Role of bridging RT in relapsed/refractory diffuse large B-cell lymphoma undergoing CAR-T therapy: a multicenter study

doi:10.21203/rs.3.rs-3573162/v1

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Role of bridging RT in relapsed/refractory diffuse large B-cell lymphoma undergoing CAR-T therapy: a multicenter study

https://doi.org/10.21203/rs.3.rs-3573162/v1

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published 09 Oct, 2024

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The optimization of bridging regimen before chimeric antigen receptor (CAR)-T cell therapy in diffuse large B-cell lymphoma (DLBCL) may impact CAR-T efficacy and outcome. This retrospective study evaluates CAR-T outcome after bridging with radiotherapy (RT) and other bridging strategies. Among 148 patients with relapsed/refractory DLBCL who underwent leukapheresis for CAR-T manufacturing, 31 received RT-bridging, 84 chemotherapy (CT), 33 no-bridging or steroid-only. CAR-T cell were infused in 96.8% of RT-group. 89.2% of CT-group and 78.8% of no-bridge group (p = 0.079). Response to bridging was generally poor, but patients receiving RT had a significant reduction in LDH levels between pre- and post-bridging (p = 0.05). The one-year PFS was 51.2% in the RT group, 28.2% in the CT group, and 47.6% in the no-bridge group (p = 0.044); 1-year OS was 86.7% in the RT group, 52.7% in the CT group and 69% in the no-bridge group (p = 0.025). We observed a higher incidence of ICANS in patients who received CT than in others (20.0% CT group, 3.3% RT group, 7.7% no-bridge group; p = 0.05).

In conclusion, RT-bridging is associated with lower drop-out rate and CAR-T toxicity, and it might be preferred to other bridging strategies for patients with localized disease or for those with one prevalent symptomatic site.

Health sciences/Diseases/Cancer/Cancer therapy/Cancer immunotherapy

Health sciences/Diseases/Cancer/Haematological cancer/Lymphoma/Non-hodgkin lymphoma/B-cell lymphoma

In relapsed/refractory diffuse large B-cell lymphoma, RT-based bridge can be associated with reduced drop-out rate and CAR-T toxicity.

Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy is an effective treatment option for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).¹ CAR-T manufacturing and delivery usually requires 3–4 weeks. Because of the disease’s aggressive nature, in the period between lymphocyte collection and lymphodepleting chemotherapy (CT), DLBCL can be highly symptomatic or life-threatening, limiting the possibility of administering CAR-T infusion.² Therefore, a bridging regimen is required for most patients during the manufacturing of CAR-T to control disease progression and potentially reduce disease burden without adding toxicity, with the aim of bringing all the candidates to the CAR-T infusion. The bridging strategy is not standardized and ranges from steroids only to CT, targeted therapy, immunotherapy, or radiotherapy (RT).^3–5 The efficacy of the bridging regimen can significantly impact the efficacy and toxicity of CAR-T treatment.^6,7 Real-life registry data show that patients who do not need bridging therapy have a better outcome.⁸ Furthermore, a large disease volume is negatively associated with post-CAR-T progression-free survival (PFS) and is also a risk factor for cytokine-release syndrome (CRS).⁹ Therefore, strategy optimization for patients needing bridging therapy may be important to improve CAR-T efficacy and toxicity.⁸

CT-resistant, relapsed/refractory aggressive B-cell lymphomas may be sensitive to RT.^10–12 Preclinical data also suggest that RT can potentially enhance the efficacy of immunotherapy via antigen exposure (abscopal effect).^13,14 Moreover, using RT instead of drugs can minimize the impact on blood counts, organ function, and performance status of bridging therapy. However, comparative clinical data on RT versus CT as a bridging regimen to CAR-T are still scant.

Based on these premises, we retrospectively evaluated the potential impact of different bridging strategies in terms of efficacy and toxicity.

Setting and design

We retrospectively collected consecutive patient candidates for CAR-T treatment for relapsed/refractory DLBCL from September 2019 to April 2022 in a real-life setting. The enrolment was multicentric, involving three Italian referral centers: IRCCS Humanitas Research Hospital (Rozzano, Italy), IRCCS Fondazione Istituto Nazionale dei Tumori (Milan, Italy), and Istituto Seràgnoli Policlinico Sant’Orsola, Bologna, Italy.

The protocol was written, and the study was conducted according to the International Guideline for Good Clinical Practice. The protocol and its annexes were approved by the competent Independent Ethics Committees (“IEC”) of the enrolling Centers (ONC/OSS-18/2021, ICH-3068).

Patients

All patients diagnosed with DLBCL relapsed or refractory to at least two lines of therapy who underwent leukapheresis for CAR-T manufacturing (tisagenlecleucel (tisa-cel), or axicabtagene ciloleucel (axi-cel)) were included. Patients receiving CAR-T treatment within an investigational study were excluded.

Treatment

Bridging therapy is defined as any treatment (CT, RT, steroids, other) administered from the date after the apheresis to the start of lymphodepleting therapy. All patients received a lymphodepleting regimen according to the standard guidelines for any CAR-T product. The decision to treat a patient with a bridging regimen was made in case of symptomatic or rapidly progressive disease. Among the patients needing a bridge, the criteria for choosing RT alone over a CT-containing regimen were the presence of localized disease or disseminated disease with a main symptomatic site. The cohort was divided into three groups: patients who did not receive any bridge (no-bridge group), patients who received RT-based bridge alone (RT group), and patients who received any other CT-based bridge (CT group).

According to Lugano criteria, disease evaluation with CT/PET scan was performed after bridging therapy and CAR-T therapy at day + 30 and + 90 after infusion.¹⁵ Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were diagnosed and classified according to autologous stem cell transplantation (ASTCT) criteria¹⁶ and were managed according to local guidelines.

Objective and endpoints

The study’s objective was to evaluate the outcome of all patients who were candidates for CAR-T treatment across the three groups. Firstly, we analyzed the direct response to bridging therapy in terms of the treatment’s ability to ensure disease control during the manufacturing period. Subsequently, we comparatively analyzed PFS (defined as the time from CAR-T infusion to disease progression, death, or loss to follow-up, whatever occurred first) and overall survival (OS; defined as the time from CAR-T infusion to death or loss to follow-up, whatever occurred first) after CAR-T infusion in the different groups. Other endpoints were the incidence of CRS, ICANS, and infections after CAR-T infusion.

Statistical analysis

Data were summarized as frequencies and proportions or medians, and range and differences were estimated by the Chi-square test (the Fisher exact test when appropriate) for categorical variables. The Logistic regression methods were used to estimate the odds ratio and their corresponding 95% confidence intervals (CI) in univariate and multivariate analysis.

Survival curves were estimated by the Kaplan-Meier method, and the log-rank test assessed the differences between groups. The multivariate Cox model was used to estimate the hazard ratio (HR) and their corresponding 95% CI. Statistical significance was set at 0.05 level.

All analyses were performed using SAS version 9.4.

Study population

We enrolled 148 DLBCL patients (136 DLBCL, 12 transformed from low-grade B-cell lymphoma). Of them, 92 (62.2%) were males; the median age was 60 years (range 21–73) (Table 1). Most patients (60.1%) received two previous lines before CAR-T indication, 23.6% three previous lines, and 14.9% four or more lines. Only 14.2% had relapsed after responding to previous treatment, whereas most patients (85.8%) had a primary refractory disease. About one out of four patients (24.2%) had received ASCT. Double/triple-hit lymphoma was reported in 16.2% of cases.

Table 1

Patient characteristics at baseline.
		CT group (n = 84)	RT group (n = 31)	No-bridge group (n = 33)	Total (n = 148)
CAR-T	Infused	75 (89.2%)	30 (96.8%)	26 (78.8%)	131 (88.5%)
	Dead before infusion	8 (9.5%)	1 (3.2%)	5 (15.1%)	14 (9.5%)
	Alive but not infused	1 (1.3%)	-	2 (6.1%)	3 (2%)
Age	Mean (range)	58 (21–73)	57 (21–70)	60 (29–71)	58 (21–73)	p = 0.83
Sex	Male	49 (58.3%)	21 (67.7%)	22 (66.7%)	92 (62.2%)	p = 0.54
	Female	35 (41.7%)	10 (32.3%)	11 (33.3%)	56 (37.8%)
Diagnosis	DLBCL	77 (91.7%)	29 (93.5%)	30 (90.9%)	136 (91.9%)	p = 1 .00
	t-DLBCL	7 (8.3%)	2 (6.5%)	3 (9.1%)	12 (8.1%)
Previous lines	2	50 (59.5%)	20 (64.5%)	19 (57.6%)	89 (60.1%)	p = 0.44
	3	18 (21.4%)	8 (25.8%)	9 (27.3%)	35 (23.6%)
	4	9 (10.7%)	1 (3.2%)	0 (-)	10 (6.7%)
	5 or more	6 (7.1%)	2 (6.5%)	4 (12.1%)	12 (8.1%)
	Missing	1 (1.2%)		1 (3.0%)	2 (1.4%)
Double-hit phenotype	Yes	12 (14.3%)	10 (32.3%)	2 (6.1%)	24 (16.2%)	p = 0.02
	No	72 (85.7%)	21 (67.7%)	31 (93.9%)	124 (83.8%)
Double-expressor phenotype	Yes	22 (26.2%)	10 (32.2%)	9 (27.2%)	41 (27.7%)	p = 0.84
	No	41 (48.8%)	14 (45.2%)	16 (8.6%)	71 (48%)
	Not available	21 (25%)	7 (22.6%)	8 (24.2%)	36 (24.3%)
Stage at diagnosis	I	3 (4.8%)	1 (3.2%)	0 (-)	4 (2.7%)	p = 0.55¹
	II	14 (16.7%)	7 (22.6%)	3 (9.1%)	24 (16.3%)
	III	11 (13.1%)	4 (12.9%)	8 (24.2%)	23 (15.4%)
	IV	55 (65.5%)	19 (61.3%)	22 (66.7%)	96 (64.9%)
	Missing	1 (1.2%)			1 (0.7)
Relapsed/refractory to last treatment	Relapsed	11 (13.1%)	4 (12.9%)	6 (18.2%)	21 (14.2%)	p = 0 .76
	Refractory	73 (86.9%)	27 (87.1%)	27 (81.8%)	127 (85.8%)
Prior ASCT	Yes	19 (22.6%)	12 (38.7%)	5 (18.2%)	36 (24.3%)	p = 0 .08
	No	65 (77.4%)	19 (61.3%)	28 (81.8%)	112 (75.7%)
CAR-T product	Tisa-cel	61 (72.6%)	15 (48.4%)	17 (51.5%)	93 (62.8%)	p = 0.02
	Axi-cel	23 (27.4%)	16 (51.6%)	16 (48.5%)	55 (37.2%)
Stage at leukapheresis	I	2 (2.4%)	2 (6.5%)	0 (-)	4 (2.7%)	p = 0.77¹
	II	14 (16.7%)	5 (16.1%)	6 (18.2%)	25 (16.9%)
	III	13 (15.4%)	2 (6.5%)	6 (18.2%)	21 (14.2%)
	IV	55 (65.5%)	22 (70.9%)	21 (63.6%)	98 (66.2%)
Apheresis-to-infusion time	Median (range)	47 (21–96)	49 (21–96)	47 (30–80)	41 (31–90)
ECOG performance status	0	54 (64.3%)	25 (80.6%)	25 (75.7%)	104 (70.3%)	p = 0.17
	1	30 (35.7%)	6 (19.4%)	8 (24.3%)	44 (29.7%)
LDH at leukapheresis IU/L	Mean	425	325	330	383	p = 0.09³
LDH at lymphodepletion IU/L	Mean	405	254	329	356	p = 0.21³
	p value²	p = 0.42	p = 0.05	p = 0.84	p = 0.22
Ferritin at leukapheresis mg/dl	Mean	588	492	423	534	p = 0.34³
Ferritin at lymphodepletion mg/dl	Mean	734	713	750	733	p = 0.97³
	p value²	p = 0.12	p = 0.80	p = 0.01	p = 0.49
CRP at leukapheresis mg/dl	Mean	9.8	10.1	2.1	8.2	p = 0.09³
CRP at lymphodepletion mg/dl	Mean	11	8.8	6.5	9.6	p = 0.21³
	p value²	p = 0.69	p = 0.71	p = 0.03	p = 0.49
¹ p value for III-IV vs I-II
² paired t-test (pre-bridge vs post-bridge)
³ t-test between bridge groups

Thirty-one patients were treated with RT alone, 33 did not receive any bridge (or received steroid-only), and 84 received various drug combinations (Table 2). No differences across the study groups were disclosed in terms of baseline characteristics.

Table 2

Bridging strategies
Group	Type of bridge	N of patients
CT bridge	Chemo-immunotherapy	71
	Chemo-immunotherapy + local RT	8
	Lenalidomide	2
	Anti-CD3-CD20 bispecific andibody	2
	Anti-CD19 immunoconjugate	1
RT bridge	Single-site radiotherapy	31
	Mean dose: 28 Gy (Range 17,5–36 Gy)
	Mean n. of fractions: 11 (range 5–20)

Administration of CAR-T infusion

Of the 148 enrolled patients, 17 (11.5%) could not receive the infusion, and 131 (88.5%) underwent CAR-T therapy: 82 patients received tisa-cel and 49 axi-cel. CAR-T products were axi-cel for 37.2% of patients and tisa-cel for 62.8%.

The reasons for not receiving CAR-T were disease progression in 12 of 17 cases (70.5%), COVID-19 infection in three of 17 cases (17.5%), psychiatric disturbance in one of 17 cases (6%); one patient was not infused because of complete remission (CR) after bridging therapy.

The probability of receiving CAR-T infusion was 96.8% in the RT group (30/31), 89.2% in the CT group (75/84), and 78.8% in the no-bridge group (26/33), respectively (p = 0.079). Mortality among patients who did not receive CAR-T infusion was 82% (14/17), and the cause was disease progression in 12/14 cases, Covid19 in 2/14 cases.

Before CAR-T infusion, most patients (90%) in the no-bridge group (including steroid-only) showed disease progression. A disease evaluation after bridging therapy was available immediately before CAR-T infusion for 126 of 148 patients. Disease progression had a similar rate across the study groups (76.7% in the RT group, 73.7% in the CT group, and 90% in the no-bridge group; p = 0.332). The analysis of biomarkers, such as LDH, ferritin, and C-reactive protein (CRP), showed no statistically significant difference across the bridge groups. We observed a significant decrease in LDH between leukapheresis and post-bridging time within the RT group and a significant increase in ferritin and CRP levels in the group not receiving any bridge (Table 1).

CAR-T efficacy

At day 30 after CAR-T infusion, CR was achieved in 43.5% of patients: 50% of patients in the RT group, 38.7% of those in the CT group, and 50% of those in the no-bridge group (p = 0.469) [Table 3]. At day 90 after CAR-T infusion, CR was reached in 53.2% of evaluable patients (n = 109): 59.3% of patients in the RT group, 45.8% of those in the CT group, and 65.2% of those in the no-bridge group (p = 0.218 for CR vs no CR).

Table 3

Response at day 30 after CAR-T by group in 131 evaluable patients
Response	CT group n = 75 (col %)	RT group n = 30 (col %)	No-bridge group n = 26 (col %)	All infused n = 131 (col %)
CR	29 (38.7%)	15 (50%)	13 (50%)	57 (43.5%)
PR	15 (20%)	7 (23.3%)	4 (15.4%)	26 (19.8%)
SD	5 (6.7%)	1 (3.4%)	2 (7.7%)	8 (6.1%)
PD	25 (33.3%)	7 (23.3%)	7 (26.9%)	39 (29.8%)
NA	1 (1.3%)	-	-	1 (0.8%)
P value for CR vs no CR: 0.469

With a median follow-up of 17 months from leukapheresis, the 1-year PFS and OS of the entire cohort were 37.6% and 63.6%, respectively. One-year PFS was 51.2% in the RT group, 28.2% in the CT group, and 47.6% in the no-bridge group, while 1-year OS was 86.7% in the RT group, 52.7% in the CT group, and 69% in the no-bridge group, respectively (Figs. 1–2).

Multivariate analysis for factors associated with PFS and OS showed that the type of bridge (CT-based bridge vs RT-based bridge; p = 0.025, p = 0.044, respectively) and stage at leukapheresis (stage IV vs I–III; p = 0.003, p = 0.014, respectively) were associated with poorer outcome (Table 4). Performance status was significantly associated only with OS (ECOG 1 vs 0; p = 0.053) (Table 4). It should be considered that ECOG 2 before the CAR-T program, is an exclusion criterion of the Ministry of Health in Italy.

Table 4

Multivariate models for progression-free survival (PFS) and overall survival (OS).
Parameter	P value	Hazard ratio	Hazard Ratio (95% Confidence Limits)
Overall Survival
No-bridge vs RT-based bridge	0.391	1.46	0.62	3.45
CT-based bridge vs RT-based bridge	0.044	2.07	1.02	4.21
Stage at lymphodepletion IV vs I-III	0.014	2.19	1.17	4.09
Performance status 1 vs 0	0.053	1.69	0.99	2.87
Progression-free Survival
NO-bridge vs RT-based bridge	0.521	1.25	0.63	2.49
CT-based bridge vs RT-based bridge	0.025	1.90	1.09	3.32
Stage at lymphodepletion IV vs I-III	0.003	2.08	1.29	3.35

Toxicity

Table 5 shows the rate of infections, CRS, and ICANS after CAR-T. CRS occurred in 80.9% of the entire cohort (4.6%; grade 3–4). CRS incidence was not different between the groups (p = 0.92). ICANS occurred in 13.7% of patients. We observed a statistically significantly higher ICANS incidence in patients who received CT-based bridge than in others (20.0% in the CT group, 3.3% in the RT group, and 7.7% in the no-bridge group). In a multivariate model comparing RT with CT groups, axi-cel use (OR = 42.4; 95% CI: 4.0–447; p = 0.004), baseline basal ECOG PS 1 (OR = 33.3; 95% CI: 0.004–0.3; p = 0.004), and CT-based bridge use (OR = 25.1; 95% CI: 1.8–347.6; p = 0.016) were confirmed as independent negative predictive factors for ICANS. We observed no association between the probability of ICANS and the disease stage at the time of leukapheresis.

Table 5

Toxicity across the groups with different bridging therapy.
	CT group n = 75 N (%)	RT group n = 30 N (%)	No-bridge group n = 26 N (%)	All n = 131 N (%)	P value
Infections	15 (20%)	7 (23.3%)	2 (7.69%)	24 (18.3%)	p = 0.273
CRS	60 (80%)	25 (83.33%)	21 (80.77%)	106 (80.9%)	p = 0.926
CRS G 3–4	4 (5.33%)	1 (3.33%)	1 (3.85%)	6 (4.6%)	p = 1.00
ICANS	15 (20%)	1 (3.33%)	2 (7.69%)	18 (13.7%)	p = 0.056
ICANS G3-4	4 (5.33%)	0 (-)	1 (3.85%)	5 (3.8%)	p = 0.823
NRM	4 (5.3%)	1 (3.3%)	1 (3.8%)	6 (1.5%)	p = 0.848
CRS = cytokine release syndrome; ICANS = immune effector cell associated neurotoxicity syndrome; NRM = non-relapse mortality events.

In the entire cohort, 18.3% of patients had at least one infectious complication; no difference in the incidence of infections was disclosed.

Six cases of non-relapse mortality were reported: one in the RT group (COVID-19), one in the no-bridge group (second tumor), and four in the CT group (one COVID-19, one septic shock, two severe neurotoxicity).

In the present study, we compared different bridging strategies on a large cohort of relapsed/refractory DLBCL adult patients who were candidates to receive tisa-cel or axi-cel in a real-life setting. The retrospective nature of the study and the selection bias of bridging strategy can affect the interpretation of our data, given that the bridging regimen has been selected for each patient according to disease characteristics and performance status. Nevertheless, homogeneous criteria for choosing RT bridging were adopted for the whole cohort, consisting in the presence of a prevalent bulky or symptomatic disease, independently from disease stage. In fact, no significant difference in baseline stage and LDH level was observed between the three groups, as shown in Table 1. This finding suggests that the outcome may have not been directly determined by differences in disease distribution and burden.

The first relevant finding of our study was the very low drop-out rate (3.2%) among patients treated with RT as a bridge, compared with those receiving a CT-based regimen (10.2%), but also compared with those receiving no bridging therapy (21.2%). Furthermore, our data showed a better outcome for patients not receiving bridging therapy in terms of OS and PFS. On the other hand, among the patients who needed a bridge, the outcome in terms of PFS and OS was more favorable for the RT group than the other regimens.

Bridging success has been reported in previous real-world reports of DLBCL as strongly related to CAR-T outcome. In contrast, the advantage of RT seems unrelated to the direct response to the bridge.¹⁷ Indeed, we observed no difference in bridging failure between the groups.

Our data are in line with a retrospective study previously published on axi-cel by Pinnix et al, which showed a better outcome for patients not needing a bridge or those undergoing RT-based bridge than those receiving CT-based bridge.¹⁸ The study’s authors speculatively attributed the poorer outcome to a higher disease burden in patients needing bridging therapy for disease control.

Furthermore, the study of Pinnix et al. included only patients treated with axi-cel, known to be more frequently associated with ICANS (up to 64% of treated patients),¹⁹ and the authors did not report any difference in terms of CAR-T toxicity between the different bridging groups.¹⁸ Differently, we reported a significantly lower rate of ICANS among patients in the RT group than in the CT group (1/31 vs 15/75), although the proportion of patients treated with axi-cel was higher in the RT group than in the CT group (16/31 vs 23/75). At multivariate analysis, RT-based bridge significantly reduced the risk of ICANS independently from the type of CAR-T and the Ann Arbor disease stage at the time of lymphodepletion. Considering one of the most well-grounded pathogenic mechanisms of ICANS onset,²⁰ it could be speculated that exposure to additional (poly-)CT cycles only a few weeks before CAR-T infusion may lead to a higher risk of neuroinflammation by increasing blood–brain barrier (BBB) permeability^21,22 and facilitating the diffusion of proinflammatory cytokines in the brain; conversely, patients receiving RT regimen might be protected by ICANS. This study was not planned to verify this hypothesis; the prospective collection of biological data on BBB damage biomarkers before and after CAR-T infusion in the different bridging groups should be considered as a future project.

We also found that only in the RT group could the LDH level be reduced by bridging, whereas we observed no improvement in inflammatory biomarkers in the other bridging group. Biomarkers, such as LDH, are related to both disease burden and inflammatory status; current evidence strongly suggests that inflammatory biomarkers are associated with CAR-T efficacy and toxicity.^23,25 Consistent with a previous report,²⁶ we hypothesize that RT has a lower impact on inflammation and endothelial damage than other bridging strategies and that this mechanism may explain the apparent lower toxicity of CAR-T after RT.

The type of bridging therapy is only one of the multiple patients- and disease-related factors that can influence the final outcome of CAR-T, in addition to age, comorbidities, general conditions, disease volume, and systemic inflammatory status.^27–29 Because of limitations arising from the retrospective nature of this study and the bias given by the non-randomized choice of bridging regimen, our findings cannot be conclusive in guiding the selection of the best bridge for each patient. Nonetheless, in our study, the type of bridging therapy was significantly associated with the drop-out rate and CAR-T toxicity. RT can be seen as an effective strategy to maximize the probability of receiving and then tolerating CAR-T infusion.

Acknowledgments

Editorial assistance was provided by Luca Giacomelli, PhD, Valentina Attanasio and Massimiliano Pianta; this assistance was supported by internal funds.

Authorship contributions

SB, DM and AS designed the study. LG analysed the data. DM wrote the manuscript, with the revision and active contribution by SB, AS, PLZ and PC. CDP, DT, AC, BC, PN, MS, PM actively managed the patients and contributed in collecting the data.

Conflict of interest disclosure

None.

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The authors have declared there is NO conflict of interest to disclose.

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Role of bridging RT in relapsed/refractory diffuse large B-cell lymphoma undergoing CAR-T therapy: a multicenter study

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INTRODUCTION

PATIENTS AND METHODS

Setting and design

Patients

Treatment

Objective and endpoints

Statistical analysis

RESULTS

Study population

Administration of CAR-T infusion

CAR-T efficacy

Toxicity

DISCUSSION

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References

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