Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL

Curran, Kevin J.; Margossian, Steven; Kernan, Nancy A.; Silverman, Lewis B.; Williams, David A.; Shukla, Neerav; Kobos, Rachel; Forlenza, Christopher J.; Steinherz, Peter G.; Prockop, Susan E.; Boulad, Farid; Spitzer, Barbara; Cancio, Maria; Boelens, Jaap Jan; Kung, Andrew L.; Khakoo, Yasmin; Szenes, Victoria; Park, Jae H.; Sauter, Craig S.; Heller, Glenn; Wang, Xiuyan; Sénéchal, Brigitte; O’Reilly, Richard J.; Rivière, Isabelle; Sadelain, Michel; Brentjens, Renier J.

doi:10.1182/blood.2019001641

Cited by 216 publications

(167 citation statements)

References 24 publications

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“…In our study, 97.4% of patients developed CRS and the rate of severe CRS was 38.5%, which was in accordance with the previous researches, which supported the safe use of CAR-T therapy in Chinese R/R B-ALL patients. However, numerically, the incidence of severe CRS was higher in this study compared with that of pediatric/young adults 33 , which might be due to the inclusion of elder patients or the insufficient samples. Furthermore, predictive markers for CRS have been increasingly described by clinical studies in requirement of toxicity management for CAR-T therapy [34][35][36] .…”

Section: Discussioncontrasting

confidence: 60%

“…CRS is classified into five stages (the fifth stage being death) according to severity and management requirements, and CRS above (including) stage 3 was considered severe and life-threatening 21 . According to previous studies, most of the R/R B-ALL patients develop CRS in response to CAR-T therapy and the incidence of severe CRS is around 30% 28,30 , but a smaller incidence is reported in younger patients 33 . In our study, 97.4% of patients developed CRS and the rate of severe CRS was 38.5%, which was in accordance with the previous researches, which supported the safe use of CAR-T therapy in Chinese R/R B-ALL patients.…”

Section: Discussionmentioning

confidence: 98%

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Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients

Liu

et al. 2020

Cell Death Dis

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This study aimed to evaluate treatment response, survival, safety profiles, and predictive factors to chimeric antigen receptor T cell (CAR-T) therapy in Chinese patients with relapsed or refractory B cell acute lymphoblast leukemia (R/R BALL). 39R/R BALL patients who underwent CART therapy were included. Baseline data were collected from patients' electronic medical records. Patients' peripheral bloods, bone marrow aspirates, and biopsies were obtained for routine examination, and treatment response and survival profiles as well as adverse events were evaluated. The rates of complete remission (CR), CR with minimal residual disease (MRD) negative/positive, and bridging to hematopoietic stem-cell transplantation (HSCT) were 92.3%, 76.9%, 15.4%, and 43.6%, respectively. The median event-free survival (EFS) was 11.6 months (95% confidence interval (CI): 4.0-19.2 months) and median overall survival (OS) was 14.0 months (95% CI: 10.9-17.1 months). Bridging to HSCT independently predicted better EFS and OS, while high bone marrow blasts level independently predicted worse EFS. The incidence of cytokine release syndrome (CRS) was 97.4%, and refractory disease as well as decreased white blood cell independently predicted higher risk of severe CRS. Other common adverse events included hematologic toxicities (grade I: 5.1%, grade II: 7.7%, grade III: 17.9%, grade IV: 69.2%), neurotoxicity (28.2%), infection (38.5%), and admission for intensive care unit (10.3%). In conclusion, CART therapy presents with promising treatment response, survival and safety profiles, and higher disease burden predicts worse survival as well as increased risk of severe CRS in Chinese R/R BALL patients.

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Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 98%

Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients

Liu

et al. 2020

Cell Death Dis

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“…The toxicities following allo-HSCT (VOD, organ dysfunction, GVHD) and CAR T cell therapy (CRS, ICANS, HLH) have been well described. 11 , 13 , 15 , 16 , 19 , 20 , 27 , 28 Severe toxicity following CAR T cell toxicity did not impact the timing of allo-HSCT in this cohort. Timing from CAR T cell therapy to allo-HSCT does appear to impact OS in this cohort ( Figure 3 ), however the number of patients who received an allo-HSCT >80 days (n=3) is too small to discern statistical significance.…”

Section: Discussionmentioning

confidence: 75%

“…Lymphodepleting chemotherapy regimens were determined based on CAR specific protocol guidelines and have been previously described. 15 Cytokine release syndrome (CRS) and severe CRS were observed in 87% (13/15 patients) and 13% (2/15 patients) respectively. Immune effector cell-associated neurotoxicity syndrome (ICANS) and severe ICANS were observed in 87% (13/15 patients) and 27% (4/15 patients).…”

Section: Resultsmentioning

confidence: 99%

“…Of note, the toxicity profile for the majority of patients included in this cohort has been previously reported and while not impacting the timing or outcome of allo-HSCT, the incidence of ICANS is different from the commercially approved CAR T cell product (Tisagenlecleucel). 15 Prospective studies are needed to define the optimal the time between allo-HSCT and CAR T cell therapy but in cases where allo-HSCT is certain there should be minimal delay.…”

Section: Discussionmentioning

confidence: 99%

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Low toxicity and favorable overall survival in relapsed/refractory B-ALL following CAR T cells and CD34-selected T-cell depleted allogeneic hematopoietic cell transplant

Fabrizio

Kernan

Boulad

et al. 2020

Bone Marrow Transplant

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To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1–20 years) with a median potential follow up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0–37%), 20% (95% CI: 0–40%), and 80% (95% CI: 60–100%), respectively. Severe toxicity following CAR T cells did not impact OS (p=0.27) while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T cell depleted (TCD; n=9) versus unmodified (n=6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24-months was 22% (95% CI: 0–49%) vs 0% (p=0.14), 0% vs. 50% [95% CI: 10–90%] (p = 0.02) and 100% vs. 50% [95% CI: 10–90%] (p=0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared to unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.

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Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia

Locatelli

Zugmaier

Rizzari

et al. 2021

JAMA

219

205

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IMPORTANCE Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).OBJECTIVE To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. DESIGN, SETTING, AND PARTICIPANTSIn this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts Ն5% and <25%) at randomization. INTERVENTION Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m 2 /d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation. MAIN OUTCOMES AND MEASURESThe primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events.RESULTS A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group.CONCLUSIONS AND RELEVANCE Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up.

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Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL

Cited by 216 publications

References 24 publications

Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients

Treatment response, survival, safety, and predictive factors to chimeric antigen receptor T cell therapy in Chinese relapsed or refractory B cell acute lymphoblast leukemia patients

Low toxicity and favorable overall survival in relapsed/refractory B-ALL following CAR T cells and CD34-selected T-cell depleted allogeneic hematopoietic cell transplant

Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia

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