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Most pediatric patients with mature B-cell lymphoma can be cured with conventional chemotherapy
.
However, patients with aggressive relapsed/refractory (R/R) B-cell lymphoma have a poor prognosis and eventually die of malignancy even if conventional chemotherapy is continued
.
Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising novel therapies available to treat such patients
.
CD19-targeted CAR-T cell therapy has been shown to achieve 6-month complete remission (CR) rates of 29%-41% in adult R/RB-cell lymphoma patients
.
Several actively recruiting trials are also evaluating CD19 CAR-T cell therapy in children and young adult patients with R/RB cell lymphoma
.
Despite the good efficacy of CD19 CAR-T, most patients still experience disease progression (PD) and relapse (RD)
.
Tumor immune escape has become a non-negligible obstacle to improving long-term survival
.
The team of Professor Zhang Yonghong from Beijing Boren Hospital designed a combination and sequential dosing strategy for different B-cell antigen-targeted CAR-T cell therapies to prevent tumor antigen escape and maintain CAR-T cell persistence.
Related studies have shown that sequential CD19 -CD22 CAR-T cell infusion induces sustained remission in pediatric patients with R/RB cell acute lymphoblastic leukemia
.
In addition, sequential murine CD19 (mCD19)-human CD22 (hCD22)-hCD20-hCD19 CAR-T cell infusion was evaluated in pediatric patients with R/R Burkitt lymphoma and reported early responses, In this study, Prof.
Yonghong Zhang's team further explored the response elicited by this strategy in children with R/R Burkitt lymphoma
.
Methods Eligible patients were children and adolescents ≤18 years of age with Burkitt's lymphoma who were refractory (never achieved a CR) or relapsed after first-line chemotherapy and after at least 2 cycles of salvage chemotherapy The best response was either partial response (PR) or no response (NR)
.
Only patients whose lymphoma cells clearly expressed CD19 or more B-cell antigens (CD20 and CD22) were eligible for the trial, as determined by immunohistochemical staining analysis of tumor biopsies obtained before enrollment
.
Treatment process ① Leukapheresis and lymphocyte depletion chemotherapy As shown in Figure 1, eligible patients underwent leukapheresis to obtain peripheral blood mononuclear cells
.
Tumors were assessed according to the International Pediatric Non-Hodgkin Lymphoma Staging System and the French-US-UK Low-Risk Criteria one week before leukapheresis
.
Lymphocyte depletion (LD) chemotherapy regimens included fludarabine (30 mg/m2/day) and cyclophosphamide (250 mg/m2/day), administered on days -5, -4, and -3
.
The target dose of CAR-T cell infusion was 2×106/kg (range: 0.
1×106-5×106/kg), except for 1 patient with a white blood cell count <103/μL 1 week before infusion
.
Figure 1 ② Response assessment and CAR-T cell detection According to the International Pediatric Non-Hodgkin Lymphoma Response Evaluation Criteria, on days 7, 15, 30, 45, and 60, and monthly from day 60 to month 6, from Response was assessed every 3 months from months 6 to 24 and was used as a clinical indication for each subsequent cycle of CAR-T cell infusion (Figure 1)
.
CAR-T cell persistence was monitored at the same time points as response assessments
.
CAR+ T cells were detected using flow cytometry (FCM), but if FCM did not detect CAR+ T cells, real-time quantitative polymerase chain reaction (qPCR) was used to measure the copy number of the CAR transgene in the T cells
.
③ The sequential infusion process of CAR-T cells is shown in Figure 1
.
All enrolled patients received the first cycle of mCD19 CAR-T cell infusion
.
Patients who achieved sustained CR received no additional therapy
.
For patients who maintained PR or NR until mCD19 CAR-T cells were no longer detectable in peripheral blood (PB) by FCM, a second cycle of hCD22 CAR-T cell infusion was performed
.
For patients who developed PD or RD after responding to mCD19 CAR-T cell therapy, a second cycle of hCD22 CAR-T cell infusion was started immediately regardless of whether mCD19 CAR-T cells were found in PB by FCM assay
.
After the second cycle of hCD22 CAR-T cell infusion, PR was maintained until patients whose hCD22 CAR-T cells were no longer detectable in PB by FCM assay received the third cycle of hCD20 CAR-T cell infusion
.
hCD22 CAR-T was detected in PB by FCM assay for patients who developed RD after first CR (CR1) after first infusion and then second CR (CR2) through second infusion After the loss of cells, a third cycle of hCD20 CAR-T cell infusion was given as consolidation therapy
.
Patients with PD received a third cycle of hCD20 CAR-T cell infusion immediately after obtaining PR (even though FCM assay found that hCD22 CAR-T cells were still detectable in PB)
.
After the third cycle of hCD20 CAR-T cell infusion, PR was maintained until the fourth cycle of hCD19 CAR-T cell infusion in patients whose hCD20 CAR-T cells were no longer detectable in PB by FCM assay
.
No patients were bridged to hematopoietic stem cell transplantation after completing sequential CAR-T cell therapy
.
Toxicity Assessment Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were graded according to the American Society for Transplantation and Cell Therapy grading scale
.
Study endpoint follow-up time was defined as the time from the last CAR-T cell infusion to the cut-off date
.
Primary endpoints included safety and CR rate
.
Key secondary endpoints included duration of CR, progression-free survival (PFS), overall survival (OS), duration of CAR-T cell persistence, and duration of B-cell hypoplasia
.
Results Clinical characteristics of enrolled patients A total of 23 patients were enrolled between January 17, 2018, and November 8, 2019
.
Baseline characteristics of all patients are shown in Table 1
.
9/23 cases (39.
1%) had mass disease, and 10/23 cases (43.
5%) showed central nervous system (CNS) involvement
.
Except for P5 and P21 patients without CD20 expression, immunohistochemical staining analysis of tumor biopsies from all patients before enrollment confirmed positive expression of CD19, CD22 and CD20 in lymphoma cells
.
Table 1 Persistence of sequential infusions of CAR-T cells and persistence of response Median time from last infusion to cut-off date (March 8, 2021) was 17 months (range: 15-23 months) )
.
21 patients achieved CR within 3 months of last infusion, of which 9 patients had NR or PR at 1 month, which improved to CR after 0.
5 to 1.
5 months; 19 patients achieved CR at 3 months ; 18 patients remained in CR by the cutoff date
.
Among all patients, the probability of achieving a CR 18 months after the last infusion was 78% (95% CI, 54%-91%)
.
Among patients who achieved a CR at 3 months, the probability of achieving a durable CR at 18 months was 95% (95% CI, 62%-99%)
.
An estimated 86% (95% CI, 62%-95%) of patients remained relapse-free for 18 months after the first CR after the last infusion (Fig.
2A)
.
Durable CR was observed for up to 34 months after the last infusion
.
At 18 months after the last infusion, the estimated PFS rate for all patients was 78% (95% CI, 55%-90%) (Figure 2B) and the OS rate was 83% (95% CI, 60%-93%) ) (Figure 2C)
.
An estimated 50% (95% CI, 28%-69%) of patients had detectable CAR-T cells in PB by qPCR 6 months after the first infusion (Fig.
3A)
.
An estimated 51% (95% CI, 31%-79%) of patients with B-cell aplasia persisted for 12 months (Fig.
3B)
.
Persistent B-cell hypoplasia was observed for up to 35 months after the first infusion
.
Figure 2 Figure 3 Toxicity of sequential CAR-T cell infusion 16/23 (69.
6%) patients developed CRS
.
The median time to onset of CRS was 1 day (range: 0-5 days), as measured by fever, hypotension, and/or hypoxia
.
Peak toxicity occurred between days 6 and 11
.
Eight patients (34.
8%) had ≤ grade 2 CRS, which resolved completely after a median of 8 days (range: 2-10 days)
.
Eight patients (34.
8%) who developed grade 3 CRS received steroids, and the median time to complete resolution of CRS was 10.
4 days (range: 8-17 days)
.
Neurotoxicity occurred in 8/23 (34.
8%) patients, and the median time to neurotoxicity was 6.
4 days (range: 5-10 days)
.
Grade 1 ICANS occurred in 3/23 (13.
0%) patients, manifesting as delayed response, impaired writing function, and mild somnolence
.
Grade 3 ICANS occurred in 5/23 (21.
7%) patients, manifesting as seizures, increased intracranial pressure, and/or localized edema on neuroimaging
.
All 5 patients were treated with intravenous and intrathecal dexamethasone and achieved remission without clinical sequelae
.
The median duration of neurotoxicity was 5.
5 days (range: 3-10 days)
.
Grade 3 CRS occurred in 2 of 13 patients (15.
4%) who received CD22 CAR-T cell infusion during the subsequent infusion
.
No treatment-related deaths occurred during follow-up
.
Efficacy and safety of sequential CAR-T cell infusion in patients with massive disease and CNS involvement.
Among the 9 patients with massive disease, 4 patients received 2 cycles of CAR-T cell infusion, and 3 patients received CAR-T cell infusion for 2 cycles.
The patient received 3 cycles
.
7/9 patients achieved sustained CR
.
Median PFS was not reached, but the estimated 18-month PFS rate in patients with bulky disease was 78% (95% CI, 37%-94%)
.
No significant difference was observed in estimated 18-month PFS rates between the bulky disease group and the non-mass disease group (P=0.
97)
.
Six of 10 patients with CNS involvement achieved sustained CR
.
The estimated 18-month PFS rate in patients with CNS involvement was 60% (95% CI, 25%-83%) and was not significantly lower than that in patients without CNS involvement (92% [95% CI, 56%-99%]) (P=0.
28)
.
Furthermore, patients with (P=1.
0) and without (P=0.
62) CNS involvement did not have any statistically significant differences in the severity of CRS and neurotoxicity
.
Conclusions This study shows that sequential CAR-T cell therapy may produce durable responses and is safe in pediatric patients with R/R Burkitt lymphoma
.
In addition, sequential CAR-T cell therapy may benefit children with CNS-involved R/R Burkitt lymphoma
.
Reference source: Ying Liu, Biping Deng, Bo Hu, Sequential different B-cell antigen–targeted CAR T-cell therapy for pediatric refractory/relapsed Burkitt lymphoma.
Blood Adv (2022) 6 (3): 717–730.
https:/ /doi.
org/10.
1182/bloodadvances.
2021004557.
Click "read the original text", we will make progress together
.
However, patients with aggressive relapsed/refractory (R/R) B-cell lymphoma have a poor prognosis and eventually die of malignancy even if conventional chemotherapy is continued
.
Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising novel therapies available to treat such patients
.
CD19-targeted CAR-T cell therapy has been shown to achieve 6-month complete remission (CR) rates of 29%-41% in adult R/RB-cell lymphoma patients
.
Several actively recruiting trials are also evaluating CD19 CAR-T cell therapy in children and young adult patients with R/RB cell lymphoma
.
Despite the good efficacy of CD19 CAR-T, most patients still experience disease progression (PD) and relapse (RD)
.
Tumor immune escape has become a non-negligible obstacle to improving long-term survival
.
The team of Professor Zhang Yonghong from Beijing Boren Hospital designed a combination and sequential dosing strategy for different B-cell antigen-targeted CAR-T cell therapies to prevent tumor antigen escape and maintain CAR-T cell persistence.
Related studies have shown that sequential CD19 -CD22 CAR-T cell infusion induces sustained remission in pediatric patients with R/RB cell acute lymphoblastic leukemia
.
In addition, sequential murine CD19 (mCD19)-human CD22 (hCD22)-hCD20-hCD19 CAR-T cell infusion was evaluated in pediatric patients with R/R Burkitt lymphoma and reported early responses, In this study, Prof.
Yonghong Zhang's team further explored the response elicited by this strategy in children with R/R Burkitt lymphoma
.
Methods Eligible patients were children and adolescents ≤18 years of age with Burkitt's lymphoma who were refractory (never achieved a CR) or relapsed after first-line chemotherapy and after at least 2 cycles of salvage chemotherapy The best response was either partial response (PR) or no response (NR)
.
Only patients whose lymphoma cells clearly expressed CD19 or more B-cell antigens (CD20 and CD22) were eligible for the trial, as determined by immunohistochemical staining analysis of tumor biopsies obtained before enrollment
.
Treatment process ① Leukapheresis and lymphocyte depletion chemotherapy As shown in Figure 1, eligible patients underwent leukapheresis to obtain peripheral blood mononuclear cells
.
Tumors were assessed according to the International Pediatric Non-Hodgkin Lymphoma Staging System and the French-US-UK Low-Risk Criteria one week before leukapheresis
.
Lymphocyte depletion (LD) chemotherapy regimens included fludarabine (30 mg/m2/day) and cyclophosphamide (250 mg/m2/day), administered on days -5, -4, and -3
.
The target dose of CAR-T cell infusion was 2×106/kg (range: 0.
1×106-5×106/kg), except for 1 patient with a white blood cell count <103/μL 1 week before infusion
.
Figure 1 ② Response assessment and CAR-T cell detection According to the International Pediatric Non-Hodgkin Lymphoma Response Evaluation Criteria, on days 7, 15, 30, 45, and 60, and monthly from day 60 to month 6, from Response was assessed every 3 months from months 6 to 24 and was used as a clinical indication for each subsequent cycle of CAR-T cell infusion (Figure 1)
.
CAR-T cell persistence was monitored at the same time points as response assessments
.
CAR+ T cells were detected using flow cytometry (FCM), but if FCM did not detect CAR+ T cells, real-time quantitative polymerase chain reaction (qPCR) was used to measure the copy number of the CAR transgene in the T cells
.
③ The sequential infusion process of CAR-T cells is shown in Figure 1
.
All enrolled patients received the first cycle of mCD19 CAR-T cell infusion
.
Patients who achieved sustained CR received no additional therapy
.
For patients who maintained PR or NR until mCD19 CAR-T cells were no longer detectable in peripheral blood (PB) by FCM, a second cycle of hCD22 CAR-T cell infusion was performed
.
For patients who developed PD or RD after responding to mCD19 CAR-T cell therapy, a second cycle of hCD22 CAR-T cell infusion was started immediately regardless of whether mCD19 CAR-T cells were found in PB by FCM assay
.
After the second cycle of hCD22 CAR-T cell infusion, PR was maintained until patients whose hCD22 CAR-T cells were no longer detectable in PB by FCM assay received the third cycle of hCD20 CAR-T cell infusion
.
hCD22 CAR-T was detected in PB by FCM assay for patients who developed RD after first CR (CR1) after first infusion and then second CR (CR2) through second infusion After the loss of cells, a third cycle of hCD20 CAR-T cell infusion was given as consolidation therapy
.
Patients with PD received a third cycle of hCD20 CAR-T cell infusion immediately after obtaining PR (even though FCM assay found that hCD22 CAR-T cells were still detectable in PB)
.
After the third cycle of hCD20 CAR-T cell infusion, PR was maintained until the fourth cycle of hCD19 CAR-T cell infusion in patients whose hCD20 CAR-T cells were no longer detectable in PB by FCM assay
.
No patients were bridged to hematopoietic stem cell transplantation after completing sequential CAR-T cell therapy
.
Toxicity Assessment Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were graded according to the American Society for Transplantation and Cell Therapy grading scale
.
Study endpoint follow-up time was defined as the time from the last CAR-T cell infusion to the cut-off date
.
Primary endpoints included safety and CR rate
.
Key secondary endpoints included duration of CR, progression-free survival (PFS), overall survival (OS), duration of CAR-T cell persistence, and duration of B-cell hypoplasia
.
Results Clinical characteristics of enrolled patients A total of 23 patients were enrolled between January 17, 2018, and November 8, 2019
.
Baseline characteristics of all patients are shown in Table 1
.
9/23 cases (39.
1%) had mass disease, and 10/23 cases (43.
5%) showed central nervous system (CNS) involvement
.
Except for P5 and P21 patients without CD20 expression, immunohistochemical staining analysis of tumor biopsies from all patients before enrollment confirmed positive expression of CD19, CD22 and CD20 in lymphoma cells
.
Table 1 Persistence of sequential infusions of CAR-T cells and persistence of response Median time from last infusion to cut-off date (March 8, 2021) was 17 months (range: 15-23 months) )
.
21 patients achieved CR within 3 months of last infusion, of which 9 patients had NR or PR at 1 month, which improved to CR after 0.
5 to 1.
5 months; 19 patients achieved CR at 3 months ; 18 patients remained in CR by the cutoff date
.
Among all patients, the probability of achieving a CR 18 months after the last infusion was 78% (95% CI, 54%-91%)
.
Among patients who achieved a CR at 3 months, the probability of achieving a durable CR at 18 months was 95% (95% CI, 62%-99%)
.
An estimated 86% (95% CI, 62%-95%) of patients remained relapse-free for 18 months after the first CR after the last infusion (Fig.
2A)
.
Durable CR was observed for up to 34 months after the last infusion
.
At 18 months after the last infusion, the estimated PFS rate for all patients was 78% (95% CI, 55%-90%) (Figure 2B) and the OS rate was 83% (95% CI, 60%-93%) ) (Figure 2C)
.
An estimated 50% (95% CI, 28%-69%) of patients had detectable CAR-T cells in PB by qPCR 6 months after the first infusion (Fig.
3A)
.
An estimated 51% (95% CI, 31%-79%) of patients with B-cell aplasia persisted for 12 months (Fig.
3B)
.
Persistent B-cell hypoplasia was observed for up to 35 months after the first infusion
.
Figure 2 Figure 3 Toxicity of sequential CAR-T cell infusion 16/23 (69.
6%) patients developed CRS
.
The median time to onset of CRS was 1 day (range: 0-5 days), as measured by fever, hypotension, and/or hypoxia
.
Peak toxicity occurred between days 6 and 11
.
Eight patients (34.
8%) had ≤ grade 2 CRS, which resolved completely after a median of 8 days (range: 2-10 days)
.
Eight patients (34.
8%) who developed grade 3 CRS received steroids, and the median time to complete resolution of CRS was 10.
4 days (range: 8-17 days)
.
Neurotoxicity occurred in 8/23 (34.
8%) patients, and the median time to neurotoxicity was 6.
4 days (range: 5-10 days)
.
Grade 1 ICANS occurred in 3/23 (13.
0%) patients, manifesting as delayed response, impaired writing function, and mild somnolence
.
Grade 3 ICANS occurred in 5/23 (21.
7%) patients, manifesting as seizures, increased intracranial pressure, and/or localized edema on neuroimaging
.
All 5 patients were treated with intravenous and intrathecal dexamethasone and achieved remission without clinical sequelae
.
The median duration of neurotoxicity was 5.
5 days (range: 3-10 days)
.
Grade 3 CRS occurred in 2 of 13 patients (15.
4%) who received CD22 CAR-T cell infusion during the subsequent infusion
.
No treatment-related deaths occurred during follow-up
.
Efficacy and safety of sequential CAR-T cell infusion in patients with massive disease and CNS involvement.
Among the 9 patients with massive disease, 4 patients received 2 cycles of CAR-T cell infusion, and 3 patients received CAR-T cell infusion for 2 cycles.
The patient received 3 cycles
.
7/9 patients achieved sustained CR
.
Median PFS was not reached, but the estimated 18-month PFS rate in patients with bulky disease was 78% (95% CI, 37%-94%)
.
No significant difference was observed in estimated 18-month PFS rates between the bulky disease group and the non-mass disease group (P=0.
97)
.
Six of 10 patients with CNS involvement achieved sustained CR
.
The estimated 18-month PFS rate in patients with CNS involvement was 60% (95% CI, 25%-83%) and was not significantly lower than that in patients without CNS involvement (92% [95% CI, 56%-99%]) (P=0.
28)
.
Furthermore, patients with (P=1.
0) and without (P=0.
62) CNS involvement did not have any statistically significant differences in the severity of CRS and neurotoxicity
.
Conclusions This study shows that sequential CAR-T cell therapy may produce durable responses and is safe in pediatric patients with R/R Burkitt lymphoma
.
In addition, sequential CAR-T cell therapy may benefit children with CNS-involved R/R Burkitt lymphoma
.
Reference source: Ying Liu, Biping Deng, Bo Hu, Sequential different B-cell antigen–targeted CAR T-cell therapy for pediatric refractory/relapsed Burkitt lymphoma.
Blood Adv (2022) 6 (3): 717–730.
https:/ /doi.
org/10.
1182/bloodadvances.
2021004557.
Click "read the original text", we will make progress together
