FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children’s Oncology Group trial AALL0631

Brown, Patrick; Kairalla, John A.; Hilden, Joanne M.; Dreyer, Zo Ann E.; Carroll, Andrew J.; Heerema, Nyla A.; Wang, Cindy; Devidas, Meenakshi; Gore, Lia; Salzer, Wanda L.; Winick, Naomi J.; Carroll, William L.; Raetz, Elizabeth A.; Borowitz, Michael J.; Small, Donald; Loh, Mignon L.; Hunger, Stephen P.

doi:10.1038/s41375-021-01177-6

Cited by 62 publications

(71 citation statements)

References 37 publications

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“…Genome-and transcriptome-wide profiling has increased our understanding of the genetic basis of ALL enormously and has led to the identification of multiple genomic events that define new subtypes of ALL. A variety of genetic alterations that lead to gene fusions that are sensitive to tyrosine kinase inhibitors (e.g., ABL1 and PDGFRB rearrangements) or JAK inhibitors (e.g., JAK2, EPOR, IL7R rearrangements) have been described in recent years for the group of BCR/ABL1-like ALL [12][13][14][15][16]. Copy number alterations, such as microdeletions and duplications, also play a role in treatment response [17].…”

Section: Introductionmentioning

confidence: 99%

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

Lühmann

Stelter

Wolter

et al. 2021

Cancers

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Acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer occurring in children. ALL is characterized by structural and numeric genomic aberrations that strongly correlate with prognosis and clinical outcome. Usually, a combination of cyto- and molecular genetic methods (karyotyping, array-CGH, FISH, RT-PCR, RNA-Seq) is needed to identify all aberrations relevant for risk stratification. We investigated the feasibility of optical genome mapping (OGM), a DNA-based method, to detect these aberrations in an all-in-one approach. As proof of principle, twelve pediatric ALL samples were analyzed by OGM, and results were validated by comparing OGM data to results obtained from routine diagnostics. All genomic aberrations including translocations (e.g., dic(9;12)), aneuploidies (e.g., high hyperdiploidy) and copy number variations (e.g., IKZF1, PAX5) known from other techniques were also detected by OGM. Moreover, OGM was superior to well-established techniques for resolution of the more complex structure of a translocation t(12;21) and had a higher sensitivity for detection of copy number alterations. Importantly, a new and unknown gene fusion of JAK2 and NPAT due to a translocation t(9;11) was detected. We demonstrate the feasibility of OGM to detect well-established as well as new putative prognostic markers in an all-in-one approach in ALL. We hope that these limited results will be confirmed with testing of more samples in the future.

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Section: Introductionmentioning

confidence: 99%

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

Lühmann

Stelter

Wolter

et al. 2021

Cancers

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“…[1][2][3][4] Although the Japanese Infant Leukemia Study Group and the Japanese Pediatric Leukemia/Lymphoma Study Group reported remarkable 5-year EFS of 96% and 93% in KMT2A-g infant ALL in MLL96/98 and MLL-10, respectively, the cohort sizes were small, the sex ratios were skewed and the results have not been replicated in other cooperative groups. [5][6][7] Children's Oncology Group (COG) AALL0631 (NCT00557193) was a phase 3 clinical trial for infants with newly diagnosed ALL with or without KMT2A-r. 8 The trial was approved by institutional review boards at participating COG member institutions and conducted in accordance with the declaration of Helsinki. Informed consent was obtained from the parents or guardians according to federal and local regulations.…”

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confidence: 99%

Outstanding outcomes in infants with <i>KMT2A</i>-germline acute lymphoblastic leukemia treated with chemotherapy alone: results of the Children’s Oncology Group AALL0631 trial

et al. 2022

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“…KMT2A-r leukemias, which are particularly resistant to standard-of-care chemotherapy regimens, continue to be one of the most aggressive and difficult to treat leukemia types, especially in infants. Several novel agents such as DOT1L and FLT3 inhibitors that demonstrated selective targeting of KMT2A-r leukemia cells in preclinical models, have unfortunately failed to live up to their expectations in clinical trials ( 21 , 22 ). While results of clinical trials testing the safety and efficacy of epigenetic regulators such as specific inhibitors of menin and histone deacetylases for application in KMT2A-r leukemia are awaited, the search for other potent drugs and novel targetable vulnerabilities remains ongoing ( 2 , 23 ).…”

Section: Discussionmentioning

confidence: 99%

Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia

et al. 2022

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Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia (MLL/KMT2A) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target KMT2A-rearranged (KMT2A-r) leukemia cells. A library containing 3707 approved drugs and pharmacologically active compounds was screened for differential activity against KMT2A-r leukemia cell lines versus KMT2A-wild type (KMT2A-wt) leukemia cell lines, solid tumor cells and non-malignant cells by cell-based viability assays. The screen yielded SID7969543, an inhibitor of transcription factor Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1), that limited the viability of 7 out of 11 KMT2A-r leukemia cell lines including 5 out of 7 lines derived from infants, without affecting KMT2A-wt leukemia cells, solid cancer lines, non-malignant cell lines, or peripheral blood mononuclear cells from healthy controls. The compound also significantly inhibited growth of leukemia cell lines with a CALM-AF10 translocation, which defines a highly aggressive leukemia subtype that shares common underlying leukemogenic mechanisms with KMT2A-r leukemia. SID7969543 decreased KMT2A-r leukemia cell viability by inducing caspase-dependent apoptosis within hours of treatment and demonstrated synergy with established chemotherapeutics used in the treatment of high-risk leukemia. Thus, SID7969543 represents a novel candidate agent with selective activity against CALM-AF10 translocated and KMT2A-r leukemias that warrants further investigation.

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FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children’s Oncology Group trial AALL0631

Cited by 62 publications

References 37 publications

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

Outstanding outcomes in infants with <i>KMT2A</i>-germline acute lymphoblastic leukemia treated with chemotherapy alone: results of the Children’s Oncology Group AALL0631 trial

Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia

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