FMS-like tyrosine kinase 3–targeted (FLT3-targeted) therapies have shown initial promise for the treatment of acute myeloid leukemia (AML) expressing FLT3-activating mutations; however, resistance emerges rapidly. Furthermore, limited options exist for the treatment of FLT3-independent AML, demonstrating the need for novel therapies that reduce toxicity and improve survival. MERTK receptor tyrosine kinase is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis. Here, we describe MRX-2843, a type 1 small-molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FLT3 and their downstream effectors. MRX-2843 treatment induces apoptosis and inhibits colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD, with a wide therapeutic window compared with that of normal human cord blood cells. In murine orthotopic xenograft models, once-daily oral therapy prolonged survival 2- to 3-fold over that of vehicle-treated controls. Additionally, MRX-2843 retained activity against quizartinib-resistant FLT3-ITD–mutant proteins with clinically relevant alterations at the D835 or F691 loci and prolonged survival in xenograft models of quizartinib-resistant AML. Together, these observations validate MRX-2843 as a translational agent and support its clinical development for the treatment of AML.

KMT2A-rearranged (KMT2A-r) infant ALL is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single cell multi-omics analyses. We uncovered the following critical new insights: leukemia cells from patients younger than 6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune mediated control. Our analysis also revealed pre-existing lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in two patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank AML. These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single cell multi-omics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.

KMT2A-rearranged (KMT2A-r) infant ALL is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single cell multi-omics analyses. We uncovered the following critical new insights: leukemia cells from patients younger than 6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune mediated control. Our analysis also revealed pre-existing lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in two patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank AML. These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single cell multi-omics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome. Disclosures Bernt: Merck: Other: Spouse is an employee of Merck.; Syndax: Research Funding.

The lack of difference in the occurrence of severe infection supports our decision to decrease unnecessary high protection in alloHSCT units to improve children's daily life.

Pediatric sarcoma patients with pleuropulmonary lesions have a dismal prognosis because the impossibility to obtain local control. The aim of this study was to determine if pleuropneumonectomy (PP) could be a therapeutic option. We retrospectively reviewed nine patients who underwent salvage PP for pleuropulmonary localization of primary localized sarcoma or metastatic recurrence. Surgery and complications were analyzed, pulmonary function tests were conducted, and quality of life was determined with EORTC-QLQ-C30 questionnaire. At the time of PP age was between 9–17 years. Underlying disease included metastatic osteosarcoma (n = 5), Ewing sarcoma (two metastatic, one primary), and one primary undifferentiated sarcoma. Early complications occurred in three patients. Mean postoperative hospitalization stay was 14.5 days. Pulmonary function test showed 19–66% reduction of total lung capacity which led to mild exercise intolerance but did not affect daily life. Four patients died of multi-metastatic relapse <14 months after PP, one patient had a local recurrence, and four patients are in complete remission between 1.5 and 12 years after PP. In conclusion, in this small patient group treated with a pleuropneumonectomy for primary or metastatic lesions, outcome is variable; however, this extended surgical technique was generally quite well tolerated. Postoperative lung function seems well preserved, and it seems to lead to at least an extension of life with good quality and therefor can be considered as salvage therapy.