Impact of high-risk cytogenetic signatures on clinical outcomes in children and young adult patients receiving CD19-targeted CAR-T therapy

Chimeric antigen receptor T-cell (CAR-T) therapy radically improves outcomes in children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) with 1-year relapse-free survival (RFS) rate can reach 60%
.

Although leukemia-associated genomic abnormalities are prognostic biomarkers at initial diagnosis, and genomic abnormalities that persist at disease relapse are associated with survival risk, the clinical significance of these abnormalities in new therapeutic approaches, such as CAR, is unclear.
-T cell therapy
.

Based on the current study, investigators have identified specific cytogenetic abnormalities that influence a patient's overall response to cytotoxic therapy as well as to specific chemotherapeutic agents
.

In the initial analysis of cases receiving CAR-T cell therapy, the investigators found that certain cytogenetic features lead to different clinical outcomes, but there are other preliminary data that contradict this finding
.

In conclusion, identifying common cytogenetic and genomic abnormalities is critical to the impact of clinical outcomes in patients receiving CAR-T cell therapy
.

Currently recognized cytogenetic and genomic abnormalities that contribute to poor prognosis include: KMT2A rearrangement (MLL rearrangement), Philadelphia chromosome positivity (Ph⁺), Philadelphia chromosome-like expression (Ph-like) gene fusions and mutations, Hypodiploidy and TCF3/HLF gene fusion by t(17;19)(q22;p13)
.

In order to determine whether the efficacy of CAR-T cell therapy targeting the CD19 antigen varies with the cytogenetic characteristics of B-ALL patients, some researchers have investigated R/R ALL patients receiving CAR-T cell drugs, tisagenlecleucel or huCART19.
The clinical outcomes of children and young adults with lymphoblastic lymphoma (LBL) or lymphoblastic lymphoma (LBL) were retrospectively analyzed, and these patients were risk stratified according to their cytogenetic features
.

Methods This retrospective study included patients aged 1-29 from 5 clinical trials of CAR-T cell therapy targeting the CD19 antigen (NCT016-26495, NCT02435849, NCT02374333, NCT02228096 and NCT02906371) or treated with tisagenlecleucel at the Children's Hospital of Philadelphia, USA Children and young adults with R/R ALL or LBL
.

The CAR-T cell drug most patients received was tisagenlecleucel (n=195), which contains the 4-1BB co-stimulatory domain; patients in the NCT02374333 trial (n=41) received huCART19, which contains anti-CD19 antibodies The scFv segment was humanized
.

This retrospective analysis excluded patients from the retreatment cohort of the NCT02374333 trial and patients who lacked information on the cytogenetic characteristics of leukemia (n=5)
.

The study ultimately included 231 patients
.

Eligible patients received lymphocyte depletion (LD) chemotherapy at the discretion of the attending physician prior to infusion
.

A total of 213 patients received LD chemotherapy.
The recommended drugs for LD chemotherapy were fludarabine (30 mg/m² daily for 4 days) and cyclophosphamide (500 mg/m² daily for 2 days)
.

All patients underwent bone marrow aspiration and biopsy after lymphodepleting chemotherapy and before CAR-T drug infusion, except for 23 patients who underwent disease staging assessment at enrollment and received bridging chemotherapy prior to infusion.
And minimal residual disease (MRD) was detected by multiparameter flow cytometry
.

Pre-infusion disease burden was determined based on the highest percentage of blasts among 3 assays: M1, <5% lymphoblastoid; M2, 5%-25% lymphoblastoid; and M3, >25% lymphoblastoid
.

Results Patient Baseline Characteristics A total of 231 patients were included in the study, of whom 74 (32%) were in the cytogenetic high-risk group: 25 (34%) KMT2A rearrangements, 18 (24%) Ph⁺, 19 ( 26%) Ph-like gene fusions and mutations, 8 (11%) hypodiploid and 4 (5.
4%) TCF3/HLF gene fusions; 28 (12%) were intermediate risk group: 10 (36%) ) Internal amplification of chromosome 21 (iAMP21), 10 (36%) IKZF1 deletions, and 8 (29%) TCF3/PBX1 gene fusions; 43 patients (19%) were in the low-risk group: 30 (70%) Hyperdiploidy, 13 patients (30%) had an ETV6/RUNX1 gene fusion; 86 patients (37%) had no abnormal features of the corresponding cytogenetic group and were classified as the non-informative group
.

There were differences in the gender and age of patients in different groups (P=0.
029 and P=0.
047), but there were no statistical differences in the distribution of other clinical characteristics, such as previous hematopoietic stem cell transplantation, the number of recurrences at referral, and the time of drug infusion.
Bone marrow disease burden
.

Fifteen patients (6.
5%) were diagnosed at <1 year of age, of whom 13 had KMT2A rearrangements, meeting the criteria for infantile ALL patients with KMT2A rearrangements
.

10% of patients had previously received belintuximab, which was more common in the high- and intermediate-risk groups compared with the low- and no-information groups (P=0.
040)
.

The specific characteristics are shown in Table 1
.

Table 1 Remission and relapse of patients The complete remission (CR) rate of all patients at 28 days after infusion was 94%, and there was no statistical difference in the CR rate among the 4 groups of patients: 93% (69/74) in the high-risk group, 93% in the middle The high-risk group was 86% (24/28), the low-risk group was 98% (42/43), and the no-information group was 97% (83/86)
.

The details are shown in Table 2
.

Table 2 The median follow-up time was 27 months, and there was no significant difference in the event-free survival (EFS) rate (P=0.
7755): the 2-year EFS rate in the high-risk group was 59% [95% CI, 48-73], and the 2-year EFS rate in the intermediate-risk group was 59% [95% CI, 48-73].
was 50% [95% CI, 33-76], 61% [95% CI, 45-83] in the low-risk group, and 56% [95% CI, 45-70] in the no-information group
.

The recurrence-free survival (RFS) rate was not statistically different between the 4 groups (P=0.
8112): the 2-year RFS rate was 63% [95% CI, 52-77] in the high-risk group and 59% [95%] in the intermediate-risk group CI, 40-86], 63% [95% CI, 47-84] in the low-risk group, and 55% [95% CI, 43-70] in the no-information group, as shown in Figure 1A
.

A separate analysis of specific cytogenetic abnormalities in high-risk patients showed no significant difference in RFS rates between KMT2A-rearranged (P=0.
1326) and Ph-like patients (P=0.
4037) compared with other patients, as shown in Figure 1B and Figure 1D
.

Ph⁺ ALL patients had improved RFS compared with other patients (P=0.
0211), with a 2-year RFS rate of 88% (95% CI, 74-100) compared with 57% (95%) in all other patients CI, 49-66), as shown in Figure 1C
.

The two-year RFS rate in 13 infants with KMT2A-rearranged B-ALL was 67%, as shown in Figure 1E
.

Figure 1.
Survival of patients There was no statistical difference in overall survival (OS) rate among the groups (P=0.
5488): the 2-year OS rate was 70% [95%CI, 60-82] in the high-risk group and 70% in the intermediate-risk group.
66% [95% CI, 50-87], 78% [95% CI, 66-93] in the low-risk group, and 79% [95% CI, 70-88] in the no-information group, as shown in Figure 2A
.

However, compared with other patients, patients with KMT2A rearrangement had a statistically lower survival rate (P=0.
0475), and the 2-year OS rate of patients with KMT2A rearrangement was 59% [95% CI, 42-82] , 76% [95% CI, 70-83] in other patients, as shown in Figure 2B
.

There was a trend toward improving overall survival in Ph⁺ B-ALL patients (P=0.
07954), with a 2-year OS rate of 88% [95%CI, 75-100] in Ph⁺ patients and 73% [95%CI] in other patients ,67-80], while there was no statistical difference between Ph-like patients and other patients, as shown in Figure 2C and Figure 2B
.

In addition, among 13 infants with KMT2A rearrangement, the 2-year OS rate was 62% [95% CI, 40-95], and the risk of all-cause mortality was increased 3.
6-fold (95% CI, 1.
04-12.
75; P=0.
0434).
, as shown in Figure 2E
.

 Figure 2 Research conclusion CAR-T cell drugs targeting CD19 antigen-huCART19 and tisagenlecleucel can make B-ALL or LBL patients achieve durable remission across cytogenetic groups.
The OS rate, RFS rate, and CR rate of patients in each risk group are similar
.

Relapsed/refractory patients with high-risk cytogenetic features, even including infants with KMT2A-rearranged B-ALL, had better 2-year RFS and OS rates
.

References Allison Barz Leahy, Kaitlin J.
Devine, Yimei Li, et al.
Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directedCAR T-cell therapy.
Blood.
2022 Apr 7;139(14): 2173-2185.
doi: 10.
1182/blood.
2021012727.
Reviewer: Quinta Typesetting: Youshi Execution: Youshi pokes "Read the original text", let's make progress together