Determining factors of relapse after CAR-T therapy in patients with relapsed and refractory acute B lymphocytic leukemia

Clinical outcomes in children, adolescents, and young adults (AYAs) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have improved significantly since the use of risk-stratified multidrug combination chemotherapy, with long-term overall survival in pediatric patients (OS) rate of 90%, and OS rate of 70% in young adult patients
.

However, there are still some patients who will experience relapse or refractory treatment, and patients with early bone marrow (BM) relapse (<18 months), relapse after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) or refractory after salvage therapy have extremely poor outcomes
.

In pediatric patients, the OS rate decreased from approximately 40% after the second salvage therapy to <20% after the third salvage therapy
.

In recent years, the advent of CAR-T immune cell therapy has brought new hope to these patients
.

Tisagenlecleucel, a CD19-targeted CAR-T cell therapy, has shown promising clinical efficacy in children with R/R BCP-ALL and patients with AYAs in previous studies; however, 30-50% of patients still face relapse
.

The factors associated with recurrence of CD19-positive (pos) and CD19-negative (neg) patients after Tisagenlecleucel treatment are currently unclear
.

Based on this, some researchers analyzed the related factors of CD19pos and CD19neg recurrence after Tisagenlecleucel treatment of R/R BCP-ALL patients
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Methods: This prospective cohort study included 51 pediatric and AYA R/R B-ALL patients receiving Tisagenlecleucel infusion
.

Tisagenlecleucel infusion is given on days 2-14 after lymphodepleting chemotherapy (LD) based on fludarabine (30 mg/m2/d for 4 days) and cyclophosphamide (500 mg/m2/d for 2 days)
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Bridging therapy is given at the discretion of the doctor
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Cytokine release syndrome (CRS) and neurologic events were retrospectively graded according to the American Society for Transplantation and Cell Therapy consensus
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B-cell aplasia (BCA) was monitored monthly for the first 3 months and then every 3 months until 12 months after Tislecagenleucel infusion
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ORR was defined as the best overall response rate, the probability of complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) at day 28, as assessed by blood, BM laboratory findings, and optional cerebrospinal fluid analysis
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Early failure was defined as the absence of CR/CRi or the presence of CR/CRi with detectable minimal residual disease (MRD)
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Study Results 1 Patient and Disease Characteristics A total of 56 eligible patients received apheresis in the study between April 2016 and December 2019, and ultimately 51 patients received Tisagenlecleucel infusion, ranging from apheresis to infusion.
Bit time is 67 days (range: 41-162 days)
.

At the time of infusion, the median patient age was 17 years (range: 1-29.
2 years), and the median number of prior lines of therapy was 3 (range: 1-6 lines)
.

Rearrangements defined as KMT2A, t(17;19)/TCF3-HLF, t(1;19)/TCF3-PBX1, haplotype/hypodiploidy (<44 chromosomes) or high-risk gene mutation signatures for TP53 mutations
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The most common genetic subgroups were as follows: Ph-positive or Ph-like (7 patients/2 patients), t(12;21)/ETV6-RUNX1 (7 patients), IKZF1 deletion (6 patients)
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The patient characteristics are detailed in Table 1
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Table 1: Patient disease characteristics 2 The results of the CRS and neurological events study showed that a total of 30 (59%) patients developed CRS following Tisagenlecleucel infusion, with a median time of 4 days (range: 1-12 days)
.

Eighteen patients (35%) required intensive care unit (ICU) management for a median of 4.
5 days (range: 1-9 days)
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The specific grading of CRS patients was as follows: 11 cases of grade 1, 9 cases of grade 2, 9 cases of grade 3, and 1 case of grade 5; 13 cases (25%) were treated with corticosteroids (CTC) and/or anti-cytokine anti-r - IL6 or IL6 monoclonal antibody, of which 11 received CTC, 12 received tocilizumab, and 6 tocilizumab-refractory patients received sertuximab
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All cases were effectively controlled except for 1 case of CRS
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Neurological events occurred in 12 (24%) patients following Tisagenlecleucel infusion with a median time of 7 days (range: 4-65 days), including 4 patients of grade ≥3
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The most common neurological events were headache (5 cases), encephalopathy (4 cases), and seizures (2 cases)
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One patient with HHV6 encephalopathy and cerebral toxoplasmosis required specific treatment
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All neurological events were effectively controlled except for 2 events
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One patient died of grade 5 CRS and encephalopathy, and the patient who developed HHV6 encephalitis had persistent autonomic abnormalities and memory impairment
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Of the 12 patients with neurological events, 11 had previous or concurrent CRS (6 patients ≥ grade 3)
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3.
Factors associated with patient outcomes A total of 49 patients in this study were evaluable at 28 days, and the ORR was 96%, of which 36 patients were CR and 13 patients were CRi
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Among CR/CRi patients, 8 patients were MRD positive at 28 days
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At a median follow-up of 15.
5 months after Tisagenlecleucel infusion, the 18-month cumulative recurrence rate (CIR), event-free survival (EFS), and OS rates were 51% (95% CI 37%–68%) and 44%, respectively.
(95%CI 28%–59%) and 74% (95%CI 57%–85%) (see Figure 1 for details)
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Figure 1: CIR, EFS, and OS of patients after Tisagenlecleucel infusion In this cohort, age was a continuous variable, and high-risk gene mutations were not associated with patients' CIR, EFS, or OS (Table 2)
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Previous receipt of Allo-HSCT was not associated with any of these outcome variables
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Among different factors of leukemia tumor burden before LD (LDH, percentage of BM blasts, MRD level), >50% BM blasts were associated with increased risk of CIR (SHR 2.
73, P=0.
03), EFS (P=0.
008) and OS (P<0.
001) shortening was significantly correlated
.

On multivariate analysis, development of CRS, lack of MRD remission, and loss of BCA were associated with increased CIR, and >50% blasts in BM before LD were associated with shorter OS
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Table 2: Univariate and multivariate analysis results related to CIR, EFS, OS 4CD19neg and CD19pos recurrence related factors High disease burden before LD (MRD≥10-2, P=0.
03) and 28-day detectable MRD (P = 0.
006) was associated with an increased risk of CD19neg recurrence (Figure 2)
.

Low disease burden before LD (P=0.
03) and loss of BCA (P=0.
004) were associated with an increased risk of CD19pos recurrence (Figure 2)
.

Figure 2: Factors associated with recurrence of CD19neg and CD19pos in patients 5 Factors associated with BCA In the entire cohort, the majority of BCA loss occurred 1 year before, and there was only 1 late event after 2 years of follow-up
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The cumulative incidence of BCA loss at 3, 6, and 12 months was 33%, 48%, and 55%, respectively
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The median time to BCA loss was 7.
7 months
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Univariate analysis revealed that the only predictor of BCA loss was MRD <10-2 before LD (P=0.
03) (Fig.
3)
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Figure 3: Effect of Pre-LD Tumor Burden on Loss of BCA (L-BCA) Conclusions The results of this study suggest that high pre-LD tumor burden adversely affects outcomes in R/R BCP-ALL patients receiving Tisagenlecleucel
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Detectable MRD and BCA deletions at 28 days after Tisagenlecleucel infusion were associated with increased risk of CD19neg and CD19pos recurrence
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Reference: Marie-Emilie Dourthe , Florence Rabian , Karima Yakouben, et al.
Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia.
Leukemia.
2021 Dec;35(12):3383-3393 .
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