Following promising results in clinical trials, the CD19-targeted chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) received approval by the European Medicines Agency for the treatment of relapsed/refractory (R/R) large B-cell lymphoma. However, data is needed regarding their safety and efficacy in real-world settings.

During the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Wolfgang Bethge presented the first outcome analysis of real-world data from Germany on the use of axi-cel and tisa-cel as standard of care (SoC) in patients with R/R large B-cell lymphoma,¹ which won the Jian-Jian Luan abstract award. The results were compared with the pivotal ZUMA-1 (NCT02348216)² and JULIET (NCT02445248)³ studies, and a summary is provided here.

Study design

Adult patients with B-cell lymphoma who were treated with SoC CAR T-cell therapy between August 2018 and February 9, 2021 at 18 centers in Germany, and who submitted data into the German Registry for Stem Cell Transplantation (DRST), were included. Patients treated within clinical trials or who had received treatment with a non-approved CAR T-cell product were not eligible. Outcomes of interest were:

Overall survival (OS)
Progression-free survival (PFS)
Non-relapse mortality (NRM)
Incidence and grade of cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS)

Patients

Characteristics of the 267 eligible patients in the registry, alongside those in the ZUMA-1 (axi-cel) and JULIET (tisa-cel) studies, are summarized in Table 1. Of note, the real-world tisa-cel cohort had a higher International Prognostic Index score (IPI; p = 0.011), higher Eastern Cooperative Oncology Group performance status (ECOG PS; p = 0.048), and a greater proportion of patients who had undergone prior stem cell transplant (p = 0.0005) or required bridging therapy (0.011) than the axi-cel cohort. Median follow-up time was short, at seven months (range, 1–24 months).

Table 1. Patient characteristics¹

Characteristic	DRST		Clinical trials
Characteristic	Axi-cel (n = 137)	Tisa-cel (n = 130)	ZUMA-1 (axi-cel) (n = 101)	JULIET (tisa-cel) (n = 111)
Median age, years (range)	59 (20–83)	61 (19–83)	58 (23–76)	56 (22–76)
Male, %	69	62	67	61
Diagnosis, n DLBCL PMBCL tFL/Other	124 9 4	128 1 1	77 8 16	88 0 23
IPI ≥ 3, %	47	63	48*	61^†
ECOG PS ≥ 2, %	7	16	0	0
Elevated LDH at lymphodepletion, %	72	70	—	—
≥ 3 previous lines of treatment, %	80	79	69	52
Bridging therapy, %^‡	72	85	0	92
Prior HSCT, %	10	27	21	49
Refractory to last treatment line, %	85	73	77	55
axi-cel, axicabtagene ciloleucel; DLBCL, diffuse large B-cell lymphoma; DRST, Deutsches Registry for Stem Cell Transplantation; ECOG PS, Eastern Cooperative Oncology Group performance status; HSCT hematopoietic stem cell transplant; IPI, International Prognostic Index; LDH, lactate dehydrogenase; PMBCL, primary mediastinal B cell lymphoma; tFL, transformed follicular lymphoma; tisa-cel, tiagenlecleucel. *IPI 3–4. ^†IPI 2–4. ^‡Between apheresis and initiation of lymphodepletion, included steroids, radiochemotherapy, radioimmunotherapy, immunotherapy, radiotherapy, chemotherapy, and chemoimmunotherapy.

Key findings

Safety

Comparative safety outcomes are given in Table 2. Overall, CRS and ICANS of any grade were reported in 68% and 30% of registry patients, respectively. Both were more common with axi-cel treatment than with tisa-cel (CRS, p = 0.0001; ICANS, p = 0.0035). However, the incidence of Grade 3–4 CRS and ICANS was comparable between treatments. The rate of NRM was 7% overall, with several cases of infections after 12 months. Admission to intensive care was necessitated in 21% of patients (n = 57).

Table 2. Comparison of safety outcomes between patients in the German registry and those included in the ZUMA-1 and JULIET trials¹

Outcome, %	DRST		Clinical trials
Outcome, %	Axi-cel	Tisa-cel	ZUMA-1 (axi-cel)	JULIET (tisa-cel)
CRS Any grade 1–4 Grade ≥ 3	79 10	57 11	93 13	58 22
ICANS Any grade 1–4 Grade ≥ 3	41 13	22 7	67 32	21 12
NRM	9	5	4	0
axi-cel, axicabtagene ciloleucel; DRST, Deutsches Registry for Stem Cell Transplantation; CRS, cytokine release sydrome; ICANS, immune effector cell‐associated neurotoxicity syndrome; NRM, non-relapse mortality; tisa-cel, tisagenlecleucel.

Efficacy

Overall response rate was lower in patients treated with tisa-cel (46%) compared to axi-cel (77%), similar to the results from the JULIET (52%) and ZUMA-1 (82%) studies. Overall, fewer patients achieved a complete response (CR) compared to the clinical trials (Table 3) and, at one year, OS was 52% and PFS was 25%. Furthermore, PFS was reduced in patients treated with tisa-cel (15%) compared to axi-cel (34%; p = 0.0090) and was lower in both real-world cohorts than the clinical trials. Subgroup analysis revealed a higher IPI score (p = 0.0377), failure to achieve CR (p < 0.0001), and elevated lactate dehydrogenase (LDH; p = 0.0112) were all associated with worse PFS.

Table 3. Comparison of efficacy outcomes¹

Outcome	DRST	Clinical trials
Outcome	DRST	ZUMA-1 (axi-cel)	JULIET (tisa-cel)
ORR, %	62	82	52
Best response, % CR PR SD PD	33 29 12 26	54 28 11 5	40 12 15 26
axi-cel, axicabtagene ciloleucel; DRST, Deutsches Registry for Stem Cell Transplantation; CR; complete response; ORR, overall response rate; PD, progressive disease; PR; partial response; SD, stable disease; tisa-cel, tisagenlecleucel.

Multivariate analyses of the registry data revealed that the following were independent prognostic factors for PFS:

CAR T-cell construct used (HR, 0.603; 95% CI, 0.447–0.813; p = 0.001)
LDH level at start of lymphodepletion (HR, 1.541; 95% CI, 1.089–2.181; p = 0.015)
Karnofsky performance status (HR, 0.990; 95% CI, 0.980–0.9999; p = 0.048)

Similarly, significant factors contributing to OS were:

CAR T-cell construct (HR, 0.576; 95% CI, 0.385–0.862; p = 0.007)
CRS grade (HR, 1.440; 95% CI, 1.187–1.747; p < 0.001)
Karnofsky performance status (HR, 0.977; 95% CI, 0.965–0.989; p < 0.001)

Conclusion

Although follow-up was limited, real-world data from Germany on the use of SoC CAR T-cell therapy in large B-cell lymphoma suggest a similar safety profile to that observed in clinical trials. However, the efficacy in this setting appears to be inferior, particularly for patients treated with tisa-cel. The authors suggested that this may be due to a higher proportion of patients with unfavorable features in the real-world cohort, such as LDH, IPI, ECOG PS, and need for bridging therapy. They also highlighted that the rate of relapse and deaths due to late toxicity warrant further investigation.

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