Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia

Dourthe, Marie‐Emilie; Rabian, Florence; Yakouben, Karima; Chevillon, Florian; Cabannes‐Hamy, Aurélie; Méchinaud, Françoise; Grain, Audrey; Chaillou, Delphine; Rahal, Ilhem; Caillat‐Zucman, Sophie; Lesprit, Emmanuelle; Naudin, J.; Rouprêt-Serzec, Julie; Parquet, Nathalie; Brignier, Anne; Khourouj, Valérie Guérin-El; Lainey, Élodie; Caye-Eude, Aurélie; Cavé, Hélène; Clappier, Emmanuelle; Mathis, Stéphanie; Azoulay, Élie; Dalle, Jean Hugues; Dhédin, Nathalie; Madelaine, Isabelle; Larghero, Jérôme; Boissel, Nicolas; Baruchel, André

doi:10.1038/s41375-021-01281-7

Cited by 103 publications

(103 citation statements)

References 27 publications

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“…Approved indications are a second or higher relapse or refractory disease of CD19 + BCP-ALL in patients ≤ 25 years of age (US and Europe) and any relapse post HSCT (Europe only) ( Figure 2 ). Since marketing approval, rapidly increasing numbers of patients have been infused with tisagenlecleucel for these indications and substantial “real-world” experience has emerged from patient cohorts treated with commercial KYMRIAH® ( 24 , 36 , 37 ).…”

Section: Summary Of Major Clinical Trials Evaluating Car-t In Paediatric R/r Bcp-allmentioning

confidence: 99%

“…The ELIANA trial excluded patients <3 years old, but ~6% of patients in the real-world cohorts were <3 years and these patients had overall responses in line with those of older children ( 24 , 37 ). A meta-analysis by Anagnostou et al ( 60 ) including 953 evaluable patients demonstrated comparable CR rates between adults and children (adults 75.3% and children 80.5%, p = 0.24), but significantly better 1-year OS in children vs. adults (69 vs. 53%, respectively; p < 0.01).…”

Section: Factors Influencing Long-term Efficacymentioning

confidence: 99%

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Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?

et al. 2022

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Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has been associated with remarkable responses in paediatric patients and adolescents and young adults (AYA) with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Tisagenlecleucel, the first approved CD19 CAR-T, has become a viable treatment option for paediatric patients and AYAs with BCP-ALL relapsing repeatedly or after haematopoietic stem cell transplantation (HSCT). Based on the chimeric antigen receptor molecular design and the presence of a 4-1BB costimulatory domain, tisagenlecleucel can persist for a long time and thereby provide sustained leukaemia control. “Real-world” experience with tisagenlecleucel confirms the safety and efficacy profile observed in the pivotal registration trial. Recent guidelines for the recognition, management and prevention of the two most common adverse events related to CAR-T — cytokine release syndrome and immune-cell–associated neurotoxicity syndrome — have helped to further decrease treatment toxicity. Consequently, the questions of how and for whom CD19 CAR-T could substitute HSCT in BCP-ALL are inevitable. Currently, 40–50% of R/R BCP-ALL patients relapse post CD19 CAR-T with either CD19− or CD19+ disease, and consolidative HSCT has been proposed to avoid disease recurrence. Contrarily, CD19 CAR-T is currently being investigated in the upfront treatment of high-risk BCP-ALL with an aim to avoid allogeneic HSCT and associated treatment-related morbidity, mortality and late effects. To improve survival and decrease long-term side effects in children with BCP-ALL, it is important to define parameters predicting the success or failure of CAR-T, allowing the careful selection of candidates in need of HSCT consolidation. In this review, we describe the current clinical evidence on CAR-T in BCP-ALL and discuss factors associated with response to or failure of this therapy: product specifications, patient- and disease-related factors and the impact of additional therapies given before (e.g., blinatumomab and inotuzumab ozogamicin) or after infusion (e.g., CAR-T re-infusion and/or checkpoint inhibition). We discuss where to position CAR-T in the treatment of BCP-ALL and present considerations for the design of supportive trials for the different phases of disease. Finally, we elaborate on clinical settings in which CAR-T might indeed replace HSCT.

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Section: Summary Of Major Clinical Trials Evaluating Car-t In Paediatric R/r Bcp-allmentioning

confidence: 99%

Section: Factors Influencing Long-term Efficacymentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?

et al. 2022

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“…In the case there is no expression of CD19 in the blasts, anti-CD19 CART-T should not be indicated. 19 Decrease in the expression of CD19 in the blasts, following the use of blinatumomab, is associated with inferior outcomes of CAR-T cell therapy when compared to patients who had not used blinatumomab. 18 , 20 Data on the previous use of inotuzumab ozogamicin indicate that its use may be associated with a lower expansion of CAR-T cells, however, this requires further validation.…”

Section: Patient Selection Logistics and Pre-infusion Evaluation And Management Before Car-t Cellsmentioning

confidence: 99%

“…The CD19-positive relapses generally occur early following the infusion and are related to poor expansion of CAR-T cells and/or a short term persistence. 19 Factors related to this type of relapse are a lower disease burden prior to lymphodepletion and a rapid loss of B-cell aplasia following the infusion. The CD19-negative relapses are described as “selection by immunological pressure” 19 and can occur at any moment following the CAR-T cell therapy.…”

Section: Patient Selection Logistics and Pre-infusion Evaluation And Management Before Car-t Cellsmentioning

confidence: 99%

“… 19 Factors related to this type of relapse are a lower disease burden prior to lymphodepletion and a rapid loss of B-cell aplasia following the infusion. The CD19-negative relapses are described as “selection by immunological pressure” 19 and can occur at any moment following the CAR-T cell therapy. Various mechanisms can result in the expression of CD19 variants and immunological escape, such as the CD19 locus deletion, de novo frameshift and missense mutations, and lower expression of SRSF3.…”

Section: Patient Selection Logistics and Pre-infusion Evaluation And Management Before Car-t Cellsmentioning

confidence: 99%

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Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia

Seber

CastroJunior

Kerbauy

et al. 2021

Hematology, Transfusion and Cell Therapy

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Results of ARI‐0001 CART19 cell therapy in patients with relapsed/refractory CD19‐positive acute lymphoblastic leukemia with isolated extramedullary disease

et al. 2022

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Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia

Cited by 103 publications

References 27 publications

Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?

Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia

Results of ARI‐0001 CART19 cell therapy in patients with relapsed/refractory CD19‐positive acute lymphoblastic leukemia with isolated extramedullary disease

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