The impact of CRS on CAR T-cell outcomes in patients with aggressive LBCL

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for aggressive large B-cell lymphoma (LBCL); however, it is often associated with adverse events, including the development of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. There are limited data regarding the impact of CRS development on CAR T-cell therapy efficacy and outcomes.¹

The Lymphoma Hub recently reported the impact of bridging therapy on CAR T-cell outcomes in patients with LBCL. Here, we summarize the article published by Bhaskar et al.¹ in Blood Advances on the impact of CRS on CAR T-cell outcomes in patients with aggressive LBCL.¹

Study design¹

This is a retrospective multicenter study that included patients aged ≥18 years with aggressive LBCL who received either axicabtagene ciloleucel or tisagenlecleucel across eight medical centers in the US.

The study outcomes included:

• progression-free survival (PFS), defined as time from CAR T-cell infusion until earliest marker of progression including disease progression, initiation of subsequent anticancer therapy, or death;
• overall survival (OS), defined as the time from CAR T-cell infusion to death from any cause; and
• complete response and overall response rates.

Results¹

Of the 351 patients who received CAR T cells, 74.4% developed CRS and the remaining 25.5% did not; 57.6% received axicabtagene ciloleucel and 42.5% received tisagenlecleucel. Baseline characteristics in patients with versus without CRS are summarized in Table 1.

Table 1. Baseline characteristics*

axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; IPI, international prognostic index; LDH, lactate dehydrogenase; tisa-cel, tisagenlecleucel; ULN, upper limit of normal. *Data from Bhaskar, et al.1
Characteristic, % (unless otherwise stated)	Patients with CRS (n = 261)	Patients without CRS (n = 90)	p value
Median age (range), years	61 (18–88)	65 (37–85)	0.005
Sex			0.895
Male	66	66.7
Female	34	33.3
Stage			0.893
I–II	19.5	18.9
III or IV	80.5	81.1
IPI score			0.226
1–2	46.6	54.5
≥3	53.4	45.5
Disease status			0.14
Primary refractory	37.6	21.8
Refractory	33.9	34.6
Relapsed	28.6	43.6
Bulky disease			0.330
Yes	18.4	13.5
No	81.6	86.5
CAR T-cell product			<0.001
Axi-cel	69.7	22.2	<0.001
Tisa-cel	30.3	77.8
Peak ferritin, >5000			<0.001
Yes	17.8	1.3
No	82.2	98.7
LDH>ULN			<0.001
Yes	62	36.9
No	32	63.1
Received steroids			<0.001
Yes	46.2	4.8
No	53.8	95.1
Received tocilizumab			<0.001
Yes	59.5	12.4
No	40.5	87.6
Received bridging therapy			0.227
Yes	65.3	72.4
No	34.6	27.6

Survival outcomes

At a median follow-up of 30 months, there were no significant differences in the PFS or OS between patients who developed CRS and those who did not.

• The median PFS for with vs without CRS was 5.89 and 5.99 months, respectively (p = 0.99).
• The median OS for with vs without CRS was 17.5 months and 26.6, respectively (p = 0.16).
• Univariate analyses showed that the CRS grade did not influence PFS or OS.

Multivariate analyses revealed that development of CRS, disease stage (Stage III-IV vs Stage I–II), disease status, or receipt of steroid treatments did not significantly impact PFS or OS; however, a peak ferritin level of >5000 within 28 days following CAR T-cell infusion, and lactate dehydrogenase before the start of lymphodepleting chemotherapy greater than the institutional upper limit of normal was significantly associated with a worse PFS or OS (p < 0.01). Moreover, the presence of bulky disease was significantly associated with a worse OS (p = 0.005), and receipt of bridging therapy was associated with a shorter PFS (p = 0.011).

Response rates and cytopenia analysis

At 30 days post CAR T-cell infusion, there was no difference in objective response rate (p = 0.081) and complete response rate (p = 0.155) between patients who developed CRS and those who did not (Figure 1), or across CRS severity (Figure 2). Further to this, the development of CRS within 28 days was significantly associated with cytopenia at Day 30 (p = 0.001); however, no association between CRS and cytopenia was observed at later time points.

CRR, complete response rate; CRS, cytokine release syndrome; ORR, overall response rate.
*Data from Bhaskar, et al.¹

 

CRR, complete response rate; CRS, cytokine release syndrome; ORR, overall response rate.
*Data from Bhaskar, et al.¹

Conclusion

This retrospective analysis showed that patients with aggressive LBCL treated with CD19-directed CAR T cells who develop CRS yield similar objective response, complete response, OS, and PFS outcomes to those who do not develop CRS. Similar to previous findings, the development of CRS was not shown to impact CAR T-cell efficacy; therefore, it is imperative not to discount CAR T-cells early in those who do not develop CRS, and the decision to initiate additional lymphoma-directed therapy post-CAR T-cell therapy should not be based on the development of CRS.

Although the development of CRS did not influence CAR T-cell outcomes, this study highlighted other factors that can impact survival outcomes, such as peak ferritin level of >5000 within 28 days of CAR T-cell infusion, lactate dehydrogenase greater than the upper limit of normal, presence of bulky disease, and receipt of bridging therapy.