paired box transcription factor 5 (PAX5) plays consistent, clear benefit compared with R‐CHOP. Preliminary re- a role in B‐cell development and normal expression of CD19.35 PAX5 sults from the POLARIX trial suggest that treatment with polatu- and CD19 regulate levels of the multifunctional transcription factor, zumab vedotin in combination with R‐CHOP improves PFS c‐MYC, through a post‐transcriptional mechanism that acts via the compared with standard of care R‐CHOP in patients with DLBCL, phosphoinositide 3‐kinase pathway, independently of B‐cell receptor but further data are awaited to confirm this.17 Efforts to improve activity.35 Increased expression of c‐MYC leads to uncontrolled cell outcomes for patients with R/R DLBCL are also ongoing through growth and tumor development. A c‐MYC–CD19 regulatory loop, in the development of novel agents with new targets, including the B‐ which CD19 and c‐MYC act synergistically, accelerates B‐cell lym- cell surface antigens CD19, CD22, CD37, and CD79B.18 Among phomagenesis and lymphoma progression.31,35 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BAILLY ET AL. - 507 F I G U R E 1 Molecular structure of CD1922 CD19 is a type I one‐pass transmembrane protein. The two extracellular C2 Ig‐like domains are separated by a small helical non‐Ig domain with possible disulfide links. The highly conserved, 242 amino acid cytoplasmic domain includes multiple tyrosine residues. Three key tyrosine residues are shown with their associated signaling kinases and molecules. Ig, immunoglobulin; PI3K, phosphoinositide 3‐kinase; PLC, phospholipase C. Figure reproduced with permission from BioMedCentral from Wang K, Wei G, Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012;1(1):36. 3 | EVIDENCE OF CD19 AS A PROMISING TARGET Tafasitamab is an Fc‐modified IgG1, humanized, anti‐CD19 IN DIFFUSE LARGE B‐CELL LYMPHOMA monoclonal antibody that binds to CD19 expressed on the surface of pre‐B and mature‐B lymphocytes. It acts by mediating ADCC and Initial attempts to target CD19 through the development of con- ADCP, and exerts a direct cytotoxic effect.41,42 Two amino acid ventional anti‐CD19 monoclonal antibodies were unsuccessful, due substitutions have been engineered in the Fc region at S239D and to a lack of efficacy of these first‐generation therapies that retain the I332E, meaning that tafasitamab has an increased affinity for Fc native Fc region of immunoglobulin G1 (IgG1).34,40 Native CD19 gamma receptors, including FcγRIIIa (expressed on the surface of NK antibodies containing unmodified Fc regions cannot elicit key anti- cells, macrophages, and many γδ T cells), and enhanced FcγRIIIa‐ body effector functions, because they do not induce growth arrest or mediated ADCC and ADCP activity.41,43 programmed cell death, and have limited effectiveness in triggering Tafasitamab has shown potent activity in preclinical studies CDC, ADCC and ADCP.40 This prompted the development of novel involving lymphoma and leukemia models, including 100‒1000‐fold anti‐CD19 targeted‐immunotherapy strategies, which have demon- enhanced ADCC relative to an anti‐CD19 IgG1 analog in vitro.41,42 strated particular promise in B‐cell NHL. Tafasitamab has demonstrated single‐agent activity in the setting of R/R DLBCL and other B‐cell malignancies, with some patients achieving durable responses.44‐47 Preclinical evidence also suggests 3.1 | Fc‐modified anti‐CD19 monoclonal antibodies: that tafasitamab acts synergistically in combination with lenalido- tafasitamab mide.42 Lenalidomide has direct antineoplastic activity and indirect effects mediated via various immune cells in the tumor microenvi- Evidence demonstrating the significance of antibody functions ronment.48 In particular, lenalidomide stimulates NK‐cell prolifera- dependent on the Fc domain provided a rationale for Fc engineering, tion and activation, thus enhancing NK‐cell–mediated ADCC by 40 to generate anti‐CD19 antibodies with enhanced efficacy. tafasitamab in vitro.42,48 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 508 - BAILLY ET AL. Phase one studies of tafasitamab have provided data on its safety, patients who had double‐ or triple‐hit lymphoma.45 In a patient‐level efficacy, pharmacokinetics and appropriate dosing to support phase matched comparison of the L‐MIND and real‐world RE‐MIND cohorts 49,50 two development. First‐MIND (NCT04134936), an ongoing phase of patients with ASCT‐ineligible R/R DLBCL (76 patients each cohort), 1b open‐label trial investigating the safety and efficacy of tafasitamab the combination of tafasitamab and lenalidomide resulted in a plus R‐CHOP or tafasitamab and lenalidomide plus R‐CHOP in adult significantly better ORR, CR, and OS compared with lenalidomide patients with newly diagnosed DLBCL, found no unexpected toxicity monotherapy (ORR 67.1% vs. 34.2%; odds ratio 3.89; 95% confidence and no effect on the relative dosage intensity of R‐CHOP with the interval 1.90–8.14; p < 0.0001).53 addition of both therapies. Preliminary efficacy analyses showed a Tafasitamab received accelerated approval from the US Food and combined overall response rate (ORR) of 83.4% and complete Drug Administration (FDA) in July 2020 for use in combination with remission rate of 75.0%.49 lenalidomide to treat transplant‐ineligible adults with R/R DLBCL.54,55 The phase two L‐MIND trial (NCT02399085) investigated the The European Medicines Agency granted marketing authorization for combination of tafasitamab plus lenalidomide followed by tafasitamab tafasitamab on 26 August 2021.56 Studies are ongoing to evaluate the monotherapy in 80 patients with DLBCL who relapsed or were re- use of tafasitamab as first‐line treatment for DLBCL (First‐MIND fractory after one to three systemic regimens (including at least one [NCT0413493657] and Front‐MIND [NCT0482409258]), and in R/R CD20‐targeting regimen), and who were ineligible for ASCT. Exclu- follicular lymphoma or marginal zone lymphoma (InMIND sion criteria included primary refractory DLBCL, defined as no [NCT0468005259]). response to, or progression during or within 6 months of, frontline therapy. Fifteen patients (19%) with primary refractory disease were included in the study. Prior to a protocol amendment, patients who 3.2 | Anti‐CD19 bispecific T‐cell engagers: relapsed within 3 months of a prior anti‐CD20‐containing regimen blinatumomab were defined as primary refractory and were excluded from L‐MIND. Patients who relapsed or progressed between 3 and 6 months after Strategies to target CD19 focusing on T cell recruitment led to the receiving frontline therapy recruited before the amendment were development of blinatumomab, a CD19xCD3 bispecific T‐cell engager considered as primary refractory but were included. In total, 42.0% that directs cytotoxic T‐cells to lyze CD19‐expressing B cells.60‐63 and 44.4% of patients were refractory to rituximab and last line of Blinatumomab exhibits linear pharmacokinetics and due to its short therapy, respectively. The median number of prior lines of systemic elimination half‐life (t1/2 1–2 h), must be administered as a 24‐h therapy was two, with 50% of patients (n = 40) receiving tafasitamab continuous intravenous infusion.64 Blinatumomab has demonstrated as second‐line therapy. A history of double‐/triple‐hit lymphoma was activity in three phase 1/2 trials in heavily pre‐treated patients with an exclusion criterion of the study; however, two patients were found aggressive R/R DLBCL, with CR rates ranging from 19% to 22%.62,65 45 to have these alterations post‐enrollment. In a pooled analysis of these studies, the median duration of CR and Any grade treatment‐emergent adverse events (TEAEs) occurred OS was not reached in patients who achieved CR or complete in 100% of patients. The most common grade 3 or higher TEAEs with metabolic response within cycle 1 (12 weeks) of blinatumomab the combination of tafasitamab and lenalidomide were neutropenia treatment (N = 17), with a median follow‐up of 15.6 and 16.4 months, (48%), thrombocytopenia (17%), and febrile neutropenia (12%). respectively. At 12 months, 62.2% of patients were still responding Infusion‐related reactions (all grade 1 and during the first infusion) and 86.5% were alive.60 In a single‐center, long‐term follow‐up study were reported in 6% of patients, none of which required treatment of blinatumomab in patients with R/R B‐NHL from the phase one discontinuation. Serious adverse events were reported in 51% of MT103‐104 trial, the median OS was 5.8 years in patients who patients and 25% of patients discontinued treatment due to adverse received a dose of ≥60 μg/m2 per day (n = 25). Median PFS was 45 events. 1.5 years and treatment‐free survival was 3.5 years.66 At ≥35 months of follow up, the ORR was 57.5% (46 patients) and Neurologic adverse events, most commonly dizziness, tremor, 40.0% (32 patients) achieved a complete response (CR). The median confusional state, and encephalopathy are reported in around half of duration of response (DOR) was 43.9 months and median PFS was patients treated with blinatumomab and frequently lead to dose 11.6 months with a median follow‐up of 33.9 months. Median overall interruption and treatment discontinuation.67 survival (OS) was 33.5 months with a median follow‐up of 42.7 months.47 Median PFS was 23.5 months in patients who received tafasitamab plus lenalidomide as second‐line therapy compared with 3.3 | Anti‐CD19 antibody–drug conjugates: 7.6 months in those who received the combination as third‐line or loncastuximab tesirine later. Median OS was 45.7 versus 15.5 months, respectively.51 In a post‐hoc subgroup analysis of patients in L‐MIND who were The characteristics of CD19 (i.e., rapid internalization kinetics, refractory to primary therapy (n = 15) or their last line of therapy broader expression profile than CD20, not shed into the circulation) (n = 35), ORRs were similar to non‐refractory patients (both 60.0%). make it a better target for antibody–drug conjugates (ADCs) than The 12‐month DOR was similar regardless of refractory status to last CD20.34,68 Loncastuximab tesirine is an ADC consisting of a CD19‐ therapy, although the 12‐month PFS and OS were lower compared targeting antibody conjugated to a cytotoxic DNA minor groove with non‐refractory patients.52 Responses were observed in two interstrand cross‐linking pyrrolobenzodiazepine dimer.69,70 After 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BAILLY ET AL. - 509 binding to CD19‐positive cells, loncastuximab tesirine is internalized costimulatory domain. However, it is unclear whether these differ- within the cell, where pyrrolobenzodiazepine is released, promoting ences affect function, efficacy or safety.80 No head‐to‐head compari- cell death.71 sons of these therapies have been performed, and clinical trials differ in The phase two, single‐arm LOTIS‐2 trial (NCT03589469) inves- their designs and patient populations.81 tigated loncastuximab tesirine in patients with R/R DLBCL or high‐ In the phase two ZUMA‐1 trial of patients with chemotherapy‐ grade B‐cell lymphoma (N = 145) who had failed at least two prior refractory large B‐cell lymphoma treated with a single infusion of systemic regimens.72,73 After a mean of 4.6 cycles, the ORR was axi‐cel (n = 101), the ORR was 82% and the CR rate was 54%. After a 48.3%, and 25% of patients achieved a CR. Median DOR was median of 15.4 months of follow‐up, 42% of patients continued to 12.6 months for the 70 responders and not reached for patients with show a response, and 40% had a CR; at 18 months, the OS was 52%.82 CR. ORRs for patients aged ≥75 years, with double‐/triple‐hit DLBCL At a median of 27.1 months of follow‐up, 83% of patients had an or with transformed disease were 52.4%, 33.3% and 44.8%, respec- objective response, and 58% had a CR. The median DOR was tively. In 15 patients who received anti‐CD19 chimeric antigen re- 11.1 months. Median OS was not reached, and the median PFS was ceptor (CAR) T‐cell therapy following treatment with loncastuximab 5.9 months.83 73 tesirine, the ORR was 46.7%. The phase two JULIET study of tisa‐cel included patients with R/R The LOTIS‐3 phase 1/2, two‐part, open‐label trial DLBCL who had previously received at least two lines of therapy (NCT03684694) is evaluating loncastuximab tesirine in combination including rituximab and an anthracycline, and were ineligible for ASCT with ibrutinib in patients with R/R DLBCL or mantle cell lymphoma.74 or had disease progression post‐transplant (N = 167). In total, 93 At data cut‐off, after a median treatment duration of 70 days, the patients received one infusion of tisa‐cel, which resulted in a best ORR was 62.9% in all patients evaluable for efficacy (n = 37), and ORR of 52% (48 patients); 37 (40%) patients had a CR and 11 (12%) 58.6% (n = 17) in 29 patients with DLBCL. Common grade 3 or higher had a partial response (PR). Durable responses were observed for up TEAEs with loncastuximab tesirine include liver enzyme abnormalities to 18.4 months.84 and cytopenias.70,72 The phase one TRANSCEND NHL 001 study of liso‐cel included Data from preclinical studies suggest that adding rituximab to an heavily pre‐treated patients with R/R large B‐cell lymphomas anti‐CD19 pyrrolobenzodiazepine ADC prolongs tumor control, (N = 344). Patients who received at least one dose of liso‐cel (n = 269) providing a rationale for combining loncastuximab tesirine with rit- had received a median of three previous lines of systemic therapy; uximab as a treatment for R/R DLBCL.75 The phase three, random- 67% had chemotherapy‐refractory disease and 44% had never ach- ized, open‐label, two‐part LOTIS‐5 trial (NCT04384484) is ieved a CR with previous treatment. Median follow‐up was investigating the efficacy of loncastuximab tesirine with rituximab 18.8 months. Of 256 evaluable patients, 186 (73%) achieved an versus rituximab/gemcitabine/oxaliplatin as standard immunoche- objective response, 136 (53%) had a CR and 51 (20%) had a PR. The motherapy in patients with R/R DLBCL.75,76 response rate at 1 year was 55% in the overall population and 65% in In a pooled safety analysis of loncastuximab tesirine, grade ≥3 those patients who achieved a CR.85 neutropenia, thrombocytopenia and anemia occurred in 32.1%, 20.0% In all three pivotal trials, a significant proportion of patients failed and 12.6% of patients with R/R DLBCL, respectively. Most of these to receive CAR T‐cells: ZUMA‐1, 10/111 (9.0%); JULIET, 54/165 events were manageable with dose delays, and did not require dose (32.7%); TRANSCEND, 75/344 (21.8%).82,84,85 77 reduction or discontinuation of treatment. Liver enzyme elevations Real‐world studies of anti‐CD19 CAR T‐cell therapies have are also common with loncastuximab tesirine, which are thought to be demonstrated similar favorable outcomes, with comparable rates of due to the pyrrolobenzodiazepine dimer warhead part of the ADC.78 durable remission reported to those in the pivotal ZUMA‐1 and Loncastuximab tesirine received FDA approval for use in patients JULIET trials, despite the fact that some patients would not have met with R/R DLBCL who have received at least two prior systemic eligibility criteria for the pivotal trials because of comorbidities, while 79 therapies. others presented with more advanced or refractory disease.86,87 CAR T‐cells are associated with clinically relevant toxicities (most commonly cytokine‐release syndrome [CRS] and neurotoxicity), which 3.4 | Anti‐CD19 chimeric antigen receptor T‐cell relate primarily to disease burden, the CAR T‐cell dose infused, and therapy patient factors including age and comorbidities. These are typically easily managed and reversible.81,88,89 In a retrospective real‐world Three anti‐CD19 CAR T‐cell therapies are approved for use in R/R analysis (N = 70), the reported incidence of CRS in patients with R/ DLBCL, after two or more lines of systemic therapy: axicabtagene R DLBCL treated with tisa‐cel or axi‐cel was 85%, with grade ≥3 ciloleucel (axi‐cel) and tisagenlecleucel (tisa‐cel), approved in both events occurring in 8% of patients. The incidence of immune cell– Europe and the USA, and lisocabtagene maraleucel (liso‐cel), approved, associated neurotoxicity syndrome was 28%, including 10% of pa- at present, in the USA only. Although all three therapies use the same tients with grade ≥3 events.86 single‐chain variable fragment (scFv) derived from clone FMC63, there Administration of CAR T‐cell therapies must be performed at an are differences between them.80 For example, axi‐cel contains a CD28 authorized center and manufacturing the CAR T‐cells is a lengthy, costimulatory domain, while tisa‐cel and liso‐cel each contain a 41‐BB complex, and costly multistep process.90,91 Some manufacturers are 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 510 - BAILLY ET AL. attempting to shorten the process by returning fewer cells to pa- relapse occurred in around 30% of patients following axi‐cel ther- tients, favoring in vivo cell expansion. Initially, there was a longer apy.105 Though the mechanisms responsible for this are not yet fully time period from leukapheresis to conditioning chemotherapy in clear, it is thought to be due to the emergence of tumor cells with low Europe than in the US, due to customs, shipping, and freezing. A or no CD19‐antigen expression within the context of targeted higher proportion of patients (up to 97%) then needed bridging removal of antigen‐positive tumor cells.105 Local resistance mecha- therapy, which is associated with poorer outcomes.86 The approval of nisms within tumors may also play a role in relapse after CAR T‐cell additional CAR T‐cell manufacturing sites by the European Medicines therapy. Lesions at high risk for local failure include high metabolic Agency has expanded production capacity in Europe to improve activity, diameter ≥5 cm, and extranodal disease. It is hypothesized turnaround time.92,93 Reported manufacturing failure rates are that resistance to CAR T‐cells may occur at the individual lesion level, around 1% for liso‐cel, 1%–3% for axi‐cel, and 7%–9% for tisa‐cel; the given that a discordant response to therapy is frequently observed, latter being notable, given that failure may directly impact on patient with some lesions remaining in remission and others progressing.100 84,87,89,94‐96 outcomes. While CAR T‐cell therapies are potentially curative and are therefore a good option for certain patients, they currently have 3.5 | Other anti‐CD19 therapies in development several limitations. In some countries, only a small proportion of with potential for use in R/R diffuse large B‐cell patients meet the strict inclusion criteria for treatment. A retro- lymphoma spective analysis conducted at a single center in France found that of 215 patients with R/R DLBCL, primary mediastinal B‐cell lymphomas, Inebilizumab is a humanized, anti‐CD19 monoclonal antibody that or transformed follicular lymphoma for whom a request for CAR‐T targets and depletes CD19‐expressing B cells via ADCC.106 In a 97 was made, 80 (37%) were ultimately deemed eligible for therapy. phase one dose‐escalation study that included six patients with R/R Of 74 R/R DLBCL patient cases discussed in Belgium, only 40 pa- DLBCL, the ORR was 50%; one patient achieved a CR and two pa- tients (54%) were deemed eligible and 38 (51%) received CAR T‐cell tients achieved a PR.107 therapy (unpublished 2019 data). Bicistronic CAR constructs have been engineered using a single Reasons for CAR T‐cell ineligibility include histology, rapid dis- vector that encodes two different CARs on the same cell, allowing ease progression, need for urgent/bridging therapy, frailty/poor per- dual targeting of CD19 and CD20, thereby overcoming the loss of formance status, central nervous system involvement, and one antigen.108 reimbursement limitations in individual countries.97,98 In some coun- tries, eligibility for CAR T‐cell therapy is based on biological fitness, while in others it is based on chronological age. For example, only 4 | SEQUENTIAL USE OF ANTI‐CD19 THERAPY patients aged <70 years with an Eastern Cooperative Oncology Group (ECOG) performance status of zero or one would be considered The recent approval of novel, CD19‐directed therapies for DLBCL eligible for CAR T‐cell therapy in Italy. Eligibility criteria are less strict presents a challenge in determining the optimal sequence and in the UK and an increasing number of patients unfit for ASCT are duration of treatments for an individual patient.1 approved for CAR T‐cell therapy. An analysis of data from the UK Level of CD19 expression is not currently used as a decision tool national CAR T‐cell service found that 250 out of 272 high‐grade for anti‐CD19 therapy since CD19 expression is highly conserved, lymphoma cases (92%) submitted were approved for treatment, with normal to high levels of expression maintained on nearly 90% of with 163 of the 232 patients (70%) who completed leukapheresis B‐cell lymphomas.22 The absence of CD19 expression may be of 99 receiving CAR T‐cells. In patients with highly proliferative disease, relevance for treatment decisions following CAR T‐cell therapy, as particularly where there is bulky disease, there is a need for bridging discussed further below. therapy between leukapheresis and CAR T‐cell therapy to provide With CAR T‐cell therapy, the intent is curative in the setting of disease control.100‐102 A proportion of patients (9%–33% in the refractory disease. With other anti‐CD19 targeted therapies, the goal pivotal trials) will not be infused because of failure to control the is to prolong remission and extend survival, with acceptable treat- disease, toxicity, or infection‐related complications or nonmeasurable ment tolerability. Although CAR T‐cell therapies can achieve durable disease before conditioning chemotherapy, despite being deemed responses, they are not currently approved for use in the second‐line 82,84,85,103 eligible to receive CAR T‐cells. Other factors to consider in setting and various barriers prevent their widespread uptake, decisions regarding CAR T‐cell therapy include patient preference, meaning only selected patients will benefit.109 ability to travel/distance from the treatment center, the presence of a caregiver for recognizing neurotoxicity, disease kinetics, and cost.87 Relapse after CAR T‐cell therapy is common, with around half of 4.1 | Treatment options for transplant‐ineligible relapses occurring within the first month in R/R DLBCL.104 Risk patients with R/R diffuse large B‐cell lymphoma factors for early progression are two or more extranodal sites, increased C‐reactive protein level, and high total metabolic tumor For transplant‐ineligible patients with R/R DLBCL, no internationally 104 volume at the time of treatment. In ZUMA‐1, CD19‐negative accepted standard has been established. Treatment options for these 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BAILLY ET AL. - 511 patients include immunochemotherapy, tafasitamab plus lenalido- 4.2 | Does previous use of anti‐CD19 therapy mide or polatuzumab vedotin with bendamustine and rituximab preclude the use of CAR‐T cells or subsequent activity (where approved).45,110 of other anti‐CD19 therapy? There is currently no overlap between ASCT and CAR T‐cell therapy in the R/R DLBCL treatment algorithm. ASCT is indicated It is not yet known whether the CD19 antigen can be targeted with a for second‐line use, with CAR T‐cell therapy approved in the third‐line different anti‐CD19 therapy after disease progression following a setting. Several trials are currently evaluating CAR T‐cells as second‐ previous CD19‐directed therapy. There are concerns regarding an- line therapy in patients with high‐grade B‐cell lymphoma.111‐114 In tigen masking and the potential for selection pressure of the prior the ZUMA‐7 trial (NCT03391466), axi‐cel demonstrated a 60% therapy, which could lead to CD19 antigen escape.120 Therefore, it is improvement in event‐free survival (EFS; defined as time to disease advisable to assess CD19 expression on a new biopsy. Some pivotal progression, start of a new therapy, or death from any cause) versus studies of anti‐CD19 CAR T‐cell therapies in aggressive lymphomas standard of care after approximately 2 years of follow‐up in patients excluded patients who had been previously treated with CD19‐ with R/R DLBCL who had failed one initial therapy.115,116 Data from an targeting therapies. In the real‐world setting, decisions regarding interim analysis of the TRANSFORM trial (NCT03575351) of liso‐cel in the use of anti‐CD19 therapy prior to CAR T‐cell therapy are made patients with high‐risk, second‐line, transplant‐eligible R/R B‐cell NHL by the physician, taking previous lines of therapy into consideration. demonstrated a significant improvement in EFS versus standard of In some European countries (e.g., Germany and the UK), CD19 levels care.112,117 It is anticipated that the use of CAR T‐cell therapy earlier in are measured prior to CAR T‐cell therapy in patients who have the treatment sequence may become the new standard for eligible previously received CD19‐targeting therapy. patients in the future. Evidence from preliminary studies suggests that prior treatment Some transplant‐ineligible patients may be eligible for CAR T‐cell with anti‐CD19 therapies in R/R DLBCL may not preclude the use of therapy based on age or biological fitness, with a lower level of anti‐CD19 CAR T‐cells.120‐122 However, these observations are fitness required for CAR T‐cell therapy compared with ASCT. These limited by small sample sizes, with heterogeneity in patient pop- may include patients with a refractory tumor response, intermediate ulations and use of prior therapies. In a study of 14 patients with performance status and level of organ function, and a moderate DLBCL relapsing or progressing after loncastuximab tesirine treat- number of comorbidities. In some patients, particularly older adults, ment (CD19‐positive, n = 10; not checked, n = 4 after treatment evaluation by performance status, cardiac function and glomerular failure), and subsequently undergoing CD19‐directed CAR T‐cell filtration rate may not be sufficient, and a formal assessment of the therapy, the best response at 3 months included six patients (43%) impact of comorbidities and functional/social decline is recom- with a CR and one patient (7%) with a PR; the ORR was 50%.121 In a 118 mended to determine potential tolerance to therapy. Eligibility post hoc analysis of 12 patients with R/R aggressive B‐NHL in the criteria for these approaches differ between countries. For example, TRANSCEND study who had received anti‐CD19 therapy prior to in Spain and the UK, ASCT is typically offered to patients aged liso‐cel therapy (where subsequent biopsy showed CD19‐positive <70 years with CAR T‐cell therapy available for patients aged lymphoma), the ORR was 92% (11 patients); 6 patients (50%) ach- <75 years (Spain) or 70–80 years (UK). In Germany, CAR T‐cell ieved a CR and 5 (42%) achieved a PR; 5 patients had a DOR therapy is offered to a similar patient population to that in Spain ≥9 months122 and the UK, while ASCT is restricted to patients with chemosensitive A case was reported of a 59‐year‐old female patient in the L‐ relapse and those aged <70 years. Furthermore, some patients are MIND trial with stable disease following 5 months of treatment ineligible for treatment with CAR‐T cells due to national regulations with tafasitamab‐lenalidomide, with subsequent progression. After 4 or lack of access. cycles of salvage chemotherapy with rituximab, gemcitabine, and Generally, transplant‐ineligible patients who are also ineligible oxaliplatin, the patient underwent CAR T‐cell therapy with axi‐cel for CAR T‐cells (discussed earlier) could be considered for treat- with a CR, and achieved sustained remission for nearly 1 year123 In ment with tafasitamab plus lenalidomide. These include patients an analysis of CD19 expression in tumor lymph node biopsies from who meet the key inclusion criteria used in the L‐MIND study six patients with R/R DLBCL treated with tafasitamab plus lenali- (relapsed or refractory after one to three systemic regimens, domide in the L‐MIND study, immunohistochemistry showed distinct including at least one CD20‐targeting regimen, adequate organ CD19 expression in all 12 pre‐ and post‐treatment biopsies, inde- 45 function, ECOG performance status of 0–2, measurable disease). pendent of treatment duration/response, or potential residual tafa- Although the goal of therapy differs with these two approaches, the sitamab exposure. Furthermore, CD19 expression levels following 43.9‐month median DOR with tafasitamab plus lenalidomide in L‐ tafasitamab treatment were similar to pre‐treatment baseline levels, MIND is similar to that which can be achieved with CAR T‐cells.47 suggesting that CD19 expression is maintained after tafasitamab In a long‐term follow‐up of patients with DLBCL treated with anti‐ therapy. These results may provide a rationale for the subsequent CD19 CAR‐T cells, 48% of treatments resulted in a DOR of over use of anti‐CD19 CAR T‐cell therapy in this patient population.124 119 3 years However, it is important to note that the characteristics These findings warrant further research, given that parental antibody of patients in L‐MIND differed from those in trials of CAR T‐cell clones of tafasitamab (4G7) and most CAR T‐cell therapies (FMC63) therapy. have been found to target overlapping, yet distinct, epitopes of CD19 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 512 - BAILLY ET AL. which are encoded by exon 2 and centered around residue R144 it might be estimated that around 35% of patients would be ‘cured’ (exon 2 encodes a portion of the extracellular domain of the trans- and 65% would be available for salvage therapy; of this latter group, membrane protein).41,125‐127 30% of patients will lose the CD19 antigen and the remainder will Phase one data from 14 patients with chronic lymphocytic leu- have CD19 expression detectable by immunohistochemistry and kemia showed that CD19 expression levels were maintained on the could be considered for anti‐CD19 immunotherapy. surface of CD24‐positive B cells following tafasitamab treatment.128 Preclinical evidence indicates that exposure to tafasitamab does not impair subsequent anti‐CD19 CAR T‐cell binding in vitro. Various cell 5 | CONCLUSION lines including DLBCL were incubated with tafasitamab to saturate the CD19 antigens. CD19 saturation did not affect CAR T‐cell The early‐stage expression and efficient internalization of CD19 effector functions such as cytokine production, degranulation, pro- make it an attractive therapeutic target compared with CD20.35 129 liferation, or antigen‐specific killing. CD19 has demonstrated value as a target in B‐cell NHL, particularly Evidence suggests that low or undetectable CD19 expression in patients with relapsed or refractory disease, as demonstrated by levels may be adequate for effective anti‐CD19 CAR T‐cell therapy. the efficacy profile of the currently available anti‐CD19 therapies. To In an analysis of CD19 expression in pre‐infusion biopsies taken from date, evidence and knowledge about the sequencing of anti‐CD19 patients in the JULIET trial of tisa‐cel, similar response rates were therapies are limited. Collection of prospective data will be essen- observed irrespective of the level of CD19 expression.84 tial to provide evidence upon which to base treatment decisions. CD19 status prior to CAR T‐cell therapy is not assessed in some Further research is also needed into the optimum duration of anti‐ countries, while in others CD19‐negative status is an exclusion cri- CD19 therapy. Selection of the most appropriate treatment strat- terion. Immunohistochemistry is most commonly used for CD19 egy should be based on individual patient characteristics (e.g., age, analysis, but may not be a reliable method of assessment. Different comorbidities, presence of very aggressive lymphoma) and the goal of CD19 antibodies have distinct epitopes yet most laboratories use therapy. only one CD19 antibody for immunohistochemistry, which could yield false negative results. Furthermore, unlike flow cytometry, A C KN O W L E D GM E N T S CD19 staining by immunohistochemistry is not standardized and is Medical writing assistance was provided by Sarah Stowell of Alligent highly variable between laboratories. Europe (Envision Pharma Group), funded by Incyte Biosciences In- ternational Sàrl. 4.3 | Use of anti‐CD19 therapies as bridging C O NF L I CT S O F I NT ER E S T therapy Sarah Bailly has acted as a speaker for Abbvie and Novartis; and as an advisor for AbbVie, Bristol‐Myers Squibb/Celgene, Janssen, Novartis, The optimal bridging therapy strategy between leukapheresis and Roche, and Takeda. CAR T‐cell therapy remains to be determined. Currently, the goal is Guillaume Cartron has acted as a consultant for Bristol‐Myers to minimize total metabolic tumor volumes with the use of a short Squibb/Celgene, MedXcell, Ownards, and Roche; and has received bridge during CAR T‐cell manufacturing. However, approaches are honoraria from AbbVie, Bristol‐Myers Squibb/Celgene, Incyte, likely to change as new data become available. Gilead, Jansen, Roche, Novartis, Sanofi, and Takeda. The use of bridging therapy was an exclusion criterion in the Sridhar Chaganti has acted as an advisor and consultant and ZUMA‐1 trial of axi‐cel but was allowed in the JULIET trial of tisa‐cel; has received meeting attendance support from Atara Bio, Bristol‐ however, not all patients received it. While evidence is lacking, we Myers Squibb/Celgene, Incyte, Kite Gilead, Novartis, Roche, and currently advise against the use of anti‐CD19 therapy before Takeda. potentially curative CAR T‐cell therapy, due to the risk of down- Raul Córdoba has acted as a speaker for Abbvie, Astra‐Zeneca, regulating the antigen. Bristol‐Myers Squibb/Celgene, Janssen, Kite, Roche, and Takeda; and acted as an advisor for Abbvie, ADC Therapeutics, Astra‐Zeneca, Beigene, Bristol‐Myers Squibb/Celgene, Genmab, Incyte, Janssen, 4.4 | Use of anti‐CD19 therapy following CAR T‐cell Kite, Kyowa‐Kirin, Roche, and Takeda; he has also reserved research therapy grants from Pfizer. Paolo Corradini has acted as a speaker for Abbvie, Bristol‐Myers It is estimated that 30%–60% of patients will progress after CAR T‐ Squibb, Kite Gilead, and Novartis; and acted as an advisor for Bei- cell therapy, with poor outcomes.130 Current options for these pa- gene, Bristol‐Myers Squibb, Kite Gilead, Novartis, Roche, Servier, and tients are entry into a clinical trial (e.g., of a bispecific antibody), Takeda. tafasitamab plus lenalidomide or polatuzumab vedotin plus bend- Johannes Düll has acted as a speaker and advisor for Incyte and amustine and rituximab (where approved), or palliative oral chemo- Morphosys. therapy. If CAR T‐cell therapy is approved in the second‐line setting, Isacco Ferrarini has acted as a speaker for Abbvie. 10991069, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/hon.3013 by Readcube (Labtiva Inc.), Wiley Online Library on [08/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BAILLY ET AL. - 513 Wendy Osborne has acted as a speaker for Abbvie, Incyte, Kite Juan‐Manuel Sancho https://orcid.org/0000-0001-7168-6538 Gilead, Kyowa Kirin, Novartis, Pfizer, Roche, and Takeda; and acted Hervé Tilly https://orcid.org/0000-0001-7022-5246 as an advisor for Autolus Therapeutics, Beigene, Kite Gilead, MSD, Eric Van Den Neste https://orcid.org/0000-0002-7846-4185 Novartis, Roche, Servier, Syneos, and Takeda. She has received travel Andreas Viardot https://orcid.org/0000-0001-9593-6327 support from Bristol‐Myers Squibb, Novartis, Pfizer, Roche, and Carlo Visco https://orcid.org/0000-0003-2863-0883 Takeda. Andreas Rosenwald has no conflicts of interest. PEER REVIEW Juan‐Manuel Sancho has acted as a speaker for Bristol‐Myers The peer review history for this article is available at https://publons. Squibb/Celgene, Gilead/Kite, Janssen, Novartis, Roche, Servier, and com/publon/10.1002/hon.3013. Takeda; and acted as an advisor for Bristol‐Myers Squibb/Celgene, Gilead/Kite, Incyte, Janssen, Novartis, Lilly, Beigene, and Roche. R E F E R E NC E S Hervé Tilly has acted as speaker for Roche and Servier; and acted 1. Harris LJ, Patel K, Martin M. Novel therapies for relapsed or re- as an advisor for Astra‐Zeneca, Incyte, Janssen‐Cilag, and Karyopharm. fractory diffuse large B‐cell lymphoma. Int J Mol Sci. 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