Children and adolescents with R/R ALL welcome new hope for cure, and long-term follow-up data reveals that CAR-T therapy bridges the survival of Allo-HSCT

Chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has shown impressive early response rates in relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), but currently The long-term follow-up data available are limited.

Tisagenlecleucel is a CAR-T cell product that targets CD19.
The results of a global phase II clinical trial for children and adolescents (CAYAs) with R/R B-ALL patients showed that on the 28th day after Tisagenlecleucel infusion, the patient’s The complete remission (CR) rate is as high as 82%.

When the median follow-up time was 13.
1 months, only 59% of patients who obtained CR were still in CR status, and most patients relapsed in the form of CD19 negative.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) can improve the long-term time-free survival (EFS) rate of patients with R/R B-ALL remission after chemotherapy.

However, the role of CAR-T cell therapy bridging Allo-HSCT in R/R B-ALL patients is currently unclear, and there are also certain differences in clinical practice in different institutions.

Professor Nirali N.
Shah and others conducted a phase I clinical study to evaluate the efficacy and safety of autologous CD19 CAR-T cells in CAYAs R/R B-ALL patients, and recently reported the longest follow-up time so far.
Long, the results of the study on the treatment of CAYAs R/R B-ALL with CD19 CAR-T cell therapy.

01 Research method The research was carried out in the Pediatric Oncology Branch of the National Cancer Institute (NCI), using CD19 CAR-T cell therapy to treat CAYAs (3-30 years old) R/R B-ALL patients in a single center, I Phase escalation study.

02 Results of the study The final analysis of 50 R/R B-ALL patients in this study, the median age of patients receiving CAR-T cell therapy was 13.
5 years (range: 4.
3-30.
4 years).

Cytokine Release Syndrome (CRS) occurred in 35 patients (70.
0%), of which 9 patients (18.
0%) were grade 3-4.

The severity of CRS is related to the disease burden of patients receiving CAR-T cell therapy.

The CR rate of 50 patients with R/R B-ALL was 62.
0%, and the negative rate of MRD detected by flow cytometry among the patients with CR reached 90.
3%.

Further analysis showed that CR obtained by patients receiving CAR-T cell therapy is related to a higher expansion ratio of CAR-T cells and the incidence of grade 3-4 CRS.

Compared with the non-FC regimen, fludarabine/cyclophosphamide (FC) used for pretreatment of CAR-T cells can improve the CR rate of patients (69% vs 25%, P=0.
041).

When the median follow-up time was 4.
8 years (range 3.
5-7.
2 years), the overall median overall survival (OS) of the patients was 10.
5 months (95% CI, 6.
3-29.
2 months).

The median EFS was 3.
1 months (95% CI, 0.
9-7.
7 months), the EFS rate at 3 months was 52.
0% (95% CI, 37.
4-64.
7), and the EFS rate at 6 months was 38% (95%).
CI, 24.
8-51.
1).

Compared with the non-FC regimen, the pretreatment regimen of CAR-T cell treatment can improve the patient's EFS and OS.

Of the 28 patients who reached MRD negative after CAR-T cell therapy, 21 patients (75%) were subsequently bridged to Allo-HSCT consolidation therapy, and 4 patients received Allo-HSCT for the second time.

The median time for patients from receiving CAR-T cell infusion to Allo-HSCT was 54 days.

All patients undergoing Allo-HSCT for the first time use a myeloablative pretreatment regimen.

The median OS of patients receiving Allo-HSCT was 70.
2 months (95% CI, 10.
4 months-cannot be estimated); the median DFS was not reached; the cumulative recurrence rate at 24 months after Allo-HSCT was 9.
5% (95% CI, 1.
5-26.
8); the 5-year EFS rate after Allo-HSCT was 61.
9% (95% CI, 38.
1-78.
8).

In addition, 7 patients with R/R B-ALL who obtained CR after CAR-T cell therapy and reached MRD-negative did not receive Allo-HSCT consolidation therapy.
The median recurrence time of these patients was the first after CAR-T cell infusion.
152 days (range 94-394 days).

Of these 7 patients, 6 were because they had received Allo-HSCT before CAR-T cell therapy, and were worried about the side effects of the second Allo-HSCT; the other 1 was because of the presence of trisomy 21, which was not performed for the first time.
Allo-HSCT.

03 Study conclusions The study showed that autologous CD19 CAR-T cells bridged with Allo-HSCT consolidation therapy can provide a higher rate of durable disease control in CAYAs patients with R/R B-ALL.

In this study, patients observed significant long-term EFS after Allo-HSCT, with significant plateau and low recurrence rate, suggesting that bridging Allo-HSCT after CD19 CAR-T cell therapy can make most of the R/R B-ALL CAYAs patients were cured.

References: Nirali N Shah, Daniel W Lee, Bonnie Yates, et al.
Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL.
J Clin Oncol.
2021 Mar 25; JCO2002262 .
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