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Recent reports suggest a favorable prognosis for PHF6 mutation ( PHF6 MUT ) in chronic myelomonocytic leukemia (CMML) and unfavorable in acute myeloid leukemia (AML). We accessed 176 consecutive patients with a spectrum of myeloid neoplasms with PHF6 MUT , including AML ( N  = 67), CMML ( N  = 49), myelodysplastic syndromes (MDS; N  = 36), myeloproliferative neoplasms (MPN; N  = 16), and MDS/MPN ( N  = 8). PHF6 mutations were classified as nonsense (43%) or frameshift (30%) with the PHD2 domain being the most frequently (64%) affected region. Median follow-up was 25 months with 110 (63%) deaths and 44 allogenic transplants. Our top-line observations include (a) a distinctly superior overall survival (OS; 81 vs. 18 months; p  < 0.01) and blast transformation-free survival (BTFS; “not reached” vs. 44 months; p  < 0.01) in patients with CMML vs. those with other myeloid neoplasms, (ii) a higher than expected frequency of isolated loss of Y chromosome, in the setting of CMML (16% vs. expected 6%) and MDS (8% vs expected 2.5%), (iii) a significant association, in MDS, between PHF6 MUT variant allele fraction (VAF) > 20% and inferior OS (HR 3.0, 95% CI 1.1–8.1, multivariate p  = 0.02) as well as female gender and inferior BTFS (HR 26.8, 95% CI 1.9–368.3, multivariate p  = 0.01), (iv) a relatively favorable median post-transplant survival of 46 months. Multivariable analysis also identified high-risk karyotype (HR 5.1, 95% CI 1.2–20.9, p  = 0.02), and hemoglobin <10 g/dL (HR 2.7, 95% CI 1.0–7.2, p  = 0.04), as independent predictors of inferior OS in patients with MDS. The current study provides disease-specific information on genotype and prognosis of PHF6 -mutated myeloid neoplasms.

Contemporary risk models in chronic myelomonocytic leukemia (CMML) focus on the prognostic relevance of individual rather than concurrent mutations. In the current study of 605 Mayo Clinic patients with CMML, we applied machine-learning algorithms in order to examine the influence of cooperative mutational interactions on blast transformation (BT). A hierarchical clustering algorithm was developed and tailored for patient stratification using survival outcomes and co-occurrence of genomic alterations. Five molecular clusters were identified with 3-year blast BT rates ranging from 0% to 100% (AUC at 3 years 0.78). A subsequent Cox regression analysis confirmed independent detrimental impact of specific mutations or their combinations including NPM1 (HR 26.7; p  < 0.01), “ NRAS  +  SETBP1 ” (HR 12.6; p  < 0.01), “ ASXL1  +  BCOR” (HR 8.4; p  < 0.01), “ ASXL1  +  RUNX1 ” (HR 2.2, p  < 0.01), JAK2 (HR 2.1; p  < 0.01), and “ ASXL1  +  TET2 ” (HR 1.7; p  = 0.02) while “ PHF6 +wild-type ASXL1” (HR 5.61e−10; p  < 0.01) had a favorable impact. Furthermore, compared to NPM1 wild-type cases , NPM1 -mutated patients were less likely to have co-occurring mutations involving ASXL1 (0% vs. 43%, p  < 0.01), RUNX1 (0% vs. 17%, p  = 0.02), and SRSF2 (7% vs. 39%, p  < 0.01) and were more likely DNMT3A (71% vs. 7%, p  < 0.01). The prognostic relevance of “ NRAS  +  SETBP1 ”, “ ASXL1  +  RUNX1 ”, NPM1 and BCOR was validated in an external cohort from Italy ( N  = 501). Taken together, these observations highlight i) the possibility of prognostic interaction of mutations in CMML that should be considered in the development of future risk models and ii) the distinct genotypic and prognostic characteristics of NPM1 -mutated CMML.

The comparative value of liposomal cytarabine/daunorubicin (CPX-351) versus venetoclax plus a hypomethylating agent (Ven-HMA) in the frontline treatment of older adults with primary (de novo) or secondary acute myeloid leukemia (AML) remains uncertain. In the current study, we retrospectively examined outcomes of 600 patients with newly diagnosed AML treated with CPX-351 ( N  = 112) or Ven-HMA ( N  = 488). AML subtypes included de novo ( N  = 277, 46%), post-myelodysplastic syndrome (post-MDS, N  = 114,19%), post-myeloproliferative neoplasm (post-MPN, N  = 70, 12%), post-MDS/MPN ( N  = 36, 6%), and t-AML ( N  = 103, 17%). Patients receiving CPX-351 were younger (median 65 vs. 73 years; p  < 0.01), predominantly female (50% vs. 38%; p  = 0.02), more likely to have secondary AML (68% vs. 51%; p  < 0.01), and less likely to harbor NPM1 MUT (5% vs. 12%; p  = 0.02). Rates of complete response with or without count recovery (CR/CRi) were comparable between CPX-351 and Ven-HMA (55% vs. 60%; p  = 0.30), including AML with myelodysplasia-related gene mutations or cytogenetic abnormalities (AML-MR 60% vs. 63%; p  = 0.70). Ven-HMA use was associated with fewer infectious complications (62% vs. 83%; p < 0.01) and yielded higher CR/CRi rates in males (60% vs. 45%; p  = 0.04), de novo AML (68% vs. 50%; p  = 0.03), and in the presence of STAG2 MUT (86% vs. 44%; p  = 0.02), or CEBPA MUT (88% vs. 50%; p  = 0.03). Overall survival censored for transplant, was similar (median 10 vs. 13 months; p  = 0.90), with Ven-HMA being superior in post-MDS AML (median 12 vs. 7 months; p  = 0.02) and CPX-351 in the presence of SF3B1 MUT (median not reached vs. 14 months; p  < 0.01). Our findings suggest that Ven-HMA is as effective and less toxic than CPX-351 in newly diagnosed AML, including AML-MR, despite selection of younger, fitter patients for CPX-351.

Allogeneic stem cell transplant (ASCT) remains the only curative option in chronic myelomonocytic leukemia (CMML). We retrospectively analyzed 138 CMML patients who underwent ASCT at the Mayo Clinic. Patients who transitioned to ASCT while in chronic phase (Group A) displayed superior post-transplant survival (PTS), compared to those in whom ASCT was performed after blast transformation (BT; Group B) (median 95 vs. 16 months; p  = 0.01). In Group A, PTS was superior in patients with <5% bone marrow (BM) blasts at time of ASCT (median 164 vs. 13.5 months; p  = 0.01). Other predictors of superior PTS included day-100 BM blast <5% or normal cytogenetics (median 164 vs. 18 months; p  = 0.01) or presence of chronic graft-versus-host-disease (GVHD; median 164 vs. 26 months; p  = 0.01). Pre-ASCT hypomethylating agent exposure (HR = 2.03; p  = 0.03), and receiving more than one line of pre-ASCT chemotherapy ( p  = 0.01) predicted inferior PTS. In multivariable analysis, predictors of superior GVHD-free and relapse-free survival (GRFS) included the use of myeloablative conditioning and the absence of morphologically or cytogenetically apparent disease at day-100. The use of post-transplant cyclophosphamide (PTCy) was associated with a higher cumulative incidence of relapse ( p  = 0.02) and numerically inferior PTS ( p  = 0.1). Group B patients also appeared to benefit from achieving BM blast <5% at the time of ASCT ( p  = 0.4) as well as at day-100 ( p  = 0.01), in terms of PTS, while full chimerism and normal cytogenetics at day-100 were associated with superior GRFS. These observations support the value of ASCT in CMML, especially if performed prior to BT and in the presence of <5% BM blasts at the time of ASCT. Additionally, the observed detrimental impact of PTCy requires additional studies to confirm and investigate the underlying mechanisms.

Background: Coronary artery calcification (CAC) can be visually estimated on computed tomography (CT) attenuation correction (CTAC) of positron emission tomography (PET). The visual estimation of CAC from CTAC scans performed for PET/CT is comparable to the standard CAC score scan. Myocardial perfusion imaging (MPI) with single-photon emission CT (SPECT) is commonly performed for risk stratification before oncologic surgery. Objective: We investigated the value of visual estimation of CAC from CTAC of PET/CT as well as other factors such as coronary artery disease (CAD) risk factors and type of cancer as predictors of MPI ischemia. Methods: Retrospectively, we identified 268 patients who underwent PET/CT and MPI for preoperative cardiac evaluation. Visual estimation of CAC was performed and classified into four categories. Results: The results of visual CAC were as follows: 47.8% - zero CAC, 32.8% - mild CAC, 14.2% - moderate CAC, and 5.2% - severe CAC. The majority of patients (85.8%) had normal MPI, whereas 14.2% were abnormal. There was a strong association between ischemia on MPI and CAC seen on CTAC (P < 0.01), dyslipidemia (P < 0.01), family history of CAD (P < 0.05), smoking (P < 0.01), and type of malignancy (P < 0.01). Conclusion: A strong association exists between visual estimation of CAC on CTAC and MPI. Zero is highly associated with normal MPI, but moderate-to-severe CAC is associated with abnormal MPI, in addition smoking, dyslipidemia, and certain cancer are associated with ischemic MPI; subsequently, preoperative cardiac testing is warranted in these subsets of patients.

No data are available in Saudi Arabia on the relationship between coronary artery calcification (CAC) and myocardial perfusion scintigraphy (MPS) in asymptomatic women, for determining subclinical coronary artery disease (CAD). The main objective of this study was to investigate the relationship between the presence of CAC and stress-induced myocardial ischemia by MPS in asymptomatic women. Single-center retrospective study over a 2-year period. One hundred and one women (mean [SD] age, 56 [11] years) without known CAD underwent both MPS and CAC scanning within 3 months. The frequency of ischemia by MPS was compared with the presence or absence of CAC and the number of CAD risk factors. The prevalence of ischemic MPS was 22% (22/101). Among the 22 patients with ischemic MPS, the CAC score was 0 in 5 patients of 22 (23%), 1 to 200 in 4 patients of 22 (18%), and more than 200 in 13 patients of 22 (59%) (P=.0001). In contrast, among the 79 patients with normal MPS, the CAC score was 0 in 44 of 79 (56%) patients, 1 to 200 in 25 of 79 (32%), and more than 200 in 10 of 79 (13%). The presence or absence of CAC was the single most important predictor of the MPS result (P=.0001). Moderate to severe CAC is associated with ischemic MPS in more than 50% of asymptomatic women with 2 or more CAD risk factors. Abnormal MPS is rarely associated with a 0 CAC score. Normal MPS does not exclude subclinical CAD. Therefore, CAC screening is an appropriate initial screening test for CAD in asymptomatic women.