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Characterized by bone marrow dysplasia and peripheral blood monocytosis, chronic myelomonocytic leukemia (CMML) is one of the most aggressive chronic leukemias and has a propensity for progression to acute myeloid leukemia (AML). Patients with newly diagnosed AML generally present with symptoms related to complications of pancytopenia but can also present with renal insufficiency. We present a 79-year-old male with a past medical history of CMML and chronic kidney disease stage 3 (baseline creatinine 1.8 mg/dL) who presented with one day of inability to urinate and 20-lb unintentional weight loss, fatigue, and bone pain over 3 months. Laboratory evaluation revealed leukocytosis of 88.5 x 103/uL (normal 4.8–10.8 x 103/uL) with 24.0% monocytes on differential, creatinine 2.94 mg/dL (baseline creatinine 1.7–1.9 mg/dL), uric acid 19.8 mg/dL, potassium 4.0 mmol/L, phosphorus 4.0 mg/dL, calcium 9.2 mg/dL, and albumin 3.2 g/dL. Urinalysis was significant for protein 200 mg/dL, 20/LPF granular casts, and 7/LPF hyaline casts. Bone marrow biopsy revealed 20–30% blasts with monocytic features of differentiation consistent with acute myeloid leukemia. Computed tomography (CT) of the abdomen and pelvis appreciated splenomegaly with retroperitoneal, and pelvic lymphadenopathy. Kidney failure can complicate the presentation of AML but can be rapidly reversible with treatment. In patients with CMML who have progressive renal insufficiency and hyperuricemia, there should be a high index of suspicion for progression to AML.

Chronic myelomonocytic leukemia (CMML) is a relatively uncommon hematologic malignancy that manifests as peripheral monocytosis, has varying degrees of bone marrow dysplasia, and is associated with poor outcomes. Despite a growing appreciation of the pathobiologic mechanisms driving CMML, current therapies have not clearly demonstrated any survival benefit. The complex pathobiology of CMML highlights the intricate aberrantly activated cellular pathways that influence disease phenotype and limit current treatment options. Understanding of these oncogenic pathways may provide novel mechanism-based treatment strategies that may ultimately offer better outcomes for patients. We reviewed the current diagnostic, prognostic, and molecular understandings, and we assessed the current and future treatment options for CMML.

INTRODUCTION: Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare hematological disorder characterized by anemia, bone marrow dysplasia with ring sideroblasts and persistent thrombocytosis, and high frequency of SF3B1 and JAK2 mutations. Despite clinical, histological and molecular similarities with MDS with ring sideroblasts (MDS-RS), the clinical outcomes of these entities are diverse. To date, there is no data evaluating specific functional pathways which might explain phenotypic and clinical differences beyond diverse frequencies of JAK2 mutation. METHODS: We evaluated a total of 24 patients (pts) with MDS/MPN-RS-T and 27 pts with MDS-RS. Diagnosis was based on WHO 2017 criteria and confirmed by two independent hematopathologists. Whole bone marrow DNA was subject to 81 gene targeted next-generation sequencing (NGS) analysis. CD34+ cells from bone marrow samples of 4 pts with MDS/MPN-RS-T, 7 pts with MDS-RS and 17 healthy individuals obtained from AllCells (Emeryville, CA) were isolated using the CD34 MicroBead Kit and RNA was isolated using the PicoPure RNA isolation kit. Fastq files were mapped to the human genome (build GRCh38) in TopHat2 using the default options. Differential gene expression analysis was conducted using DESeq2 in R version 3.6.2. Pathway enrichment analysis was performed using gene set enrichment analysis, with the fgsea library in R. RESULTS: Patients with MDS/MPN-RS-T had higher median bone marrow ring sideroblast percentage (47% vs 32%, p=0.04) and absolute neutrophil count (4.34x109/L vs 2.99x109/L, p=0.001). Frequency of identified mutations and their VAFs compared to MDS-RS are shown in Figure 1A. The median number of mutations was higher in MDS/MPN-RS-T than in MDS-RS (3 vs 2, p CONCLUSIONS: MDS/MPN-RS-T is characterized by co-dominance of SF3B1 and JAK2 mutations and presence of minor kinase signaling mutations not observed in MDS-RS. Upregulation of cytokine and interleukin signaling mediated through GPC receptors, and downregulation of genes involved in apoptosis and DNA damage are unique transcriptomic features of MDS/MPN-RS-T likely driven by genotype. These unique genomic and transcriptomic characteristics of MDS/MPN-RS-T supports the classification of MDS/MPN-RS-T based on genomic features beyond presence of SF3B1 mutation, and might represent potential therapeutic avenues for this rare disease. Figure Disclosures Sasaki: Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Kantarjian:Sanofi: Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BioAscend: Honoraria; Novartis: Honoraria, Research Funding; Delta Fly: Honoraria; Pfizer: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Ascentage: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy.

The leishmaniases constitute a group of parasitic diseases caused by species of the protozoan genus Leishmania. In humans it can present different clinical manifestations and are usually classified as cutaneous, mucocutaneous, and visceral (VL). Although the full range of parasite—host interactions remains unclear, recent advances are improving our comprehension of VL pathophysiology. In this review we explore the differences in VL immunobiology between the liver and the spleen, leading to contrasting infection outcomes in the two organs, specifically clearance of the parasite in the liver and failure of the spleen to contain the infection. Based on parasite biology and the mammalian immune response, we describe how hypoxia-inducible factor 1 (HIF1) and the PI3K/Akt pathway function as major determinants of the observed immune failure. We also summarize existing knowledge on pancytopenia in VL, as a direct effect of the parasite on bone marrow health and regenerative capacity. Finally, we speculate on the possible effect that manipulation by the parasite of the PI3K/Akt/HIF1 axis may have on the myelodysplastic (MDS) features observed in VL.

Background Morphologic and cytogenetic assessments are required to characterize diagnostic and prognostic features of myelodysplastic syndromes (MDS). We assessed whether these assessments were performed among newly diagnosed MDS patients in the Netherlands. Methods MDS cases were retrieved from the nationwide Netherlands Cancer Registry (N = 9159; period 2001–2014) and the regional PHAROS MDS registry (N = 676; period 2008–2011). Results The proportion of unclassified MDS decreased from 58% in 2001 to 13% in 2014. Data from the more detailed PHAROS registry revealed that the degree of bone marrow dysplasia was only reported in ∼30% of all evaluable bone marrow aspirates. Further, the International Prognostic Scoring System was undetermined in 55% of patients, primarily owing to unperformed cytogenetics in 46% of patients. Conclusion The classification of MDS is improving in the Netherlands. Nevertheless, particular diagnostic and prognostic procedures that are essential for the diagnosis and subsequent treatment decision-making of MDS were not fully utilized in particular patient subsets.

The pathological hallmark of myelodysplastic syndromes (MDS) is marrow dysplasia, which represents the basis of the WHO classification of these disorders. This classification provides clinicians with a useful tool for defining the different subtypes of MDS and determining individual prognosis. The WHO proposal has raised some concern regarding minimal diagnostic criteria particularly in patients with normal karyotype without robust morphological markers of dysplasia (such as ring sideroblasts or excess of blasts). Therefore, there is clearly a need to refine the accuracy to detect marrow dysplasia. Flow cytometry (FCM) immunophenotyping has been proposed as a tool to improve the evaluation of marrow dysplasia. Rationale for the application of FCM in the diagnostic work up of MDS is that immunophenotyping is an accurate method for quantitative and qualitative evaluation of hematopoietic cells and that MDS have been found to have abnormal expression of several cellular antigens. To become clinically applicable, FCM analysis should be based on parameters with sufficient specificity and sensitivity, data should be reproducible between different operators and the results should be easily understood by clinicians. In this report, we reviewed the most relevant progresses in detection of marrow dysplasia by FCM in MDS as defined by WHO criteria.

Bone marrows from 23 patients with haemopoietic dysplasia were cultured in agar-gel and the patients were followed for at least 6 months after culture. The incidence of colonies, microclusters and macroclusters and the colony to cluster and microcluster to macrocluster ratios were compared to those of a control group. In the control patients a normal wide range of colonies and clusters was observed and colony growth correlated with cluster growth. About half of the dysplastic patients showed a normal growth pattern and ran a stable and benign course. The other dysplastic patients had defective colony growth, a low colony to cluster ratio, an increased microcluster to macrocluster ratio and a deficient macrocluster growth early in culture. These patients more often presented with cytopenia and had a malignant course with increasing bone marrow dysplasia and a frequent need of blood transfusions. Some patients died of cytopenia or transformed into acute leukaemia. The bone marrow cultures of haemopoietic dysplasia did not predict the short term (within 6 months) risk of leukaemia transformation. However, the results indicate that examination of culture growth can be used to differentiate stable and benign patients from those in whom clonal abnormalities may suggest a progressive and malignant course.

Little is known about factors contributing to disease-evolution in early-phase myelodysplastic syndromes (MDS). In this article, low erythropoietin (EPO) production is discussed as a ‘non-oncogenic’ co-factor responsible for disease-manifestation in a group of patients with low-risk MDS. The hypothesis is based on the observations that (i) individuals with bone marrow dysplasia and MDS-related karyotypes but relatively high EPO levels may present without anemia and thus without frank MDS over years, (ii) several elderly patients with idiopathic anemia are low EPO producers and their anemia can be corrected with EPO therapy, and (iii) the well-known fact that low-risk MDS patients typically respond to EPO therapy when they have low endogenous EPO levels.

The myelodysplastic syndromes (MDS) are a collection of hematopoietic disorders with varying degrees of mono- to trilineage cytopenias and bone marrow dysplasia. In recent years much progress has been made in the treatment of MDS and there are now several therapeutic compounds used with varying levels of success. These compounds typically cause side effects that make them unattractive for treatment of patients in the early stages of MDS. Naturally occurring compounds that are not toxic may provide a means to treat patients in the initial stages of disease. We conducted a pilot study to test the efficacy of coenzyme Q10 (coQ10) in MDS patients with low to intermediate-2 risk disease. A variety of responses were observed in 7 of 29 patients including two trilineage and two cytogenetic responses. Sequencing mitochondrial DNA (mtDNA) from pretreatment bone marrows showed multiple mutations, some resulting in amino acid changes, in 3/5 nonresponders, 1/4 responders and in two control samples. We conclude that coQ10 may be of clinical benefit in a subset of MDS patients, but responders cannot be easily pre-selected on the basis of either the conventional clinical and pathologic characteristics or mtDNA mutations.

Dysplastic features of cells in peripheral blood and bone marrow were studied in 51 patients with myelodysplastic syndromes (MDS) to evaluate the significance of the degree of neutrophil granulation (G-score) and the percentage of pelgeroid polymorphs (ppp) in the peripheral blood, as indices of dysplastic changes in the bone marrow. There was a good correlation between peripheral blood and bone marrow findings, both for G-score figures (r = 0.92, P0.01) and ppp (r = 0.82, P0.01). Significantly lower G-score figures were found among patients with an increased percentage of bone marrow blasts (P0.05), while high ppp correlated with the presence of ring sideroblasts, the degree of bone marrow fibrosis, and findings of complex chromosomal abnormalities. Patients with a high degree of bone marrow dysplasia had significantly lower G-score (P0.01) and significantly higher ppp (P0.05) figures, than those with less pronounced myelodysplasia. In addition, extreme hypogranulation (G-score150) or very high ppp (or = 20%) was generally a sign of bi- and tri-lineage dysplasia in the bone marrow. The results thus show that quantitative estimation of peripheral blood polymorph dysplasia by G-score figures and ppp seems to reflect the total degree of bone marrow dysplasia in MDS and may serve as a complement to bone marrow evaluation when the diagnosis of MDS is difficult.