Ardeshna, Kirit M.

Caimi, Paolo F.

Carlo-Stella, Carmelo

Hamadani, Mehdi

Kahl, Brad S.

Solh, Melhem

Thapa, Bicky

English

Digital Commons@Becker

Washington University School of Medicine Digital Commons@Becker Open Access Publications 2020 CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy Bicky Thapa Paolo F. Caimi Kirit M. Ardeshna Melhem Solh Carmelo Carlo-Stella See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Bicky Thapa, Paolo F. Caimi, Kirit M. Ardeshna, Melhem Solh, Carmelo Carlo-Stella, Brad S. Kahl, and Mehdi Hamadani COMMENTARYTO THE EDITOR:CD19 antibody-drug conjugate therapy in DLBCL does not precludesubsequent responses to CD19-directed CAR T-cell therapyBicky Thapa,1 Paolo F. Caimi,2 Kirit M. Ardeshna,3 Melhem Solh,4 Carmelo Carlo-Stella,5 Brad S. Kahl,6 and Mehdi Hamadani11BMT & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, WI; 2University Hospitals Cleveland Medical Center/Case Western Reserve University,Cleveland, OH; 3Department of Hematology, University College London Hospitals, NHS Foundation Trust, London, United Kingdom; 4Blood and Marrow Transplant Program atNorthside Hospital, Atlanta, GA; 5Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico,Humanitas University, Rozzano, Milan, Italy; and 6Oncology Division, Department of Medicine, Washington University, St. Louis, MODiffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkinlymphoma (NHL), with aggressive clinical behavior.1 Approximately 40% to 50% of DLBCL patients arerefractory to or relapse after frontline chemoimmunotherapies.2 Management of relapsed/refractory DLBCLis challenging, and treatment options include salvage therapy followed by autologous hematopoietic celltransplantation (autoHCT), in younger, chemosensitive patients.3 CD19-directed chimeric antigen receptor(CAR) modified T-cell therapy is another potentially curative option for patients with relapse after autologoushematopoietic cell transplantation or those with refractory disease.4 Axicabtagene ciloleucel andtisagenlecleucel are 2 anti-CD19 CAR T-cell treatments approved by the US Food and Drug Administrationfor relapsed/refractory DLBCL.5,6The CD19 antigen is an attractive target for immunotherapy in B-cell non-Hodgkin lymphoma. It is expressedduring B-cell development only after B-lineage commitment and is thus not present on hematopoietic stemcells.7 CD19 expression is lost during terminal plasma cell differentiation but maintained in hematologic B-cellmalignancies.7 Several clinical trials using monoclonal antibodies,8 antibody-drug conjugates (ADCs),9 andbispecific T-cell engagers targeting the CD19 antigen are ongoing in B-cell non-Hodgkin lymphoma. Studiesinvestigating CD19-directed CAR T-cell therapies in aggressive lymphomas frequently excluded patientspreviously treated with CD19 targeting immunotherapies. Hence, the feasibility and efficacy of anti-CD19CARs in lymphoma patients with prior CD19-directed immunotherapies are not known. Loncastuximabtesirine is an ADC comprising a humanized anti-CD19 monoclonal antibody stochastically conjugated toa pyrrolobenzodiazepine dimer toxin, SG3199.10 A phase 1 first-in-human study of loncastuximab tesirinedemonstrated encouraging clinical activity in patients with relapsed/refractory DLBCL,9 and a phase 2 studyrecently finished patient accrual (#NCT03589469).We sought to evaluate the outcomes of anti-CD19 CAR T-cell therapy in relapsed, refractory DLBCLpreviously treated with CD19-directed immunotherapy. Adult (age $18 years) DLBCL patients wereidentified from 2 multicenter, open-label studies of loncastuximab tesirine (phase 1: #NCT02669017and phase 2: #NCT03589469), who subsequently received anti-CD19 CAR T-cell therapy. Thisretrospective analysis was approved by the institutional review board. Deidentified patient data werecollected in collaboration with 6 academic medical centers (US centers 5 4; United Kingdom5 1; Italy5 1) involved in the loncastuximab tesirine trials. Cytokine release syndrome was graded using Lee et al2014 criteria,11 and neurotoxicity was graded as per Common Terminology Criteria for Adverse Events,version 5.0.A total of 14 DLBCL patients with disease relapsing or progressing after treatment with loncastuximabtesirine and subsequently undergoing CD19-directed CAR T-cell therapy were identified (Table 1).Among the 14 patients, 11 patients (79%) were male, and 13 patients (93%) were white. The medianage was 58.5 years (range, 27 to 86). Ten had de novo DLBCL (germinal center B-cell–like 5 4;non–germinal center B-cell5 2; not known5 4), and 4 patients had DLBCL transforming from indolenthistologies (marginal zone lymphoma 5 1; follicular lymphoma 5 1; nodular lymphocyte predominantHodgkin lymphoma 5 1). Five patients (36%) had a high-intermediate international prognostic index atthe time of diagnosis. c-MYC gene rearrangement was identified in 3 patients (21%) (1 patient hadtriple-hit lymphoma), whereas c-MYC status was unknown in 3 patients (21%). The median intervalbetween diagnosis of DLBCL and initiation of loncastuximab tesirine was 21.5 months (range, 6.8to 258). These patients received a median of 2 cycles (range, 1 to 7) of loncastuximab tesirine.3850 25 AUGUST 2020 x VOLUME 4, NUMBER 16Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/16/3850/1759285/advancesadv2020002587.pdf by WASHINGTON UNIVERSITY SCHOOL user on 02 December 2020The antitumor response to loncastuximab tesirine in these 14 patientswas as follows: 8 patients (57%) had refractory disease, 5 patients(36%) attained partial response, and 1 patient (7%) achieveda complete response (overall response rate [ORR] 5 43%). Allresponding patients had progression of the disease before pro-ceeding with CAR therapy.Table 2 summarizes details of CAR T-cell therapy in these subjects.The median interval between loncastuximab tesirine and CAR T-celltherapy was 120 days (range, 22 to 600). Six patients receivedadditional lines of therapy between loncastuximab tesirine and CART-cell treatment (median of 1 therapy line; range, 1 to 3). The CD19expression was assessed by immunohistochemical staining onrepeat biopsies in 10 patients (71%) in between loncastuximabtesirine and CAR administration. All 10 tested patients were positivefor CD19 after ADC failure. This information was not available in4 patients (29%). Before CAR T-cell administration, 13 patients hadrefractory or progressive disease, whereas 1 patient was in partialremission. All patients received standard lymphodepletion withfludarabine and cyclophosphamide before CAR T-cell therapy. Thetype of anti-CD19 CAR T-cell therapy received by the patientsincluded axicabtagene ciloleucel (n 5 5), tisagenlecleucel (n 5 2),JCAR017 (n5 3), and investigational CARs targeting CD19 (n5 4;including 2 patients with CARs targeting dual antigens; Table 2).The median follow-up of survivors was 6 months (range, 3 to 22).Grade 1 to 2 cytokine release syndrome was common (n5 7; 50%).Grade 1 immune effector cell–associated neurotoxicity syndrome(ICANS) was identified in 4 patients (29%), and only 1 patient hadgrade 4 ICANS. Following CAR therapy, the best response at3 months included 6 patients (43%) with a complete response and1 patient (7%) with a partial response (ORR 5 50%). Seven patientshad refractory disease following CAR therapy. Five of 6 completeTable 1. Patient demographics and disease characteristicsPatients (N 5 14)Age, median (range), y 58.5 (27-86)Sex, n (%)Male 11 (79)Female 3 (21)Race, n (%)White 13 (93)African American/black 1 (7)Lymphoma subtypeDLBCL* 10Transformed DLBCL 4IPI at diagnosis, n (%)Low (0, 1) 3 (21)Low-intermediate (2) 3 (21)High-intermediate (3) 5 (36)Unknown 3 (21)Advanced stage (III/IV) at diagnosis 4 (29)c-MYC rearrangement, n (%)Yes 3 (21)No 8 (57)Unknown 3 (21)Median interval between diagnosis and start ofloncastuximab tesirine (range), mo21.5 (6.8-258)Best response to loncastuximab tesirine, n (%)Complete response 1 (7)Partial response 5 (36)Percentages may not add up to 100 due to rounding.IPI, International Prognostic Index.*One patient had mediastinal large B-cell lymphoma.Table 2. CAR T-cell therapy in DLBCL patients failing CD19-directedtreatmentPatients (N 5 14)CD19 expression on lymphoma cells after loncastuximabtesirine therapy, n (%)Positive 10 (71)Not checked 4 (29)Median interval between loncastuximab tesirine and CAR T-celltherapy (range), d120 (22-600)Additional therapy between loncastuximab tesirine andCAR T-cell therapy, n (%)Yes* 6 (43)No 8 (57)Disease status before CAR T-cell therapy, n (%)Refractory disease 5 (36)Progressive disease 8 (57)Partial remission 1 (7)Flu/Cy lymphodepletion, n (%) 14 (100)Type of CAR T-cell therapy, n (%)Axicabtagene ciloleucel 5 (36)Tisagenlecleucel 2 (14)Investigational targeting CD19† 4 (29)JCAR017 3 (21)Best response to CAR T-cell therapy, n (%)Complete response 6 (43)Partial response 1 (7)Refractory disease 7 (50)CRS grade, n (%)None 6 (43)1 3 (21)2 4 (29)3 1 (7)ICANS grade, n (%)None 8 (57)1 4 (29)2 1 (7)3 0 (0)4 1 (7)CRS, cytokine release syndrome; Flu/Cy, lymphodepletion with fludarabine/cyclophosphamide.*Additional therapy between loncastuximab tesirine and CAR T-cell therapy includedradiation alone (n 5 3), radiation, ifosphamide/vinblastine/etoposide (n 5 1), radiation;rituximab/methotrexate (n 5 1), lenalidomide, anti-CD47 antibody, ibrutinib (n 5 1).†One patient each received a CD19/CD22-directed CAR, and a CD19/CD20-directedCAR. Neither patient responded to CAR treatment.25 AUGUST 2020 x VOLUME 4, NUMBER 16 COMMENTARY 3851Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/16/3850/1759285/advancesadv2020002587.pdf by WASHINGTON UNIVERSITY SCHOOL user on 02 December 2020remissions are ongoing at a median of 6 months (range, 6 to 11). Onepatient with complete remission relapsed after 11 months and wasalive at last follow-up (122 months), whereas the patient achievinga partial remission subsequently died because of progressivelymphoma. Six out the 7 patients not achieving a CR expired ata median of 5 months (range, 1 to 9) after CAR therapy. None of the2 patients receiving dual-antigen targeting CARs (targeting CD19/CD22 and CD19/CD20) achieved a response. All 4 patients withunknown CD19 expression status after loncastuximab tesirine achieveda complete remission with anti-CD19 CAR T-cell therapy, making itunlikely that these patients had relapsed with a CD19-negative disease.This is the first report, to our knowledge, evaluating the efficacy ofanti-CD19 CAR T-cell therapy after anti-CD19 immunotherapy. Inthis series of 14 cases, favorable outcomes of CAR T-cell therapy(ORR 5 50%) were seen in patients with relapsed/refractoryDLBCL after anti-CD19–targeted treatment with a pyrrolobenzo-diazepine dimer–based ADCs. The toxicity profile of CAR treatmentin these subjects appears consistent with published data.5,6 CD19expression on DLBCL was reassessed in 10 patients after relapseor progression on loncastuximab tesirine treatment; no cases ofCD19 antigen-negative relapse were seen. We wish to acknowledgethat this report is limited by small sample size and retrospectivedesign. In conclusion, our report suggests that prior treatment withanti-CD19 ADCs in relapsed/refractory DLBCL does not precludesubsequent responses to anti-CD19CAR T-cell therapies. Additionaldata on the feasibility of CAR therapy in patients receiving CD19monoclonal antibodies and bispecific T-cell engagers are needed.Send data sharing requests to the corresponding author, MehdiHamadani (mhamadani@mcw.edu).Acknowledgment: This work is supported by the UniversityCollege London/University College London Hospitals BiomedicalResearch Center (K.M.A.).Contribution: B.T. and M.H. designed research, performed re-search, analyzed data, and wrote the paper; and P.F.C., K.M.A.,M.S., C.C.-S., B.S.K. and M.H. contributed patients, designed re-search, and critically reviewed and approved the manuscript.Conflict-of-interest disclosure: M.H. reports research support/funding from Takeda Pharmaceutical Company and SpectrumPharmaceuticals; consultancy fees from Incyte Corporation, ADCTherapeutics, Celgene, Pharmacyclics, Omeros, AbGenomics,Verastem, TeneoBio; and serves on speakers bureaus for SanofiGenzyme and AstraZeneca. P.F.C. reports research support/fund-ing from Genentech; consultancy fees from Genentech, KitePharmaceuticals, ADC Therapeutics, Kite Pharmaceuticals, Vera-stem, Amgen, and Bayer; and serves on the speakers bureau forCelgene. C.C.-S. reports research support from ADCT RhizenPharmaceuticals; serves as consultant/advisor for Servier, Novartis,Genenta Science srl, ADCT, Roche, Boehringer Ingelheim, andSanofi; and receives honoraria from Bristol-Myers Squibb, MerckSharp & Dohme, Janssen Oncology, and AstraZeneca. Theremaining authors declare no competing financial interests.ORCID profiles: C.C.-S., 0000-0003-3144-0124; B.S.K., 0000-0003-0459-6609; M.H., 0000-0001-5372-510X.Correspondence: Mehdi Hamadani, Division of Hematology andOncology, Medical College of Wisconsin, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226; e-mail: mhamadani@mcw.edu.References1. Non-Hodgkin Lymphoma - Cancer Stat Facts. SEER. https://seer.cancer.gov/statfacts/html/nhl.html. Accessed 25 September 2019.2. Sarkozy C, Sehn LH. Management of relapsed/refractory DLBCL.BestPract Res Clin Haematol. 2018;31(3):209-216.3. Hamadani M, Hari PN, Zhang Y, et al. Early failure of frontlinerituximab-containing chemo-immunotherapy in diffuse large B celllymphoma does not predict futility of autologous hematopoietic celltransplantation. Biol Blood Marrow Transplant. 2014;20(11):1729-1736.4. Jain T, Bar M, Kansagra AJ, et al. Use of chimeric antigen receptorT cell therapy in clinical practice for relapsed/refractory aggressiveB cell non-Hodgkin lymphoma: an expert panel opinion from theAmerican Society for Transplantation and Cellular Therapy. Biol BloodMarrow Transplant. 2019;25(12):2305-2321.5. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators.Tisagenlecleucel in adult relapsed or refractory diffuse large B-celllymphoma. N Engl J Med. 2019;380(1):45-56.6. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CART-cell therapy in refractory large B-cell lymphoma.N Engl J Med. 2017;377(26):2531-2544.7. Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphomadiagnosis and immunotherapy. Leuk Lymphoma. 1995;18(5-6):385-397.8. Jurczak W, Zinzani PL, Gaidano G, et al. Phase IIa study of the CD19antibody MOR208 in patients with relapsed or refractory B-cellnon-Hodgkin’s lymphoma. Ann Oncol. 2018;29(5):1266-1272.9. Kahl BS, Hamadani M, Radford J, et al. A phase I study of ADCT-402(loncastuximab tesirine), a novel pyrrolobenzodiazepine-basedantibody-drug conjugate, in relapsed/refractory B-cell non-Hodgkinlymphoma. Clin Cancer Res. 2019;25(23):6986-6994.10. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBDdimer-containing antibody drug conjugate targeting CD19-expressingmalignancies. Blood. 2018;131(10):1094-1105.11. Lee DW, Gardner R, Porter DL, et al. Current concepts in thediagnosis and management of cytokine release syndrome [publishedcorrection appears in Blood. 2015;126(8):1048]. Blood. 2014;124(2):188-195.DOI 10.1182/bloodadvances.2020002587© 2020 by The American Society of Hematology3852 COMMENTARY 25 AUGUST 2020 x VOLUME 4, NUMBER 16Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/16/3850/1759285/advancesadv2020002587.pdf by WASHINGTON UNIVERSITY SCHOOL user on 02 December 2020

CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy

https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=10809&amp;context=open_access_pubs

CD19 antibody-drug conjugate therapy in DLBCL does not preclude subsequent responses to CD19-directed CAR T-cell therapy

Abstract

Similar works

Full text

Available Versions

Digital Commons@Becker