Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets

Hoell, Jessica I.; Ginzel, Sebastian; Kuhlen, Michaela; Kloetgen, Andreas; Gombert, Michael; Fischer, Ute; Hein, Daniel; Demir, Salih; Stanulla, Martin; Schrappe, Martin; Stadt, Udo zur; Bader, Peter; Babor, Florian; Schuster, Friedhelm R.; Strahm, Brigitte; Alten, Julia; Moericke, Anja; Escherich, Gabriele; Stackelberg, Arend von; Thiele, Ralf; McHardy, Alice C.; Peters, Christina; Bornhäuser, Beat; Bourquin, Jean‐Pierre; Krause, Stefan W.; Enczmann, Juergen; Meyer, Lüder Hinrich; Eckert, Cornelia; Meisel, Roland

doi:10.1182/bloodadvances.2019000051

Cited by 5 publications

(5 citation statements)

References 60 publications

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“…A recent study showed that p53-mutant subclones that were detected at first relapse can give rise to clonal p53 mutations detectable in post-stem cell transplantation relapses. Furthermore, in these patients, p53 mutations correlated with an extremely short time to relapse (112). Various reactivators of mutant p53 that induce restoration of the wildtype conformation are in preclinical investigation (113).…”

Section: Drugs Targeting Mutant P53mentioning

confidence: 99%

“…Various reactivators of mutant p53 that induce restoration of the wildtype conformation are in preclinical investigation (113). Interestingly, leukemic blasts from a patient with T-ALL who relapsed after stem cell transplantation showed sensitivity ex vivo to the p53 reactivator APR-246 (112). APR-246 has already shown promising results for p53-mutant patients affected by other hematologic malignancies (NCT00900614) and could be a suitable option for patients with T-ALL who relapse after stem cell transplantation and present with p53 mutations.…”

Section: Drugs Targeting Mutant P53mentioning

confidence: 99%

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T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with TALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent TALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of TALL and gives a comprehensive overview of the novel treatments for patients with TALL that are currently under clinical investigation or that are emerging from preclinical research. Significance: TALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.

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Section: Drugs Targeting Mutant P53mentioning

confidence: 99%

Section: Drugs Targeting Mutant P53mentioning

confidence: 99%

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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“…PEST-rich alterations were more prevalent in relapsed cases than in non-relapsed cases at diagnosis ( Kimura et al, 2019 ). Similarly, Hoell et al (2019) studied leukemic blasts from 10 children with post-allogeneic stem cell transplantation (SCT) relapses and discovered that NOTCH1 was the sole recurrent gene among the 50 genes in T-cell leukemia. In their study using targeted exome sequencing, Zhang et al (2020) observed distinct mutation patterns between B-ALL and T-ALL patients.…”

Section: Overview Of Next-generation Sequencing Technologymentioning

confidence: 99%

Advances in next-generation sequencing for relapsed pediatric acute lymphoblastic leukemia: current insights and future directions

Mohd Nippah,

Abu,

Ab Mutalib

et al. 2024

Front. Genet.

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Leukemia is one of the most common cancers in children; and its genetic diversity in the landscape of acute lymphoblastic leukemia (ALL) is important for diagnosis, risk assessment, and therapeutic approaches. Relapsed ALL remains the leading cause of cancer deaths among children. Almost 20% of children who are treated for ALL and achieve complete remission experience disease recurrence. Relapsed ALL has a poor prognosis, and relapses are more likely to have mutations that affect signaling pathways, chromatin patterning, tumor suppression, and nucleoside metabolism. The identification of ALL subtypes has been based on genomic alterations for several decades, using the molecular landscape at relapse and its clinical significance. Next-generation sequencing (NGS), also known as massive parallel sequencing, is a high-throughput, quick, accurate, and sensitive method to examine the molecular landscape of cancer. This has undoubtedly transformed the study of relapsed ALL. The implementation of NGS has improved ALL genomic analysis, resulting in the recent identification of various novel molecular entities and a deeper understanding of existing ones. Thus, this review aimed to consolidate and critically evaluate the most current information on relapsed pediatric ALL provided by NGS technology. In this phase of targeted therapy and personalized medicine, identifying the capabilities, benefits, and drawbacks of NGS will be essential for healthcare professionals and researchers offering genome-driven care. This would contribute to precision medicine to treat these patients and help improve their overall survival and quality of life.

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“…Children with relapsed BCP-ALL and a TP53 mutation have a dismal prognosis with standard, intensive treatment protocols for relapse ( 146 ), including HSCT ( 147 ). CD19 CAR-T followed by consolidation with HSCT was associated with a worse prognosis in patients with a TP53 mutation compared with patients with wildtype TP53 ( 148 ).…”

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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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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Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets

Abstract: Key Points Pediatric ALL relapses after allogeneic stem cell transplantation display highly diverse, dynamic and patient-individual genetic lesions. Nine of 10 relapsing pediatric transplant recipients present with genetic alterations for which novel targeted therapies are available.

Cited by 5 publications

References 60 publications

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Advances in next-generation sequencing for relapsed pediatric acute lymphoblastic leukemia: current insights and future directions

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

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