TO THE EDITOR:
Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), with aggressive clinical behavior.1 Approximately 40% to 50% of DLBCL patients are refractory to or relapse after frontline chemoimmunotherapies.2 Management of relapsed/refractory DLBCL is challenging, and treatment options include salvage therapy followed by autologous hematopoietic cell transplantation (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 autologous hematopoietic cell transplantation or those with refractory disease.4 Axicabtagene ciloleucel and tisagenlecleucel are 2 anti-CD19 CAR T-cell treatments approved by the US Food and Drug Administration for relapsed/refractory DLBCL.5,6
The CD19 antigen is an attractive target for immunotherapy in B-cell non-Hodgkin lymphoma. It is expressed during B-cell development only after B-lineage commitment and is thus not present on hematopoietic stem cells.7 CD19 expression is lost during terminal plasma cell differentiation but maintained in hematologic B-cell malignancies.7 Several clinical trials using monoclonal antibodies,8 antibody-drug conjugates (ADCs),9 and bispecific T-cell engagers targeting the CD19 antigen are ongoing in B-cell non-Hodgkin lymphoma. Studies investigating CD19-directed CAR T-cell therapies in aggressive lymphomas frequently excluded patients previously treated with CD19 targeting immunotherapies. Hence, the feasibility and efficacy of anti-CD19 CARs in lymphoma patients with prior CD19-directed immunotherapies are not known. Loncastuximab tesirine is an ADC comprising a humanized anti-CD19 monoclonal antibody stochastically conjugated to a pyrrolobenzodiazepine dimer toxin, SG3199.10 A phase 1 first-in-human study of loncastuximab tesirine demonstrated encouraging clinical activity in patients with relapsed/refractory DLBCL,9 and a phase 2 study recently finished patient accrual (#NCT03589469).
We sought to evaluate the outcomes of anti-CD19 CAR T-cell therapy in relapsed, refractory DLBCL previously treated with CD19-directed immunotherapy. Adult (age ≥18 years) DLBCL patients were identified from 2 multicenter, open-label studies of loncastuximab tesirine (phase 1: #NCT02669017 and phase 2: #NCT03589469), who subsequently received anti-CD19 CAR T-cell therapy. This retrospective analysis was approved by the institutional review board. Deidentified patient data were collected in collaboration with 6 academic medical centers (US centers = 4; United Kingdom = 1; Italy = 1) involved in the loncastuximab tesirine trials. Cytokine release syndrome was graded using Lee et al 2014 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 loncastuximab tesirine 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 median age was 58.5 years (range, 27 to 86). Ten had de novo DLBCL (germinal center B-cell–like = 4; non–germinal center B-cell = 2; not known = 4), and 4 patients had DLBCL transforming from indolent histologies (marginal zone lymphoma = 1; follicular lymphoma = 1; nodular lymphocyte predominant Hodgkin lymphoma = 1). Five patients (36%) had a high-intermediate international prognostic index at the time of diagnosis. c-MYC gene rearrangement was identified in 3 patients (21%) (1 patient had triple-hit lymphoma), whereas c-MYC status was unknown in 3 patients (21%). The median interval between diagnosis of DLBCL and initiation of loncastuximab tesirine was 21.5 months (range, 6.8 to 258). These patients received a median of 2 cycles (range, 1 to 7) of loncastuximab tesirine. The antitumor response to loncastuximab tesirine in these 14 patients was as follows: 8 patients (57%) had refractory disease, 5 patients (36%) attained partial response, and 1 patient (7%) achieved a complete response (overall response rate [ORR] = 43%). All responding patients had progression of the disease before proceeding with CAR therapy.
Table 1.
Patient demographics and disease characteristics
| Patients (N = 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 subtype | |
| DLBCL* | 10 |
| Transformed DLBCL | 4 |
| IPI 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 of loncastuximab tesirine (range), mo | 21.5 (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 summarizes details of CAR T-cell therapy in these subjects. The median interval between loncastuximab tesirine and CAR T-cell therapy was 120 days (range, 22 to 600). Six patients received additional lines of therapy between loncastuximab tesirine and CAR T-cell treatment (median of 1 therapy line; range, 1 to 3). The CD19 expression was assessed by immunohistochemical staining on repeat biopsies in 10 patients (71%) in between loncastuximab tesirine and CAR administration. All 10 tested patients were positive for CD19 after ADC failure. This information was not available in 4 patients (29%). Before CAR T-cell administration, 13 patients had refractory or progressive disease, whereas 1 patient was in partial remission. All patients received standard lymphodepletion with fludarabine and cyclophosphamide before CAR T-cell therapy. The type of anti-CD19 CAR T-cell therapy received by the patients included axicabtagene ciloleucel (n = 5), tisagenlecleucel (n = 2), JCAR017 (n = 3), and investigational CARs targeting CD19 (n = 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 (n = 7; 50%). Grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS) was identified in 4 patients (29%), and only 1 patient had grade 4 ICANS. Following CAR therapy, the best response at 3 months included 6 patients (43%) with a complete response and 1 patient (7%) with a partial response (ORR = 50%). Seven patients had refractory disease following CAR therapy. Five of 6 complete remissions are ongoing at a median of 6 months (range, 6 to 11). One patient with complete remission relapsed after 11 months and was alive at last follow-up (+22 months), whereas the patient achieving a partial remission subsequently died because of progressive lymphoma. Six out the 7 patients not achieving a CR expired at a median of 5 months (range, 1 to 9) after CAR therapy. None of the 2 patients receiving dual-antigen targeting CARs (targeting CD19/CD22 and CD19/CD20) achieved a response. All 4 patients with unknown CD19 expression status after loncastuximab tesirine achieved a complete remission with anti-CD19 CAR T-cell therapy, making it unlikely that these patients had relapsed with a CD19-negative disease.
Table 2.
CAR T-cell therapy in DLBCL patients failing CD19-directed treatment
| Patients (N = 14) | |
|---|---|
| CD19 expression on lymphoma cells after loncastuximab tesirine therapy, n (%) | |
| Positive | 10 (71) |
| Not checked | 4 (29) |
| Median interval between loncastuximab tesirine and CAR T-cell therapy (range), d | 120 (22-600) |
| Additional therapy between loncastuximab tesirine and CAR 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 included radiation alone (n = 3), radiation, ifosphamide/vinblastine/etoposide (n = 1), radiation; rituximab/methotrexate (n = 1), lenalidomide, anti-CD47 antibody, ibrutinib (n = 1).
One patient each received a CD19/CD22-directed CAR, and a CD19/CD20-directed CAR. Neither patient responded to CAR treatment.
This is the first report, to our knowledge, evaluating the efficacy of anti-CD19 CAR T-cell therapy after anti-CD19 immunotherapy. In this series of 14 cases, favorable outcomes of CAR T-cell therapy (ORR = 50%) were seen in patients with relapsed/refractory DLBCL after anti-CD19–targeted treatment with a pyrrolobenzodiazepine dimer–based ADCs. The toxicity profile of CAR treatment in these subjects appears consistent with published data.5,6 CD19 expression on DLBCL was reassessed in 10 patients after relapse or progression on loncastuximab tesirine treatment; no cases of CD19 antigen-negative relapse were seen. We wish to acknowledge that this report is limited by small sample size and retrospective design. In conclusion, our report suggests that prior treatment with anti-CD19 ADCs in relapsed/refractory DLBCL does not preclude subsequent responses to anti-CD19 CAR T-cell therapies. Additional data on the feasibility of CAR therapy in patients receiving CD19 monoclonal antibodies and bispecific T-cell engagers are needed.
Acknowledgment:
This work is supported by the University College London/University College London Hospitals Biomedical Research Center (K.M.A.).
Footnotes
Send data sharing requests to the corresponding author, Mehdi Hamadani (mhamadani@mcw.edu).
Contribution: B.T. and M.H. designed research, performed research, 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 research, and critically reviewed and approved the manuscript.
Conflict-of-interest disclosure: M.H. reports research support/funding from Takeda Pharmaceutical Company and Spectrum Pharmaceuticals; consultancy fees from Incyte Corporation, ADC Therapeutics, Celgene, Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio; and serves on speakers bureaus for Sanofi Genzyme and AstraZeneca. P.F.C. reports research support/funding from Genentech; consultancy fees from Genentech, Kite Pharmaceuticals, ADC Therapeutics, Kite Pharmaceuticals, Verastem, Amgen, and Bayer; and serves on the speakers bureau for Celgene. C.C.-S. reports research support from ADCT Rhizen Pharmaceuticals; serves as consultant/advisor for Servier, Novartis, Genenta Science srl, ADCT, Roche, Boehringer Ingelheim, and Sanofi; and receives honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, and AstraZeneca. The remaining authors declare no competing financial interests.
Correspondence: Mehdi Hamadani, Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Suite C5500, Milwaukee, WI 53226; e-mail: mhamadani@mcw.edu.
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