BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286–based combinations as a promising therapy for AML with MLL1r or mtNPM1.

PURPOSE: The development of targeted therapeutics has revolutionized treatment for elderly patients with AML. Two doublet regimens are approved in the frontline setting for intensive chemotherapy (IC)–ineligible AML: venetoclax (VEN) in combination with hypomethylating agent (HMA) therapy and azacitidine (AZA) plus ivosidenib (IVO) specifically for IDH1 -mutated AML. Although both regimens have improved AML outcomes, most patients will either not respond to frontline therapy or relapse, with dismal salvage outcomes. METHODS: We herein report on 60 newly diagnosed IC-ineligible patients treated at our institution with triplet regimens for isocitrate dehydrogenase ( IDH )–mutant AML. Patients received either AZA + VEN + IVO on NCT03471260 ( IDH1 -mutated patients only) or oral decitabine + VEN + IVO/enasidenib on NCT04774393 (arms for IDH1- and IDH2 -mutant disease, respectively). RESULTS: The triplet regimens were well tolerated with low early mortality (n = 1 [2%] in 60 days) and a similar safety profile to HMA + VEN and isocitrate dehydrogenase inhibitor doublet regimens. The composite complete remission rate (CRc) was 92% (55/60), with an overall response rate of 95% (57/60). With a median follow-up of 27.4 months, the median overall survival (OS) has not yet been reached. The 2-year OS was 69% with a 2-year cumulative incidence of relapse of 24%. Patients with treated-secondary AML (tsAML) experienced inferior outcomes with a CRc of 71% (12/17) and a 2-year OS of 34%; the 2-year OS was 84% in patients without tsAML. Nineteen patients (32%) transitioned to stem cell transplant, and 51% remain on study. CONCLUSION: Given the excellent outcomes of IDH-triplet therapy for newly diagnosed, IC-ineligible IDH -mutant AML, further prospective studies comparing IDH-triplet versus IDH-doublet regimens are warranted.

We sought to develop a survival model in chronic myelomonocytic leukemia (CMML) that is primarily based on clinical variables and examine additional impact from mutations and karyotype. 457 molecularly-annotated patients were considered. Multivariable analysis identified circulating Blasts ≥2% (1 point), Leukocytes ≥13 x 109/L (1 point), and severe (2 points) or moderate (1 point) Anemia as preferred risk variables in developing a clinical risk Stratification Tool for overall survival (OS), acronymized to "BLAST": low-risk (0 points; median 63 months); intermediate-risk (1 point; median 28 months; HR 2.2, 95% CI 1.6-3.0), and high-risk (2-4 points; median 13 months; 5.4, 4.1-7.3); the corresponding 3/5 year OS rates were 68%/53%, 43%/18%, and 12%/1%. BLAST model performance (AUC 0.77/0.85 at 3/5-years) was shown to be comparable to that of the molecular CMML-specific prognostic scoring system (CMML-mol; AUC 0.73/0.75) and the international prognostic scoring system-molecular (IPSS-M; AUC 0.73/0.74). Multivariable analysis of mutations and karyotype identified PHF6MUT and TET2MUT as being "favorable" and DNMT3AMUT, U2AF1MUT, BCORMUT, SETBP1MUT, ASXL1MUT, NRASMUT, PTPN11MUT, RUNX1MUT, TP53MUT, and adverse karyotype, "unfavorable". Molecular information was subsequently encoded in a combined clinical-molecular risk model (BLAST-mol; AUC 0.80/0.86 at 3/5-years) that included the aforementioned BLAST clinical risk variables and a 3-tiered molecular risk score. BLAST and BLAST-mol were subsequently validated by two separate external cohorts. Independent risk factors for blast transformation included DNMT3AMUT, ASXL1MUT, PHF6WT, leukocytes ≥13 x 109/L, and ≥2% circulating or ≥10% bone marrow blasts. The current study proposes an easy to implement, globally applicable, and molecularly adaptive risk model for CMML.

The role of inhaled antifungals for prophylaxis and treatment of invasive fungal pneumonias remains undefined. Herein we summarize recent clinically relevant literature in high-risk groups such as neutropenic hematology patients, including those undergoing stem cell transplant, lung and other solid transplant recipients, and those with sequential mold lung infections secondary to viral pneumonias. Although there are several limitations of the available data, inhaled liposomal amphotericin B administered 12.5 mg twice weekly could be an alternative method of prophylaxis in neutropenic populations at high risk for invasive fungal pneumonia where systemic triazoles are not tolerated. In addition, inhaled amphotericin B has been commonly used as prophylaxis, pre-emptive, or targeted therapy for lung transplant recipients but is considered as a secondary alternative for other solid organ transplant recipients. Inhaled amphotericin B seems promising as prophylaxis in fungal pneumonias secondary to viral pneumonias, influenza, and SARS CoV-2. Data remain limited for inhaled amphotericin for adjunct treatment, but the utility is feasible.

Response patterns and impact of MRD in patients with IDH1/2-mutated AML