Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response

Lee, Shawn H. R.; Yang, Wenjian; Gocho, Yoshihiro; John, August; Rowland, Lauren; Smart, Brandon; Williams, Hannah; Maxwell, Dylan; Hunt, Jay D.; Yang, Wentao; Crews, Kristine R.; Roberts, Kathryn G.; Jeha, Sima; Cheng, Cheng; Karol, Seth E.; Relling, Mary V.; Rosner, Gary L.; Inaba, Hiroto; Mullighan, Charles G.; Pui, Ching‐Hon; Evans, William E.; Yang, Jun J.

doi:10.1038/s41591-022-02112-7

Cited by 42 publications

(38 citation statements)

References 57 publications

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“…Consistent with pre-clinical data for T-ALL [ 20 , 21 , 22 , 23 ], there are case descriptions or case series in T-ALL and T-NHL, with a few paediatric reports within mainly data from adults. Among those, the most significant paediatric data are a report by Gibson et al on venetoclax use in ALL/LL in 18 children/AYA, 13 of which had a T-cell disease.…”

Section: Introductionmentioning

confidence: 59%

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey

et al. 2023

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Venetoclax, the best established BH3 mimetic, is a practice-changing proapoptotic drug to treat blood cancers in adults. In paediatrics, the data are less but exciting results were recently presented in relapsed or refractory leukaemias demonstrating significant clinical activity. Importantly, the interventions could be potentially molecularly guided as vulnerabilities to BH3 mimetics were reported. Currently, venetoclax is not incorporated into paediatric treatment schedules in Poland but it has been already used in patients that failed conventional therapy in Polish paediatric haemato-oncology departments. The aim of the study was to gather clinical data and correlates of all paediatric patients treated thus far with venetoclax in Poland. We set out to gather this data to help choose the right clinical context for the drug and stimulate further research. The questionnaire regarding the use of venetoclax was sent to all 18 Polish paediatric haemato-oncology centres. The data of November 2022 were gathered and analysed for the diagnoses, triggers for the intervention, treatment schedules, outcomes and molecular associations. We received response from 11 centres, 5 of which administered venetoclax to their patients. Clinical benefit, in most cases consistent with haematologic complete remission (CR), was reported in five patients out of ten, whereas five patients did not show clinical benefit from the intervention. Importantly, patients with CR included subtypes expected to show venetoclax vulnerability, such as poor-prognosis ALL with TCF::HLF fusion. We believe that BH3 mimetics have clinical activity in children and should be available to paediatric haemato-oncology practitioners in well-selected applications.

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Section: Introductionmentioning

confidence: 59%

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey

et al. 2023

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“…The compounds used for this analysis are asparaginase, prednisone, vincristine, 6TG and 6MP. The entire ALL pharmacotype dataset was previously published [20].…”

Section: All Datasetmentioning

confidence: 99%

“…The entire ALL pharmacotype dataset used in this study was previously published [20]. Information about downloading the data is available online at that article's web page (https://www.nature.com/articles/s41591-022-02112-7#data-availability).…”

Section: Declarations Ethical Approval and Consent To Participatementioning

confidence: 99%

Bayesian modelling of response to therapy and drug-sensitivity in acute lymphoblastic leukemia

Cremaschi

Yang

Evans

et al. 2023

Preprint

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Acute lymphoblastic leukemia (ALL) is a heterogeneous haematologic malignancy involving the abnormal proliferation of immature lymphocytes and accounts for most paediatric cancer cases. The management of ALL in children has seen great improvement in the last decades thanks to greater understanding of the disease leading to improved treatment strategies evidenced through clinical trials. Common therapy regimens involve a first course of chemotherapy (induction phase), followed by treatment with a combination of anti-leukemia drugs. A measure of the efficacy early in the course of therapy is the presence of minimal residual disease (MRD). MRD quantifies residual tumor cells and indicates the effectiveness of the treatment over the course of therapy. MRD positivity is defined for values of MRD greater than 0.01%, yielding left-censored MRD observations. We propose a Bayesian model to study the relationship between patient features (leukemia subtype, baseline characteristics, and drug sensitivity profile) and MRD observed at two time points during the induction phase. Specifically, we model the observed MRD values via an auto-regressive model, accounting for left-censoring of the data and for the fact that some patients are already in remission after the first stage of induction therapy. Patient characteristics are included in the model via linear regression terms. In particular, patient-specific drug sensitivity based on ex vivo assays of patient samples is exploited to identify groups of subjects with similar profiles. We include this information as a covariate in the model for MRD. We adopt horseshoe priors for the regression coefficients to perform variable selection to identify important covariates. We fit the proposed approach to data from three prospective paediatric ALL clinical trials carried out at the St. Jude Children’s Research Hospital. Our results highlight that drug sensitivity profiles and leukemic subtypes play an important role in the response to induction therapy as measured by serial MRD measures.

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“…This includes GWAS analyses that identified inherited genetic contributors associated with patient relapse (4,5) and persistence of minimal residual disease (MRD) after induction chemotherapy (3), which is an early indicator of treatment failure (6)(7)(8)(9). In addition, ex vivo chemotherapeutic drug sensitivity testing using primary ALL cells from patients serves as an informative pharmacological phenotype (10). When integrated with genotype profiling for GWAS, these analyses identify variants contributing to antileukemic drug resistance that reflects in vivo and ex vivo resistance and is therefore predictive of treatment outcome in patients (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, ex vivo chemotherapeutic drug sensitivity testing using primary ALL cells from patients serves as an informative pharmacological phenotype (10). When integrated with genotype profiling for GWAS, these analyses identify variants contributing to antileukemic drug resistance that reflects in vivo and ex vivo resistance and is therefore predictive of treatment outcome in patients (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment

Bhattarai

Mobley

Barnett

et al. 2023

Preprint

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Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response. Defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. We therefore mapped inherited noncoding variants associated with chemotherapeutic drug resistance and/or treatment outcome to ALL cis-regulatory elements and investigated their gene regulatory potential and genomic connectivity using massively parallel reporter assays and promoter capture Hi-C, respectively. We identified 53 variants with reproducible allele-specific effects on transcription and high-confidence gene targets. Subsequent functional interrogation of the top variant (rs1247117) determined that it disrupted a PU.1 consensus motif and PU.1 binding affinity. Importantly, deletion of the genomic interval containing rs1247117 sensitized ALL cells to vincristine. Together, these data demonstrate that noncoding regulatory variation associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to chemotherapeutic agents in ALL.

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Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response

Cited by 42 publications

References 57 publications

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey

Bayesian modelling of response to therapy and drug-sensitivity in acute lymphoblastic leukemia

Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment

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