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Objectives: We assess the epidemiology and risk factors for mortality of bloodstream infection (BSI) in patients with acute leukemia (AL)., Methods: Prospectively collected data of a cohort study from July 2004 to February 2016. Multivariate analyses were performed., Results: 589 episodes of BSI were documented in 357 AL patients, 55% caused by gram-positive bacteria (coagulase-negative staphylococci 35.7%, Enterococcus spp 10.8%) and 43.5% by gram-negative bacteria (E. coli 21%, PA 12%). We identified 110 (18.7%) multidrug-resistant (MDR) microorganisms, especially MDR-Pseudomonas aeruginosa (7%) and extended-spectrum beta-lactamase producing Enterobacteriaceae (7%). The 30-day mortality was 14.8%. Age (OR 3.1; 95% CI 1.7-5.7); chronic lung disease (4.8; 1.1-21.8); fatal prognosis according to McCabe index (13.9; 6.4-30.3); shock (3.8; 1.9-7.7); pulmonary infection (3.6; 1.3-9.9); and MDR-PA infections with inappropriate treatment (12.8; 4.1-40.5) were related to mortality. MDR-PA BSI was associated to prior antipseudomonal cephalosporin use (9.31; 4.38-19.79); current use of betalactams (2.01; 1.01-4.3); shock (2.63; 1.03-6.7) and pulmonary source of infection (9.6; 3.4-27.21)., Conclusions: MDR organisms were commonly isolated in BSI in AL. Inappropriate empiric antibiotic treatment for MDR-PA is the primary factor related to mortality that can be changed. New treatment strategies to improve the coverage of MDR-PA BSI should be considered in those patients with risk factors for this infection., Competing Interests: The authors have declared that no competing interests exist.

Mixed phenotype acute leukemias are infrequent and considered high risk. The optimal treatment approach and the role of allogeneic hematopoietic stem cell transplantation are not entirely clear. In this study, we investigated 519 patients with mixed phenotype acute leukemia in first complete remission who underwent allogeneic hematopoietic stem cell transplantation between 2000 and 2014, and who were reported to the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Median age was 38.1 years (range 18-75). Cytogenetics classified 49.3% as poor risk. At three years, relapse incidence was 31.4% (26.9-35.9), non-relapse mortality was 22.1% (18.4-26.1), the leukemia-free survival was 46.5% (41.7-51.4), and the overall survival was 56.3% (51.5-61.2). At six months, 32.5% had developed acute graft- versus -host disease, while at three years, 37.5% had developed chronic graft- versus -host disease (32.6-42.3). In a multivariate analysis, age and year of transplant had a strong impact on outcome. Myeloablative conditioning using total body irradiation correlated with a better leukemia-free survival. Our study suggests that mixed phenotype acute leukemia is potentially sensitive to graft- versus -leukemia and thus can benefit from allogeneic hematopoietic stem cell transplantation with a potential for cure., (Copyright© 2017 Ferrata Storti Foundation.)

Background: Appropriate chemotherapy dosing for obese patients with malignant diseases is a significant challenge because limiting chemotherapy doses in these patients may negatively influence outcome. There is a paucity of information addressing high-dose chemotherapy in obese patients undergoing hematopoietic stem cell transplantation (HSCT)., Methods: The Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) designed an electronic survey to assess current practice of dose adjustment of chemotherapy in obese patients undergoing HSCT., Results: A total of 56 EBMT centers from 27 countries responded to the online survey. Overall, 45 centers declared that they routinely adjust chemotherapy doses for obese patients (80.5%), and only 11 (19.5%) declared they do not adjust dose. Among the former group, most used body mass index as the parameter for defining obesity (28 centers, 62%). The method for determining the weight for chemotherapy calculation was actual body weight (ABW) in 16 centers, ideal body weight (IBW) in 10 centers, IBW plus 25% of the difference between IBW and ABW in 16 centers, and other methods for the rest. Among centers that used dose adjustment, 44% also capped the dose at 2 m(2) for a chemotherapy dose based on body surface area (BSA), whereas 56% did not cap. Interestingly, most of the centers (9 of 11) that did not adjust dose for weight also did not cap the BSA at 2 m(2)., Conclusion: This EBMT survey revealed large diversity among transplant centers regarding dose-adjustment practice for high-dose conditioning chemotherapy. Our next step is to analyze outcomes of transplantation according to dose-adjustment practice and, subsequently, to formulate a methodology for future prospective studies., (©AlphaMed Press.)

Simple Summary: In spite of the recent expansion of the therapeutic landscape for acute myeloid leukemia (AML), resistance mechanisms and relapsed disease still pose a serious barrier to achieve curation for most patients. Considering the high inter- and intrapatient heterogeneity, disruptive therapeutic approaches are expected to provide a clinical solution for this unmet need. An in silico drug discovery program identified a new family of lysosome- and mitochondria-targeting compounds that specifically eradicate leukemia ex vivo and in vivo in relevant preclinical models by inducing both mitochondrial damage and apoptosis, and the simultaneous lysosomal membrane leakiness. Moreover, the compounds are effective in a wide panel of cancer cell lines, as their mechanism of action targets a common neoplastic feature. These compounds possess adequate pharmacological properties rendering them promising drug candidates for AML and unrelated neoplasias, and support their further clinical development. Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+–TFEB–MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias. [ABSTRACT FROM AUTHOR]

BACKGROUND: The presence of TP53 mutations is associated with an unfavorable outcome in patients allografted for acute myeloid leukemia (AML), leading some to question the benefit of an allogeneic stem cell transplantation (allo‐SCT) for this patient group, although this has not been studied in a large cohort. METHODS: A total of 780 patients with AML in first complete remission, with either intermediate‐ or adverse‐risk cytogenetics, whose TP53 mutation status was reported, were included in this study from the European Society for Blood and Marrow Transplantation. RESULTS: Two‐year overall survival (OS) was impaired in patients (n = 179) with evidence of a TP53 mutation at diagnosis (35.1%; 95% confidence interval [CI], 26.7–43.7) as compared to the cohort without (n = 601) (64%; 95% CI, 59.1–68.4; P =.001). In patients with mutant TP53 AML with no evidence of either chromosome 17p loss (17p–) and/or complex karyotype (CK) (n = 53, 29.6%), 2‐year OS was 65.2% (95% CI, 48.4–77.6). This was not significantly different to patients without TP53 mutations. In patients with mutant TP53 AML with either 17p– and/or CK (n = 126, 70.4%), the OS was lower (24.6%; 95% CI, 16.2–34; P =.001). CONCLUSIONS: In summary, the adverse prognostic effect of TP53 mutations in AML following an allo‐SCT is not evident in patients with neither co‐occurring 17p– and/or CK, and these data inform decisions regarding allo‐SCT in patients with TP53 mutant AML. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor C (VEGFC) stimulates leukemia cell proliferation and survival, and promotes angiogenesis. We studied VEGFC expression in bone marrow samples from 353 adult acute myeloid leukemia (AML) patients and its relationship with several clinical, cytogenetic, and molecular variables. We also studied the expression of 84 genes involved in VEGF signaling in 24 patients. We found that VEGFC expression was higher in AML patients with myelodysplasia-related changes (AML-MRC) than in patients with non-AML-MRC. We also found an association between VEGFC expression and the patient cytogenetic risk group, with those with a worse prognosis having higher VEGFC expression levels. No correlation was observed between VEGFC expression and survival or complete remission. VEGFC expression strongly correlated with expression of the VEGF receptors FLT1, KDR, and NRP1. Thus, in this series, VEGFC expression was increased in AML-MRC and in subgroups with a poorer prognosis, but has no impact on survival. [ABSTRACT FROM AUTHOR]

Objectives: The prognostic impact of immunophenotypic markers in acute myeloid leukemia (AML) is controversial. Methods: We retrospectively analyzed the value of CD34, CD117, CD7, and CD123 expression in a consecutive series of 592 adult patients with de novo AML. Results: CD34+ measured as a percentage (≥2.88%) and CD34 mean fluorescence intensity (MFI) (≥146.79, arbitrary units [AU]) expression had a prognostic impact in terms of overall survival (OS; P = .005, P = .003), leukemia-free survival (LFS; P = .011, P < .001), and cumulative incidence of relapse (CIR; P = .014, P =. 001). The percentage of CD117+ cells (61.29%) was associated with shorter LFS (P =. 043), and CD117 MFI (≥284.01 AU) was associated with a shorter OS (P =. 033) and LFS (P =. 028). In the multivariate analysis, high CD34 MFI retained the independent value as predictor of LFS and CIR (P =. 012; hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.11- 2.28 and P =. 045; HR, 1.58; 95% CI, 1.01-2.46). Conclusions: CD34 positivity threshold with prognostic relevance is low (3% positive cells). Immunophenotypic findings in AML probably could only be fully exploited after a complex analysis that takes into account unconventional thresholds and the MFI. [ABSTRACT FROM AUTHOR]

Burkitt's lymphoma (BL) and Burkitt-like acute lymphoblastic leukemia (ALL) are uncommon lymphoproliferative disorders after solid organ or stem cell transplantation. Although their prognosis is considered to be poor, there are scarce data on the clinical characteristics and the response to specific therapies. We report the main clinical characteristics and the results of a specific intensive chemotherapy in 5 adult patients with postransplant BL/ALL3 included in the PETHEMA ALL3/97 protocol. Two patients died in induction, another died in consolidation phase and the remaining 2 patients are in continuous complete remission 6 and 18 months from the diagnosis. [ABSTRACT FROM AUTHOR]

The prognostic impact of global DNA methylation and hydroxymethylation was assessed in 90 patients with de novo myelodysplastic syndrome (MDS). DNA was isolated from bone marrow samples obtained at diagnosis and global methylation and hydroxymethylation were determined by ELISA. Patients with a percentage of methylated DNA above 2.73% had a shorter overall survival than those with lower levels (P=0.018) and presented a negative trend in terms of leukemia-free survival (P=0.084), that was statistically significant after censoring 9 patients that received disease-modifying treatments both in univariate and multivariate analyses. Similarly, the low-risk MDS patients defined by the IPSS, WPSS and IPSS-R with 5-mC percentage in total DNA above 2.73% had a shorter overall survival (P=0.032; P=0.023; P=0.031). No cut-off value for the 5-hydroxymethylcytosine percentage with statistical significance for overall or leukemia-free survival was obtained. This study suggests that global DNA methylation predicts overall survival in myelodysplastic syndromes. [ABSTRACT FROM AUTHOR]