Real‐world treatment of large B‐cell lymphoma with chimeric antigen receptor T‐cell therapy after loncastuximab tesirine

Abstract

[...]there is limited data regarding the feasibility and efficacy of anti-CD19 CAR-T after prior CD19-directed treatment. Characteristic No. (%) No. of patients 16 No. of centers 15 Age at start of loncastuximab, median (range), years 63.2 (42.5–79.9) Male 12 (75) Race White 13 (81) Black or African American 1 (6) Asian 1 (6) Unknown 1 (6) Ethnicity Hispanic or Latino 4 (25) Not Hispanic or Latino 12 (75) Karnofsky performance score prior to CAR-T 90–100 4 (25) 80–90 5 (31) <80 5 (31) Not reported 2 (13) Sub-disease classification Transformed follicular 1 (6) DLBCLa 15 (94) Disease stage at diagnosis Stage I/II 3 (19) Stage III/IV 11 (69) Not reported 2 (13) IPI at diagnosis Low 1 (6) Low intermediate 3 (19) High intermediate 1 (6) High 2 (13) Not reported 9 (56) Prior HCT No 12 (75) Yes 4 (25) No. of prior lines of therapy, median (range)b 4 (2–7) Primary disease refractory to the first line of therapy No 7 (44) Yes 6 (38) Not assessed 3 (19) Lymphodepleting regimen Bendamustine 2 (13) Cyclophosphamide + fludarabine 12 (75) Cyclophosphamide + other 1 (6) Fludarabine 1 (6) Type of therapy in which loncastuximab was givenc Last line of therapy 5 (31) Bridging therapy 11 (69) Number of cycles of the line of therapy, median (range)d 1 (1-5) Disease status at CAR-T Refractory disease 10 (63) Sensitive relapsee 6 (38) Follow-up, median (range), months 24.2 (6.4–37.4) Patients largely received pre-CAR-T lonca bridging therapy (n = 11, 69%). In this small, observational, real-world study of 16 patients receiving post-lonca CAR-T, the overall response rate (ORR) was 63% among the overall population, 64% with lonca bridging therapy, and 60% with lonca as the last pre-CAR-T LOT. [...]our report suggests that treatment of patients with lonca prior to CAR-T infusion does not preclude subsequent responses to CD19-directed CAR-T therapy.

To the Editor,

The most common non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL) accounts for 30%–40% of new cases annually [1]. Although DLBCL is often curable, 30%–35% of patients have primary refractory disease or relapse following first-line chemoimmunotherapy [2, 3]. Expressed only after B-lineage commitment, the CD19 antigen is an attractive immunotherapy target in B-cell lymphomas since B-cell malignancies maintain expression, but not hematopoietic stem cells [1]. CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) revolutionized DLBCL treatment as a potentially curative option in second-line and beyond depending on the timing of treatment failure and prospective autologous hematopoietic cell transplantation (autoHCT). Three CD19-targeted CAR-Ts are Food and Drug Administration (FDA)-approved for the treatment of DLBCL: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel [4]. While CAR-T is effective, wider application is restricted by cost, manufacturing logistics, lack of effective bridging therapy, and limited access, highlighting the need for novel therapies. In April 2021, loncastuximab tesirine (lonca), a first-in-class CD19-directed antibody-drug conjugate, was FDA-approved for relapsed/refractory DLBCL after 2+ prior lines of systemic therapy.

CD19 antigen loss is an important mechanism of resistance to anti-CD19 CAR-T. Although the limited available evidence suggests that lonca does not cause CD19 antigen loss, studies investigating CD19-directed CAR-T in aggressive lymphomas frequently excluded patients with prior CD19-targeting immunotherapy. [1, 5]. Consequently, there is limited data regarding the feasibility and efficacy of anti-CD19 CAR-T after prior CD19-directed treatment. This study examined real-world treatment patterns and outcomes among patients in the United States who received lonca as either bridging therapy or the last line of therapy (LOT) prior to their first CAR-T infusion.

Adults (aged 18 and older) with DLBCL who received lonca as either bridging therapy or the last LOT before their first anti-CD19 CAR-T infusion during 2018–2022 were identified from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. CIBMTR is a research collaboration between the Medical College of Wisconsin and the National Marrow Donor Program. Approximately 360 medical centers worldwide submit clinical data to CIBMTR about HCT, CAR-Ts, and other cellular therapies; CIBMTR's Research Database includes long-term clinical data from > 675,000 patients.

Outcomes assessed included the response to lonca (i.e., complete remission [CR], partial remission [PR], stable disease/no response, and progressive disease), best response to CAR-T, progression-free survival (PFS), overall survival (OS), relapse/progression post-CAR-T, and cause of death. Kaplan-Meier estimates were provided for OS (death due to any cause constituted an event) and PFS at 12 months post-CAR-T. Cumulative incidence function estimates were provided for post-CAR-T relapse. All patients without events were censored at the last contact date.

Sixteen patients from 15 centers met the inclusion criteria; the median age was 63 years (range: 42–79 years); 75% (n = 12) were male; 81% (n = 13) were white, and 25% (n = 4) were Hispanic or Latino (Table 1). All patients had DLBCL at diagnosis, except for one patient initially diagnosed with follicular lymphoma. Stage III/IV disease was present in 69% (n = 11) of patients at diagnosis and 38% (n = 6) had primary disease refractory to their first LOT. A quarter (n = 4) of patients had a prior autoHCT.

TABLE 1 Patient demographic and clinical characteristics.

Characteristic	No. (%)
No. of patients	16
No. of centers	15
Age at start of loncastuximab, median (range), years	63.2 (42.5–79.9)
Male	12 (75)
Race
White	13 (81)
Black or African American	1 (6)
Asian	1 (6)
Unknown	1 (6)
Ethnicity
Hispanic or Latino	4 (25)
Not Hispanic or Latino	12 (75)
Karnofsky performance score prior to CAR-T
90–100	4 (25)
80–90	5 (31)
<80	5 (31)
Not reported	2 (13)
Sub-disease classification
Transformed follicular	1 (6)
DLBCLa	15 (94)
Disease stage at diagnosis
Stage I/II	3 (19)
Stage III/IV	11 (69)
Not reported	2 (13)
IPI at diagnosis
Low	1 (6)
Low intermediate	3 (19)
High intermediate	1 (6)
High	2 (13)
Not reported	9 (56)
Prior HCT
No	12 (75)
Yes	4 (25)
No. of prior lines of therapy, median (range)b	4 (2–7)
Primary disease refractory to the first line of therapy
No	7 (44)
Yes	6 (38)
Not assessed	3 (19)
Lymphodepleting regimen
Bendamustine	2 (13)
Cyclophosphamide + fludarabine	12 (75)
Cyclophosphamide + other	1 (6)
Fludarabine	1 (6)
Type of therapy in which loncastuximab was givenc
Last line of therapy	5 (31)
Bridging therapy	11 (69)
Number of cycles of the line of therapy, median (range)d	1 (1-5)
Disease status at CAR-T
Refractory disease	10 (63)
Sensitive relapsee	6 (38)
Follow-up, median (range), months	24.2 (6.4–37.4)

Patients largely received pre-CAR-T lonca bridging therapy (n = 11, 69%). Patients received a median of 1 cycle of lonca (range: 1–5) with a median duration of 43 days (first, third quartile [Q1, Q3]: 24, 43 days) for lonca bridging therapy and 57 days (Q1, Q3: 57, 91 days) with lonca as their last LOT. The distribution of best response to lonca overall was 13% CR, 25% PR, 6% stable disease/no response, 31% progressive disease, and 25% not assessed (Table 2). The best response to lonca bridging therapy was 9% CR, 18% PR, 9% stable disease/no response, 27% progressive disease, and 36% not assessed; and 20% CR, 40% PR, and 40% progressive disease for lonca as the last LOT. The median duration from the end of lonca treatment to CAR-T infusion was 16 days (range: 1–257).

TABLE 2 Time to treatment and treatment outcomes.

	Lonca therapy type
Last LOT N = 5	Bridging N = 11	Total N = 16
Time from apheresis to CAR-T, days
Mean (SD)	29.4 (3.4)	39.0 (22.8)	36.0 (19.2)
Median (Q1, Q3)	28 (27–33)	33 (28–40)	31 (28–35)
Range	26–33	23–104	23–104
Time from end of loncastuximab therapy to CAR-T, days
Mean (SD)	146.8 (122.2)	22.7 (29.0)	61.5 (89.8)
Median (Q1, Q3)	211 (28–237)	13 (6–28)	17 (7–74)
Range	1–257	1–100	1–257
Response to loncastuximab line of therapy, no. (%)
Complete remission	1 (20)	1 (9)	2 (13)
Partial remission	2 (40)	2 (18)	4 (25)
No response/stable disease	0 (0)	1 (9)	1 (6)
Progressive disease	2 (40)	3 (27)	5 (31)
Not assessed	0 (0)	4 (36)	4 (25)
The best response to CAR-T, no. (%)
Complete remission	3 (60)	4 (36)	7 (44)
Partial remission	0 (0)	3 (27)	3 (19)
No response/stable disease	1 (20)	2 (18)	3 (19)
Progressive disease	1 (20)	2 (18)	3 (19)

Patients received a median of 4 pre-CAR-T infusion LOTs (range: 2–7). All patients received axicabtagene ciloleucel. Median post-CAR-T follow-up was 24.2 months (range: 6.4–37.4 months). The distribution of best response to CAR-T overall was 44% CR, 19% PR, 19% stable disease/no response, and 19% progressive disease. The best response to CAR-T with lonca bridging therapy was 36% CR, 27% PR, 18% stable disease/no response, and 18% progressive disease; and 60% CR, 0% PR, 20% stable disease/no response, and 20% progressive disease with lonca as the last LOT. Median CAR-T duration of response was 162 days (range: 47–1044).

Among the overall population, the 1-year post-CAR-T OS was 33% (95% confidence interval [CI]: 11.8–59.4), PFS was 28% (95% CI: 8.4–53.9), and the cumulative incidence of relapse/progression was 56% (95% CI: 31.0–79.9). Patients with lonca bridging therapy had a 1-year post-CAR-T OS of 15% (95% CI: 0.1–47.9) and a 64% (95% CI: 32.0–89.8) cumulative incidence of relapse/progression; PFS was not estimable. Among patients with lonca as their last LOT, 1-year post-CAR-T OS was 60% (95% CI: 18.7–94.0), PFS was 60% (95% CI: 18.7–94.0), and the cumulative incidence of relapse/progression was 40% (95% CI: 3.4–85.8). The primary causes of death were primary disease (n = 8, 50%), infection (n = 2, 13%) and organ failure not due to graft-versus-host disease (n = 1, 6%).

In this small, observational, real-world study of 16 patients receiving post-lonca CAR-T, the overall response rate (ORR) was 63% among the overall population, 64% with lonca bridging therapy, and 60% with lonca as the last pre-CAR-T LOT. In comparison, two other studies of patients who received post-lonca CAR-T reported ORRs of 50% and 47% among 14 and 15 patients, respectively [5, 6]. This lower ORR may be due to the sequencing of treatment; in one study, six of the 14 patients had other LOTs between their lonca and CAR-T LOTs [5]. Inherent limitations of observational, voluntary databases include potentially incomplete reporting of data and selection bias in reporting from centers. Another limitation is the small sample size in this report, which can make confidence intervals of outcomes wide or unstable. Although real-world registries such as CIBMTR collect safety data, there is the potential for incomplete reporting of post-CAR-T toxicity information. In conclusion, our report suggests that treatment of patients with lonca prior to CAR-T infusion does not preclude subsequent responses to CD19-directed CAR-T therapy. These post-lonca CAR-T responses may be due to differential targeting of CD19 epitopes; CD19-targeted CAR-Ts bind the FMC63 epitope of CD19 while loncastuximab was designed to target the RB4 epitope [7]. Studies in a large patient population are warranted to confirm the findings.

AUTHOR CONTRIBUTIONS

All authors participated in the research design, analysis, and results interpretation of this study. All authors critically reviewed and approved the manuscript.

ACKNOWLEDGMENTS

Medical writing and editorial support, provided by Grace Lin of Novosys Health (Green Brook, NJ, USA), was funded by ADC Therapeutics SA and Sobi.

CONFLICT OF INTEREST STATEMENT

Mehdi Hamadani has received research support/funding from ADC Therapeutics, Spectrum Pharmaceuticals, and Astellas Pharma; has served as a consultant for ADC Therapeutics, Omeros, CRISPR, BMS, Kite, Abbvie, Caribou, and Genmab; and served on a speaker's bureau for ADC Therapeutics, AstraZeneca, BeiGene, and Kite. Melanie Lucero and Lei Chen were employees of ADC Therapeutics at the time the study was conducted and own stock. Jakob D. DeVos has no competing financial interests.

FUNDING INFORMATION

This study was funded by ADC Therapeutics SA and partially funded by Sobi.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions.

ETHICS STATEMENT

This study was approved by the National Marrow Donor Program Institutional Review Board.

PATIENT CONSENT STATEMENT

This study was conducted in accordance with the Declaration of Helsinki. All patients gave their informed consent to participate in this study and permitted the use of the patient data in this publication.

CLINICAL TRIAL REGISTRATION

The authors have confirmed clinical trial registration is not needed for this submission.

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