The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.

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Objectives: Acute myeloid leukemia (AML) carrying internal tandem duplication (ITD) of Fms-Like Tyrosine Kinase 3 (FLT3) is associated with high relapse risk and adverse outcome. This single-arm, phase 2 study evaluated efficacy and safety of combination treatment with FLT3 inhibitor quizartinib and protein translation inhibitor omacetaxine mepesuccinate (OME), referred herein QUIZOM - in elderly patients with newly diagnosed FLT3-ITD AML or young patients with relapsed/refractory (R/R) diseases, whose outcome is hitherto dismal. Methods: R/R FLT3-ITD AML patients ≥ 18 years old or newly diagnosed patients ≥ 65 years old were recruited. Treatment comprised quizartinib 30 mg daily and OME [2 mg daily for 7 (first course) or 5 days (second course onwards) every 21-28 days] until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). Quizartinib was given as post HSCT maintenance after engraftment at doses ranging from 30 mg twice weekly to 30 mg daily, depending on blood counts. Primary endpoint was composite complete remission (CRc) defined by CR+CRi (CR with incomplete haematological recovery). Secondary endpoints were leukaemia-free (LFS) and overall survival (OS). Molecular responses were evaluated by FLT3-ITD based on PCR and NPM1 variant allele frequency (VAF) based on digital PCR (ddPCR). Mutation profiling was performed by MiSeq Next Generation Sequencing (NGS) based on IDT xGen Lockdown probes custom panel of 67 genes or TruSight myeloid panel of 54 genes. Results: Twenty-nine patients (R/R case=22; newly diagnosed case=7) were recruited between November 2017 and July 2019. Their clinicopathologic characteristics were shown in Table 1. Twenty-seven patients completed at least one course of QUIZOM (median= 2 courses, range: 1-20 courses) of whom 22 (R/R=19; newly diagnosed=3) achieved CR/CRi [CR=2 (7%); CRi=20 (74%), CRc=22 (81%)], 3 patients showed partial remission (PR) and 2 patients did not respond. All 6 patients who had prior FLT3 inhibitors (sorafenib or midostaurin) achieved CR/CRi. Median LFS and OS of CR/CRi group were 5.2 and 11.07 months (Figure 1). Seven patients received allogeneic HSCT of whom all have remained in remission post HSCT as of 31 July 2019 (OS 6.43 to 19.8 months) (Figure 1). Deep molecular responses (DMR) as defined by FLT3-ITD VAF ≤0.1% and NPM1 VAF ≤ 0.001% could be accomplished in 78% and 27% patients. Adverse effects associated with QUIZOM were primarily haematological and non-haematologic adverse effects were scarce. Two patients succumbed before commencement and on day 1 of QUIZOM due to pneumonia and intracranial haemorrhage. None of recurrently mutated genes was significantly associated with treatment responses in this cohort. Conclusion: QUIZOM is effective and safe for newly diagnosed and R/R FLT3-ITD AML. Acknowledgements: Li Shu Fan Medical Foundation, S.K. Yee Medical Foundation, Croucher Foundation, LKS Faculty of Medicine, University of Hong Kong, Daiichi Sankyo Inc. Disclosures No relevant conflicts of interest to declare.

Isocitrate dehydrogenase 2 (IDH2) mutations occur in more than 15% of cytogenetically normal acute myeloid leukemia (CN-AML) but comparative studies of their roles in leukemogenesis have been scarce. We generated zebrafish models of IDH2R172K and IDH2R140Q AML and reported their pathologic, functional and transcriptomic features and therapeutic responses to target therapies. Transgenic embryos co-expressing FLT3ITD and IDH2 mutations showed accentuation of myelopoiesis. As these embryos were raised to adulthood, full-blown leukemia ensued with multi-lineage dysplasia, increase in myeloblasts and marrow cellularity and splenomegaly. The leukemia cells were transplantable into primary and secondary recipients and resulted in more aggressive disease. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in T-cell development at embryonic and adult stages. Single-cell transcriptomic analysis revealed increased myeloid skewing, differentiation blockade and enrichment of leukemia-associated gene signatures in both zebrafish models. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in interferon signals at the adult stage. Leukemic phenotypes in both zebrafish could be ameliorated by quizartinib and enasidenib. In conclusion, the zebrafish models of IDH2 mutated AML recapitulated the morphologic, clinical, functional and transcriptomic characteristics of human diseases, and provided the prototype for developing zebrafish leukemia models of other genotypes that would become a platform for high throughput drug screening.

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