While targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, patient bene t with OXPHOS inhibitors in the clinic has yet to be achieved. Based on promising preclinical data, we advanced IACS-010759, a highly potent and selective small-molecule inhibitor of mitochondrial complex I, into two phase I trials in patients with acute myeloid leukemia (NCT02882321) or advanced solid tumors (NCT03291938). Clinical ndings revealed that IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities that included elevated blood lactate and neurotoxicity, obstructing efforts to maintain target plasma exposure. Consequently, only modest on-target inhibition and limited antitumor activity were observed. Follow-up reverse translational studies uncovered that IACS-010759 reduced oxygen consumption rates in neurons and damaged myelin. Further, IACS-010759-treated mice displayed behaviors indictive of neuropathy, which were minimized with the co-administration of a histone deacetylase 6 inhibitor. Our ndings urge caution in the continued development of complex I inhibitors as antitumor agents.

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Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24–88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07–0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2mutAML.Clinical trial registration information: https://clinicaltrials.gov/.NCT03683433

Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)‐related karyotype, or history of prior MDS. We evaluated 415 patients with AML‐MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML‐MRC, therapy type and mutation profile. Criteria for AML‐MRC included: cytogenetic abnormalities (AML‐MRC‐C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML‐MRC‐H) and 28 (7%) with previously treated MDS (AML‐MRC‐TS), and 97 (23%) with multilineage dysplasia (AML‐MRC‐M). Median age was 70 years (range 18‐94). Among 95 evaluable patients, a total of 37 (39%) had secondary‐type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML‐MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML‐MRC‐M (HR 0.56, CI 0.38‐0.84, P = .004) and AML‐MRC‐H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML‐MRC‐M/AML‐MRC‐H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML‐MRC‐M (HR 0.42, CI 0.19‐0.94, P = .036) and with improved EFS in AML‐MRC‐M and AML‐MRC‐H (HR 0.26, CI 0.10‐0.63, P = .003). This data suggests that not all diagnostic criteria for AML‐MRC define high‐risk patients and that specific subgroups may benefit from different therapeutic interventions.

Acute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact. In a retrospective analysis, we identified 172 adult patients with KMT2Ar AML and compared them to 522 age-matched patients with diploid AML. KMT2Ar AML had fewer mutations, most commonly affecting RAS and FLT3 without significant impact on prognosis, except for patients with ≥2 mutations with lower overall survival (OS). KMT2Ar AML had worse outcomes compared with diploid AML when newly diagnosed and at relapse, especially following second salvage (median OS of 2.4 vs 4.8 months, P < 0.0001). Therapy-related KMT2Ar AML (t-AML) had worse outcomes compared with de novo KMT2Ar AML (median OS of 0.7 years vs 1.4 years, P < 0.0001). Allogeneic hematopoietic stem cell transplant (allo-HSCT) in first remission was associated with improved OS (5-year, 52 vs 14% for no allo-HSCT, P < 0.0001). In a multivariate analysis, translocation subtypes causing KMT2Ar did not predict survival, unlike age and allo-HSCT. In conclusion, KMT2Ar was associated with adverse outcomes regardless of translocation subtype. Therefore, AML risk stratification guidelines should include all KMT2Ar as adverse.