【Blood Adv】CD19 CAR-T therapy for DLBCL patients without residual lymphoma is safe and effective

CD19 CAR-T

CD19 CAR-T cell therapy is a major breakthrough in the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), with data from pivotal trials and real-world practice demonstrating excellent efficacy
in these refractory patients.
However, CAR-T can also have unique toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and long-term cytopenias
.
Data suggest that pre-treatment disease burden correlates with toxicity and outcome after CAR-T cell therapy, but since CAR-T cell dynamics are affected by CAR binding to its target antigen, pre-treatment disease burden may be a prerequisite for CAR-T cell expansion, thus influencing treatment outcomes
.

In 2019, Bishop et al.
reported the outcome of tisagenlecleucel (tisa-cel) infusion in 7 patients without residual disease, and 5 patients (71%) remained in remission 1 year after treatment, and the peak and toxicity of CAR-T cell expansion were comparable to the original JULIET cohort, but the cases in this study were few and tisa-cel
was used alone.

Recently, "Blood Advances" reported the real-world data of 33 R/R DLBCL patients without residual disease at the time of CAR-T cell infusion analyzed by Professor Miguel-Angel Perales of Memorial Sloan Kettering Cancer Center, which can provide us with more insights
.

Study results

This retrospective multicenter analysis included adults ≥ 18 years of DLBCL who received commercially available CAR-T cell therapy (axi-cel or tisa-cel) at eight US academic centers with data collected from 01.
05.
2018 to 30.
06.
2021
。 Of the 364 patients who received CD19 CAR-T cell therapy during the study period, 33 received CD19 CAR-T cell therapy when the disease state was CR and there was no residual disease (9 axi-cel and 24 tisa-cel).

。 Table 1 shows baseline characteristics and details of 33 patients with a median age of 63.
8 years for which no disease was detected at CAR-T cell therapy, and indications for CAR-T cell therapy included 23 cases of R/R primary DLBCL, 5 cases of high-grade B-cell lymphoma (HGBL), and 6 cases of translational DLBCL
.

Of the 33 patients, 26 (78.
8%) had measurable disease at apheresis and achieved CR after bridging (systemic therapy n = 20, radiotherapy n = 4, and corticosteroid n = 2), and the remaining 7 patients who achieved CR before apheresis were high-risk disease (including 5 patients receiving multiple lines, 1 relapse after ASCT, and 1 not suitable for ASCT).

The median time from leukoapheresis to CAR-T cell infusion was 48 days, and the median time from pre-infusion PET-CT to CAR-T cell infusion was 14 days
.
Cleansing chemotherapy was administered according to the specific CAR-T drug label, and of the 24 patients receiving tisa-cel, 15 patients were given bendamustine, leaving 9 tisa-cel patients and all axi-cel-treated patients receiving fludarabine and cyclophosphamide
.
The proportion of patients with no residual disease at the time of infusion is lower and the median LDH before treatment is lower compared with those with detectable disease (Table 1).

CRS developed in 12 patients (36.
3%), including 5 of 9 axi-cel and 7 of 24 tisa-cel, with a median onset time of 3 days post-infusion and no ≥ grade 3 CRS events
.
Four patients received tocilizumab and two received standard-dose corticosteroids (≤40 mg/day dexamethasone or equivalent) for CRS
.
Two patients (6.
1%) developed ICANS requiring glucocorticoid therapy (grade 1 n = 1 and grade 4 n = 1, both axi-cel).

The incidence of CRS and ICANS was significantly reduced in patients without residual lymphoma on CAR-T cell therapy (Table 1).

It is important to note that the use of tisa-cel was significantly higher in patients without residual disease (72.
7 versus 40.
2 percent) compared with patients with disease, which may partly explain the difference between CRS and ICANS, as tisa-cel has a lower incidence of CAR-T toxicity than axi-cel, and axi-cel is more used in the residual disease patient cohort
in this study.

At day +100, 26 patients (78.
8%) were still in remission (3 relapsed within the first 30 days).

There were no dose-related deaths within the first 100 days, and the incidence of grade 3 long-term cytopenia (> 28 days) was low ≥ (3 patients ≥grade 3 neutropenia, 4 patients ≥grade 3 thrombocytopenia), only 1 patient (3%) developed grade 4 neutropenia and 2 patients (6%) developed grade 4 thrombocytopenia (requiring thrombopoietin receptor agonists).

At a median follow-up of 16 months at the time of data cut-off, 13 patients (39.
3%) had relapse, and a 1-year recurrence rate was 37.
3% (4 DLBCL, 1 HGBL).

Of the 13 patients who relapsed after CAR-T cell therapy, CD19 status was available at the time of relapse, including 6 patients
with CD19+ recurrence.
As of the last follow-up, 6 patients (18.
1%) had died, including disease progression in 5 patients and treatment-related MDS
in 1 patient.
The 1-year EFS and OS of the 33 patients without residual disease at the time of infusion were 59.
6% (and 81.
3%, respectively), which was significantly higher than that of patients with detectable disease on CAR-T cell infusion (Figure 1).

discuss

Although the number of patients in this report is relatively small, this is the largest study in this field to date, and it is also a real-world practice
.
This study confirmed that the safety and outcome of the use of CAR-T cells in patients with no disease detected at the time of infusion were excellent, and the survival of these 33 patients appeared to be better than that of patients with persistent disease during CAR-T cell infusion, highlighting the safety and efficacy
of pre-treatment disease burden that significantly affects CAR T cells.

The incidence of CRS and ICANS was low
in this study.
This study also suggests that significant disease burden at infusion is not a prerequisite for
CAR-T cell function.

A potential problem in treating patients with CR is that no antigen stimulation drives CAR T cell expansion, but CRS and ICANS were indeed observed in this study, suggesting that CAR T cells are expanded, which may be driven in part by residual normal B cells
.
In addition, while preclinical data suggest that optimal expansion of T cells in the setting of lymphopenia is driven by specific antigen recognition, T cells are also expanded in part by homeostatic proliferation
.
In this study, three cases of early recurrence after CAR T cell infusion could be explained by endogenous CAR T cell defects or other host-related factors
.

While the recommendations regarding bridging therapy in pivotal studies are very specific, real-world data show that clinicians are increasingly using bridging therapy, often chemoimmunotherapy
, in patients, including axi-cel recipients.
The potential benefit of bridging is reduced tumor burden, which may translate into higher efficacy and lower toxicity
.
However, patients may also develop complications associated with bridging therapy, which may delay treatment or even prevent them from continuing with CAR-T cell therapy, or increase tumor burden due to progression during bridging
.
Interpretation of bridging data may also be affected by selection bias, and patients without residual disease at infusion may be biologically distinct patient groups with a higher probability of performing well after treatment compared with patients with higher
disease burden.
A lower baseline disease burden may also provide an ideal effector-to-target ratio compared to patients with higher disease burden, whereas patients requiring bridging may have a highly proliferative disorder and are less likely to respond
to CAR T cells.
In conclusion, the exact role and/or benefit of bridging therapy, and the optimal bridging therapy, remains an open question
.

This review supports further exploration of CAR-T in patients with unmeasurable disease in prospective trials to better understand the impact of
CAR-T as consolidation therapy.

References

Wudhikarn K,et al.
Low toxicity and excellent outcomes in patients with DLBCL without residual lymphoma at the time of CD19 CAR T-cell therapy.
Blood Adv .
2022 Nov 10; bloodadvances.
2022008294.
doi: 10.
1182/bloodadvances.
2022008294.

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