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In 2022, the World Health Organization (WHO) and International Consensus Classification (ICC) recognized TP53 as an entity-defining alteration in myeloid neoplasms, yet with differing criteria that could lead to discrepant diagnoses and affect clinical trial eligibility. We studied 67 patients with TP53 mutant myeloid neoplasms, reclassifying them using both criteria. While most cases fulfill the criteria for TP53 mutant defined entities, most discrepancies were found in cases with ≥20% blasts. Patients were stratified into three groups based on blast count (<10%, 10–19%, and ≥20%) which revealed comparable clinicopathologic features, genetic characteristics, and outcomes. Notably, patients with ≥10% blasts had shorter overall survival compared to those with <10% blasts (8.1 vs. 12.4 months; p = 0.03). This study is among the few to examine TP53 mutant myeloid neoplasms as a single entity and suggests that the 10% blast count threshold could serve as a gateway to a more harmonized classification for these patients. [ABSTRACT FROM AUTHOR]

AbstractAccess to allogeneic and autologous hematopoietic stem cell transplantation (SCT) remains inadequate despite its curative potential across hematologic malignancies. In 2015, Hartford HealthCare (HHC) and the Memorial Sloan Kettering Cancer Center (MSK) established the Shared Care Model (SCM) with a primary aim of enhancing SCT access for HHC patients. The SCM comprises several components: an SCT-dedicated nurse-navigator, a health-information exchange for record sharing, telemedicine, and ongoing training of HHC clinicians in transplant patient selection and management. We evaluated the SCM’s impact on SCT access across 126 patients with acute leukemia, myelodysplastic syndrome, and multiple myeloma from 2016-2020. The SCM facilitated 34 referrals. Socio-economic status of HHC referrals by Area Deprivation Index was significantly inferior (38 vs. 14, p < 0.001) when compared to 3,108 non-SCM referrals to MSK during the same period. Allogeneic recipients spent 68-247 days away from home, and autologous recipients 15-48, both requiring few subsequent visits to MSK. [ABSTRACT FROM AUTHOR]

The boundary between myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) has been revised in the latest World Health Organization classification of myeloid malignancies. These changes were motivated by the description of a subgroup of MDS patients identified as oligomonocytic chronic myelomonocytic leukemia (OM-CMML) at risk of evolving into overt CMML. Various studies will be reviewed describing the clinical and biological features of MDS patients evolving to CMML. The efforts to discover biomarkers enabling the identification of these patients at the time of MDS diagnosis will be discussed. Finally, the molecular landscape of these patients will be presented with a specific focus on the biallelic inactivation of TET2 in light of its functional impact on hematopoietic stem cells, granule-monocytic differentiation, and its tight interplay with inflammation. [ABSTRACT FROM AUTHOR]

Objectives: MDS and AML characterized by TP53 variations have a poor prognosis in general. However, specifically, differences in prognosis have also been observed in patients with different TP53 variants and VAFs. Methods: Here, we retrospectively analyzed datasets of patients with MDS, MPN, and AML who underwent targeted DNA sequencing from February 2018 to December 2023, and patients with reportable TP53 variations were screened. Demographic data and clinical data were collected, and the relationship between TP53 alterations and patient prognosis (AML/MDS) was analyzed using the cBioPortal and Kaplan–Meier Plotter databases. The relationship between the VAFs of TP53 variations and prognoses was analyzed using data from the present study. Results: Sixty-two variants of TP53 were identified in 58 patients. We mainly identified single mutations (79.31%, 46/58), followed by double (17.24%, 10/58) and triple (3.45%, 2/58) mutations. The variations were mainly enriched in exon4–exon8 of TP53. Missense (72.58%, 45/62) mutations were the main type of variations, followed by splice-site (9.68%, 6/62), nonsense (9.68%, 6/62), frameshift (6.45%, 4/62), and indel (1.61%, 1/62) mutations. In this study, p.Arg175His and p.Arg273His were high-frequency TP53 mutations, and DNMT3A and TET2 were commonly co-mutated genes in the three types of myeloid neoplasms; However, we reported some new TP53 variants in MPN that have not been found in the public database. Moreover, MDS or AML characterized by altered TP53 had a shorter OS than patients in the unaltered group (P<0.01), low TP53 mRNA levels were associated with shorter OS in patients with AML (P<0.01). Data from our center further found higher VAF (≥10%) associated with shorter OS in patients with MDS (median 2.75 vs. 24 months) (P<0.01). Conclusion:TP53 mutations are mainly enriched in exon4–exon8, are missense and single mutations in myeloid neoplasms, and are associated with poor prognosis of MDS/AML, and higher VAF (≥10%) of TP53 mutations associated with a shorter OS in patients with MDS. [ABSTRACT FROM AUTHOR]

AbstractThe mutations in SRSF2 and TET2 genes are frequently present in various myeloid neoplasms. The potential impact of SRSF2/TET2 co-mutations on patient survival is incompletely understood. We identified 412 patients with SRSF2/TET2 co-mutations from our NextGen sequencing database of around 8000 patients and reported likely the largest cohort study. Our study demonstrated the presence of these co-mutations in a spectrum of myeloid neoplasms, which show different genetic and molecular characteristics. Most of the patients with these co-mutations had normal karyotype. Interestingly, our study provided insights into the prevalence of additional mutations such as ASXL1, RUNX1, and KRAS with this co-mutation and their potential impact on patients’ prognosis. We found that ASXL1, RUNX1, and KRAS can negatively impact these patients’ survival with different impacts in different morphological diagnosis categories, suggesting a complex interaction between these genes. This study underscores the need for personalized approaches in the treatment of myeloid neoplasms. [ABSTRACT FROM AUTHOR]

The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF-mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF-mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is characterized by activated inflammatory signaling and affects prognosis. Targeting inflammatory signaling may provide a way to treat the disease. We were curious whether there were changes in A20 in peripheral blood mononuclear cells (PBMC) of MDS patients. Therefore, we conducted a study with 60 clinical samples, including 30 MDS patients and 30 healthy controls. All patients with MDS were diagnosed and classified according to the criteria of the 2016 World Health Organization. The study was performed in accordance with the guidelines of the Declaration of Helsinki. Using Quantitative Real-Time RT–PCR, we discovered that A20 mRNA expression in PBMC of the MDS group was significantly lower than that in the control group (P < 0.001). Additionally, using Luminex Liquid Suspension Chip, we observed elevated plasma levels of pro-inflammatory IL-8 and TNF-α in the MDS group compared to the healthy control group (P < 0.001). We did not find a significant correlation between A20 mRNA and clinical characteristics (age, sex, concentration of hemoglobin, neutrophils count, platelets count, percent of blasts, and WHO classification) of the patients, nor between A20 mRNA and plasma cytokines (data not shown). Our study found down-regulated of A20 and increased levels of pro-inflammatory cytokines in the peripheral blood of MDS patients, providing further evidence for the activation of inflammatory signals in MDS. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a prevalent hematological neoplastic disorder in clinics and its immunopathogenesis has garnered growing interest. Oral and intravenous arsenic agents have long been used to treat hematological malignancies. The main component of oral arsenic is realgar (arsenic disulfide), while arsenic trioxide is the main component of intravenous arsenic. This study aimed to assess the effects of ATO and Realgar on the enhancement of peripheral blood, drug safety, and T cell immune status in the NUP98-HOXD13 (NHD13) mice model of MDS, specifically in the peripheral blood, spleen, and liver. The study findings indicate that realgar and arsenic trioxide (ATO) can improve peripheral hemogram in mice, whereas realgar promotes higher peripheral blood cell production than ATO. Furthermore, the clinical administration method and dose did not cause significant toxicity or side effects and thus can be considered safe. Coexistence and interconversion of hyperimmune function and immunosuppression in mice were also observed in this study. In addition, there were interactions between immune cells in the peripheral blood, spleen, and liver to regulate the immune balance of the body and activate immunity via T-cell activation. In summary, oral and intravenous arsenic agents are beneficial in improving peripheral hemogram and immunity in mice. [ABSTRACT FROM AUTHOR]

Hematopoietic cell transplantation (HCT) has evolved to an essential treatment in younger and more recently in elderly patients with myelodysplastic syndrome (MDS), the age group with the highest incidence. Less intense conditioning regimens and improvements in supportive therapy have reduced considerably transplant related mortality and in the same time increased the access to this curative treatment. Timing of HCT in the course of the disease assumes a crucial role. Detection of disease progression, geriatric assessment, comorbidity evaluation, and identification of transplant-specific risks are becoming increasingly important in this context. Novel statistical methods, molecular biomarkers, and quantification of tumor burden pre- and post-HCT will play an essential role in years to come. More effective and less toxic treatments to reduce the tumor burden before and/or after HCT are expected to improve the outcome. In this review article we discuss the current views and what we can expect. [ABSTRACT FROM AUTHOR]

We conducted a retrospective analysis of 68 newly diagnosed myelodysplastic syndrome (MDS) patients who were treated in the Department of Hematology at Yuncheng Central Hospital affiliated to Shanxi Medical University from October 2017 to March 2022. Based on the serum ferritin (SF) level, the newly diagnosed MDS patients were divided into two groups: iron overload (IOL) group (SF > 1000 ng/mL) and non-iron overload (NIOL) group(SF ≤ 1000 ng/mL). General clinical data, peripheral blood cells, lymphocyte subsets and marrow karyotypes were compared. We found that MDS patients with IOL had lower hemoglobin (Hb), lower reticulocyte (RET) counts, and lower absolute natural killer (NK) cell counts compared with NIOL group (p < 0.05). The correlation analysis also showed a negative correlation between the NK cell counts and SF level (r = −0.270, P = 0.026). Furthermore, we found IOL group had higher incidence of complex and poor karyotypes. In conclusion, we found that IOL is correlated with anemia in MDS patients, which may lead to a decrease in T lymphocyte cells, especially in NK cells, that play a role in the immune pathogenesis of MDS, thereby suppressing immune surveillance function. Additionally, IOL may contribute to the pathogenesis of MDS by affecting karyotypes. [ABSTRACT FROM AUTHOR]

The development of an effective treatment for myelodysplastic syndrome (MDS) is needed due to the insufficient efficacy of current therapies. Gambogenic acid (GNA) is a xanthone constituent of gamboge, a resin secreted by Garcinia hanburyi Hook. f. GNA exhibits antitumor and apoptosis-inducing activities against some cancer cells, but the mechanism is unknown. This study aimed to validate the anti-proliferative and apoptosis-inducing effects of GNA on MDS cells and to elucidate the mechanisms underlying those activities. Apoptosis, proliferation and cell cycle of MDS-L cells were assessed by the caspase 3/7 assay, cell counting and flow cytometry, respectively. The levels of apoptotic, tubulin, NF-κB pathways, and Fas proteins were determined by Western blotting. CRISPR/Cas9 knockout (KO) plasmids were used to generate KO cells of p65 and Fas. MDS cell growth in a xenograft model was evaluated by the AkaBLI system. GNA induced MDS cell apoptosis, accompanied by a reduction in the anti-apoptotic protein MCL-1 expression, and inhibited their growth in vitro and in vivo. GNA combined with the MCL-1 inhibitor MIK665 potently suppressed the proliferation of MDS cells. GNA interfered with tubulin polymerization, resulting in G2/M arrest. GNA induced NF-κB activation and upregulation of Fas, the latter of which was inhibited by p65 KO. GNA-induced apoptosis was attenuated in either p65 KO or Fas KO cells. These results demonstrate that GNA inhibited tubulin polymerization and induced apoptosis of MDS cells through upregulation of Fas expression mediated by the NF-κB signaling pathway, suggesting a chemotherapeutic strategy for MDS by microtubule dynamics disruption. [ABSTRACT FROM AUTHOR]

Management of higher-risk myelodysplastic syndromes (HR-MDS) is challenging in the real world. We studied 200 patients with HR-MDS within a large US community hospital network. We describe the clinical presentation, patient-related factors, prognostic characteristics, treatment patterns, clinical outcomes and resource utilization. Patients with HR-MDS, treated in our community setting, were elderly (median age 76 years) with a high comorbidity burden. First-line therapy was hypomethylating agent (HMA) monotherapy (20%), lenalidomide (2%), and venetoclax (2%), while the rest were treated with supportive care. Sixty-one percent of the 200, were subsequently hospitalized within 6 months of initial diagnosis. Overall survival was 11.8 months. Curative transplantation was infrequent, HMA-based therapy was underutilized, responses were not durable, most patients became transfusion-dependent or transformed to AML, and resource utilization was substantial and was highly correlated with total in-hospital days. There is a clear unmet need for tolerable treatments that can produce durable remissions in this population. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) might be effective for myelodysplastic syndrome (MDS) by apoptosis induction and demethylation. But ATO has not been widely recommended for small sample and conflicting conclusion of existing trials. This review aimed to systematically evaluate the efficacy of regimens containing ATO for the MDS and explore optimal combination. Randomized clinical trials (RCTs) about ATO regimens were retrieved from China National Knowledge Infrastructure, Embase and PubMed. With odds ratio (OR) as the effect size, network meta-analysis (NMA) and component network meta-analysis (CNMA) were conducted by R and 'netmeta' package, after study selection, quality assessment and data extraction. Thirty-night RCTs were included with a total of 2125 patients, including 1235 treated by ATO containing regimen. With support therapy alone as reference, no inconsistency and heterogeneity were observed. Although NMA did not demonstrate better efficacy of ATO alone, the result of CNMA indicated that ATO was effective in the improvement of overall remission (ORR) [OR = 2.09(1.61, 2.71)] and complete remission (CR) [OR = 1.66(1.25, 2.21)]. Five ATO-containing regimens reported could effectively improve ORR, some of them benefit in CR or hematological improvement (HI) as well. ATO + Traditional Chinese Medicine (TCM), ATO + Thalidomide (T)+TCM, ATO + Chemotherapy (Chem)+T + TCM were regarded as the optimal combination, which improved both ORR, CR and HI in theory. ATO did not increase the risk of common adverse events compared to supportive therapy [(OR = 0.90(0.67, 1.21)]. ATO may be an effective and well-tolerant option for patients with myelodysplastic syndrome. [ABSTRACT FROM AUTHOR]

The study aims to analyze genetic mutation and clinical characteristics and study their correlation with survival prognosis of patients with myelodysplastic syndromes (MDS). Moreover, the differential DNA methylation profiles between TET2 mutated (Mut)/ASXL1 wild-type (WT) and TET2-Mut/ASXL1-Mut MDS samples were investigated to explore the mechanism of MDS patients with TET2/ASXL1 mutations. The clinical data of 195 patients diagnosed with MDS were selected and statistically analyzed. The DNA methylation sequencing data set was obtained from the GEO and bioinformatics analyzed. Of the 195 MDS patients, 42 (21.5%) carried TET2 mutations. 81% of TET2-Mut patients could detect comutated genes. The most commonly comutated gene in MDS patients with TET2-Mut was ASXL1, which had a tendency towards poorer prognosis (P = 0.08). GO analysis showed that highly methylated differentially methylated genes (DMGs) was mainly enriched in biological processes such as cell surface receptor signal pathway and cell secretion. Hypomethylated DMGs was mainly enriched in cell differentiation and cell development. KEGG analysis showed that hypermethylated DMGs was mainly enriched in Ras signal pathway and MAPK signal pathway. Hypomethylated DMGs was mainly enriched in extracellular matrix receptor interaction and focal adhesion. PPI network analysis identified 10 hub genes of hypermethylated and hypomethylated DMGs that may be associated with patients with TET2-Mut/ASXL1-Mut respectively. Our results illustrate the interrelationships between genetic mutations and clinical phenotypes and disease outcomes, with substantial potential for clinical application. Differentially methylated hub genes might represent potential biomarkers and provide novel insights and possible targets for MDS with double TET2/ASXL1 mutations. [ABSTRACT FROM AUTHOR]

The meta-analysis sought to evaluate the efficacy and safety of a combination of venetoclax (Ven) and azacitidine (AZA) in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We searched PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, and Web of Science for eligible studies from inception to June 2022. We used the Cochrane Risk of Bias 2.0 (RoB 2.0) and Methodological Index for Non-Randomized Studies (MINORS) to evaluate the quality of the included literature. The inverse variance method was used to calculate the pooled proportion and 95% confidence interval (CI). The meta-analysis included nineteen studies with a total of 1615 patients. The pooled overall CR/CRi (complete response (CR)/complete response with incomplete blood count recovery (CRi)) rate for AML and MDS was 57.9% (95% CI 49.5-65.9%, I2 = 83%). Subgroup analyses showed that the rate of pooled CR/CRi was 67.5% (95% CI 61.1-73.3%, I2 = 54%) for the new-diagnosed (ND) AML group, 30% (95% CI 20-44.1%, I2 = 66%) for relapsed/refractory (R/R) AML, and 67.6% (95% CI 52.6-79.8%, I2 = 65%) for MDS, respectively. One randomized controlled trial (RCT) showed that CR/CRi was 64.7% in ND-AML patients. A total of 9 studies reported adverse events, with neutropenia being the most common of grade 3–4 adverse events, with a rate of 53.7% (95% CI 61.1-73.3%, I2 = 54%). The present meta-analysis demonstrated that the Ven + AZA regimen is efficacious for the treatment of AML and MDS, with it being more effective for ND-AML than R/R AML. The most common adverse effects of this regimen are grade 3–4 neutropenia and neutropenia with fever. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a clonal malignancy that develops from hematopoietic stem cells (HSCs), but the underlying mechanisms of MDS initiation are not well understood. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is often dysregulated in MDS. To investigate how PI3K inactivation affects HSC function, we generated a mouse model in which three Class IA PI3K genes were deleted in hematopoietic cells. Surprisingly, PI3K deficiency caused cytopenias, reduced survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. PI3K-deficient HSCs had impaired autophagy, and pharmacologic treatment with autophagy-inducing reagents improved HSC differentiation. Furthermore, a similar autophagic degradation defect was observed in MDS patient HSCs. Therefore, our study uncovered a crucial protective role for Class IA PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation. [ABSTRACT FROM AUTHOR]

To explore the characteristics of hemogram in patients with aplastic anemia (AA), especially mean corpuscular volume (MCV) and red cell distribution width (RDW). We examined the blood routine of 180 new-onset AA patients and used 166 patients with myelodysplastic syndrome (MDS) as controls. Among the 180 AA patients, 105 (58.3%) were diagnosed with severe AA (SAA), while 75 (41.7%) were diagnosed with non-severe AA (NSAA). Compared to MDS, patients with SAA generally had unfavorable hemogram, including significantly lower white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), platelet (PLT) and reticulocyte counts (RET). However, WBC, ANC and lymphocyte counts were higher in the NSAA group than in the MDS group; Hb and Ret were comparable between the two groups. 8.5% of SAA patients and 58.1% of NSAA patients presented with macrocytic anemia, whereas 25.7% of SAA and 64.0% of NSAA had a high RDW. In the MDS group, 54.7% of patients presented with macrocytic anemia, and 84.7% had increased RDW. WBC, ANC, PLT, and Ret in a high-RDW group (25.7% of SAA) were significantly higher than in a normal-RDW group (74.3% of SAA). Overall, most SAA patients exhibited normocytic–normochromic anemia, and their hemograms decreased more significantly; more than half of NSAA patients showed macrocytic-heterogeneous anemia, and their hemograms were similar to those of MDS. Patients with elevated RDW may have better residual bone marrow hematopoietic function than those with normal RDW but with more severe anemia. [ABSTRACT FROM AUTHOR]

A molecular scoring system (IPSS-M) was recently proposed for myelodysplastic syndrome (MDS). We conducted a retrospective study of adults with MDS referred 2019–2021. The primary outcomes were leukemia-free survival (LFS) and overall survival (OS). One hundred and forty-four patients diagnosed between 2011 and 2021 were analyzed. After IPSS-M re-stratification, 33% of patients were up-staged and 11% down-staged. Median follow-up was 2.8 years and 53 patients died (37%). Cumulative incidence of acute myeloid leukemia (AML) transformation was 20% at 3 years post-diagnosis. International Prognostic Scoring System (IPSS), revised version (IPSS-R) was significantly associated with LFS (log-rank p = 9.2e–05; 'very high' vs. 'low' risk HR = 3.85, p = 5.8e–04) and OS (log-rank p = 7.2e–06; 'very high' vs. 'low' HR = 5.09, p = 1.7e–04). IPSS-M was also a significant predictor of LFS (log-rank p = 1.1e–06; 'very high' vs. 'low' HR = 4.97, p = 2.2e–05) and OS (log-rank p = 4.8e–07; 'very high' vs. 'low' HR = 6.42, p = 2.5e–05) while providing better discrimination than IPSS-R for both outcomes. This mutation-incorporating prognostic index has greater discriminative potential than IPSS-R to predict AML transformation and any-cause mortality. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases without a care standard and show variability in treatment outcomes. This Spanish, observational, prospective study ERASME (CEL-SMD-2012-01) assessed the evolution of newly diagnosed and treatment-naïve high-risk MDS patients (according to IPPS-R). 204 patients were included: median age 73.0 years, 54.4% males, 69.6% 0-1 ECOG, and 94.6% with comorbidities. Active treatment was the most common strategy (52.0%) vs. stem cell transplantation (25.5%) and supportive care/watchful-waiting (22.5%). Overall (median) event-free survival was 7.9 months (9.1, 8.3, and 5.3); progression-free survival: 10.1 months (12.9, 12.8, and 4.3); and overall survival: 13.8 months (15.4, 14.9; 8.4), respectively, with significant differences among groups. Adverse events (AEs) of ≥3 grade were reported in 72.6% of patients; serious AEs reported in 60.6%. 33.1% of patients died due to AEs. Three patients developed second primary malignant neoplasms (median: 8.2 months). Our study showed better outcomes in patients receiving active therapy early after diagnosis. [ABSTRACT FROM AUTHOR]

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described, late-onset, acquired autoinflammatory disorder caused by mutations in the UBA1 gene. The various clinical manifestations of VEXAS broadly divided into inflammatory or haematological. VEXAS defines a new disease category – the hematoinflammatory disorders triggered by somatic mutations restricted to blood but causing systemic inflammation with multi-organ involvement and associated with aberrant bone marrow status. VEXAS causes significant morbidity and reduced life expectancy, but the optimum standard of care remains undefined This review describes the discovery of VEXAS, relevant genetic causes and immunopathology of the disease. A detailed account of its various clinical manifestations and disease mimics is provided. Current treatment and management options are discussed. New rare variants in UBA1 and VEXAS-like UBA1 negative cases are reported. Consensus diagnostic criteria might be required to define VEXAS and its related disorders. Investigation of sporadic, VEXAS-like cases will require the application of deep sequencing using DNA obtained from various cellular or tissue locations. Prospective studies are needed to define the optimal supportive and treatment options for patients with varying disease severity and prognosis. VEXAS-specific hematopoietic stem cell transplant selection criteria also require development. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder with a high propensity to develop into acute myeloid leukemia (AML). Although abnormal microRNA expression has been implicated in MDS, the exact role of miR-181a-2-3p has not been entirely elucidated. Here, we investigated miR-181a-2-3p levels in bone marrow (BM), and described its utility as a potential indicator for MDS diagnosis and prognosis. We evaluated miR-181a-2-3p expression in BM samples of 54 newly diagnosed MDS cases, 16 sAML patients and 32 healthy donors and then assessed its association with clinical characteristics and its potential value for MDS diagnosis and prognosis. Compared with healthy controls, miR-181a-2-3p levels were decreased in the total cohort of MDS patients. Additionally, in MDS patients with secondary AML (sAML), miR-181a-2-3p was over-expressed relative to levels in those without this form. The areas under the curve of receiver operating characteristic curves were 0.700 and 0.750 to distinguish MDS patients from controls and sAML from newly diagnosed MDS, respectively. Kaplan–Meier analysis showed a positive correlation between miR-181a-2-3p expression and overall survival (OS). Further, multivariate analysis indicated that miR-181a-2-3p was an independent prognostic index for MDS with respect to OS. Decreased miR-181a-2-3p expression in MDS patients may be considered as one of the underlying markers reflecting MDS progression and prognosis. [ABSTRACT FROM AUTHOR]

Background: Several studies scatteredly identified the myelodysplastic syndromes' transcriptomic profiles (MDS). However, the exploration of transcriptional signatures, key signalling pathways, and their association with prognosis and diagnosis in the integrated multiple datasets remains lacking. Methods: We integrated the GSE4619, GSE19429, GSE30195, and GSE58831 microarray datasets of CD34 + cells for identifying the differentially expressed genes (DEGs) in the MDS. The series of bioinformatics methods are applied to identify the key hub genes, gene clusters, prognostic hub genes, and genes associated with diagnostic efficacy. Finally, we validated the expression differences of hub genes in the GSE114922 dataset. Results: We explored the DEGs related to gene ontology enrichment and KEGG pathways. We identified significant hub genes, including 168 upregulated hub genes (such as STAT1, IFIH1, EPRS, GRB2, RAC2, MAPK14, CASP1, and SPI1) and 52 downregulated hub genes (such as CREBBP, HIF1A, PIK3CA, EZH2, PIK3R1, MDM2, IRF4, CXCR4, PCNA, and CD19) in the MDS. In addition, we identified six significant molecular complex detection (MCODE)-derived upregulated gene clusters and one downregulated gene cluster, respectively. Moreover, we found that the higher expression level of MX2, GBP2, PXN, IFI44, FDXR, PLCB2, ASS1, ERCC4, PML, and RRAGD and the lower expression level of CD19, PAX5, TCF3, LEF1, NUSAP1, and TIMELESS hub genes are significantly correlated with shorter survival times of MDS patients. Furthermore, the area value under the ROC curve (AUC) of PXN, FDXR, PLCB2, PML, CD19, PAX5, and LEF1 prognostic genes are more than 0.80, indicating that these genes could be effectively used for the diagnostic efficacy of MDS patients. Conclusions: Identifying key hub genes and their association with the prognosis and diagnostic efficacy may provide substantial clues for the treatment and diagnosis of MDS patients. [ABSTRACT FROM AUTHOR]

We present a systematic review and meta-analysis to evaluate outcomes after venetoclax (VEN) with hypomethylating agents (HMA) in myelodysplastic syndromes (MDS). We performed a literature search on PubMed, Cochrane Library, EMBASE, and Clinicaltrials.gov. After screening 2004 manuscripts, 16 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed. We analyzed the outcomes of 373 patients from 11 retrospective studies and five phase 1 b clinical trials. Pooled complete response with or without hematological recovery was 60% (95% CI 0.49–0.7, I2= 67%, n = 373). Hematopoietic cell transplantation was performed in 32% of patients (95% CI 0.2–0.46, I2= 62%, n = 187). Overall mortality was 45% (95% CI 0.31–0.59, I2=54%, n = 140). VEN-HMA combination therapy demonstrated promising outcomes in MDS. Prospective randomized data is needed to ascertain the benefit of VEN and its impact in MDS patients. [ABSTRACT FROM AUTHOR]

Although the effect of gene mutations on overall response rate (ORR) and overall survival (OS) in myelodysplastic syndrome (MDS) treated with hypomethylating agents (HMAs) has been explored, the effect is still controversial. We performed this meta-analysis to investigate the effect. The pooled odds ratio (OR) and 95% confidence interval (CI) for ORR and the pooled hazard ratio (HR) and 95%CI for OS were chosen to estimate the effect. The pooled OR of TET2 was 0.73 (95%CI: 0.59–0.91, p = 0.005) and the pooled OR of ASXL1 was 1.38 (95%CI: 1.12–1.71, p = 0.003). As for prognosis, the pooled HR of RUNX1 was 1.45 (95%CI: 1.15–1.85, p = 0.002). The pooled HR of TP53 was 2.30 (95%CI: 1.83–2.90, p < 0.001) and the pooled HR of U2AF1 was 1.41 (95%CI: 1.15–1.74, p = 0.001). There was no statistical difference shown in other genes. Therefore, TET2 mutation and ASXL1 wild-type were the predictor of better response to HMAs. Mutations of TP53, RUNX1, and U2AF1 were associated with poor prognosis in MDS. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) have a major impact on quality of life (QoL). We performed a post hoc analysis of two multicenter trials of azacitidine-based disease-modifying therapy for patients with MDS and low blast count acute myeloid leukemia (AML), to identify factors associated with QoL. 231 patients were included (median age 70 years). At baseline, higher initial hemoglobin, but not neutrophil or platelet count, was associated with better global QoL and physical function (p < 0.001 and p = 0.001, respectively). During therapy, increase in hemoglobin was associated with improvement in QoL and physical function (p = 0.005 and p < 0.001, respectively). Lower initial hemoglobin was associated with higher dyspnea and fatigue scores (p < 0.001 and p = 0.001, respectively), and hemoglobin response was associated with improvement in dyspnea and fatigue (p < 0.001 for each). In patients with MDS and low blast count AML, hemoglobin level was strongly correlated with global QoL, physical functioning, dyspnea and fatigue, both before and during azacitidine-based therapy. [ABSTRACT FROM AUTHOR]

Ribonucleotide Reductase (RNR) is a two-subunit (RRM1, RRM2) enzyme, responsible for the conversion of ribonucleotides to deoxyribonucleotides required for DNA replication. To evaluate RNR as a biomarker of response to 5-azacytidine, we measured RNR mRNA levels by a quantitative real-time PCR in bone marrow samples of 98 patients with myelodysplastic syndrome (MDS) treated with 5-azacytidine with parallel quantification of the gene promoter's methylation. Patients with low RRM1 levels had a high RRM1 methylation status (p = 0.005) and a better response to treatment with 5-azacytidine (p = 0.019). A next-generation sequencing for genes of interest in MDS was also carried out in a subset of 61 samples. Splicing factor mutations were correlated with lower RRM1 mRNA levels (p = 0.044). Our results suggest that the expression of RNR is correlated with clinical outcomes, thus its expression could be used as a prognostic factor for response to 5-azacytidine and a possible therapeutic target in MDS. [ABSTRACT FROM AUTHOR]

To evaluate whether outcomes following allogeneic hematopoietic cell transplantation differ according to disease type, a three-way comparison for patients with de novo acute myeloid leukemia (AML) (n = 3318), AML evolving from myelodysplastic syndromes (MDS) (n = 208), and MDS with excess blasts (MDS-EB) (n = 994) was performed. The 5-year probabilities of overall survival (OS) for de novo AML, AML evolving from MDS, and MDS-EB were 60%, 42%, and 41% (p < 0.001), respectively. Multivariate analysis revealed that, compared to de novo AML, AML evolving from MDS was associated with a higher risk of NRM (p = 0.030) and MDS-EB with a higher risk of relapse (p < 0.001), both leading to lower OS (p = 0.010 and p < 0.001, respectively). These findings demonstrate inter-disease differences in post-transplant outcomes and highlight the needs to reduce NRM for AML evolving from MDS and to reduce relapse for MDS-EB. [ABSTRACT FROM AUTHOR]

TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are under scrutiny as a participant in the pathophysiology of myelodysplastic syndrome (MDS) and the progression of MDS to acute myeloid leukemia (AML). Measurement of intracellular ROS (iROS) is particularly important since iROS is a direct indicator of cellular health and integrity. We developed a technique to measure standardize iROS (siROS) level in lymphocytes and bone marrow (BM) CD34+ hematopoietic progenitors using the fluorescent probe dichlorofluorescein (DCF). We then quantified the siROS in 38 consecutive BM specimens from 27 MDS patients over the course of 10 months. Disease outcome of these patients were also assessed. High serum ferritin, high blast count and poor IPSS were associated with inferior survival and AML progression in this cohort. High blast MDS patients had lower siROS in their BM CD34+ cells than those of low blast patients, consistent with increased reliance on glycolysis and enhanced ROS defense in high blast MDS. We also observed narrower siROS distribution in the BM CD34+ cells of high blast patients, suggesting that loss of heterogeneity in ROS content accompanies the clonal evolution of MDS. Furthermore, we observed a strong correlation between CD34+ cells siROS and serum ferritin level in high blast patients. In one case, iron chelation therapy (ICT) resulted in parallel decreases in serum ferritin and CD34+ cells siROS. Our findings established the siROS profile in early hematopoietic cells of MDS patients and its relationship with blast count and iron overload. [ABSTRACT FROM AUTHOR]

Venetoclax has transformed the treatment landscape in hematologic malignancies, especially in elderly population. With high rates of remission, deep and durable responses, and safe toxicity profile, venetoclax in combination therapy has been extremely effective, garnering accelerated approval and becoming standard of care in lymphoid and myeloid malignancies. Preclinical and clinical experience of venetoclax monotherapy and combination therapy in relapsed/refractory and frontline CLL, AML, ALL, high-risk MDS and BPDCN with an emphasis on key clinical trials and efficacy of combination regimens in distinct mutational landscapes. Strategies to mitigate myelosuppression and manage dose adjustments and infectious complications are addressed. Targeting BCL-2 offers a safe and highly effective adjunct to available therapies in hematologic malignancies. Despite success and frequent utilization of venetoclax, several resistance mechanisms have been elucidated, prompting the development of novel combinatorial strategies. Further, on-target myelosuppression of venetoclax is a key obstacle in clinical practice, requiring diligent monitoring and practice-based knowledge of dose modifications. Despite these limitations, venetoclax has gained tremendous popularity in hematologic-oncology, becoming an integral component of numerous combination regimes, with ongoing plethora of clinical trials encompassing standard chemotherapy, targeted agents and immune-based approaches. [ABSTRACT FROM AUTHOR]

Treatment for acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy is a major challenge for clinicians. We enrolled 154 patients ineligible for intensive chemotherapy who were prescribed D-IA regimen (decitabine 15–20 mg/m2 days 1 to 3–5, followed by idarubicin 3 mg/m2 for 5–7 days and cytarabine 30 mg/m2 for 7–14 days). For AML and MDS patients, the overall response rate after two cycles was 66.4% and 76.6%, respectively, and the 2-year overall survival rates were 29% and 31%, respectively. Fourteen (13.1%) AML and five (10.6%) MDS patients underwent allo-HSCT after complete remission. The allo-HSCT group survival time was significantly longer than the control group (median survival time not reached in HSCT group, 13 and 18.5 months in non-HSCT AML and MDS group). We concluded that D-IA regimen was effective and well tolerated for patients with AML or higher-risk MDS ineligible for intensive chemotherapy. [ABSTRACT FROM AUTHOR]

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation. [ABSTRACT FROM AUTHOR]

The low grade chronic lymphoproliferative disorders include chronic lymphocytic leukemia, Waldenstroms macroglobulinemia, follicular lymphoma and hairy cell leukemia. Traditionally considered incurable, these disorders have been associated with a risk of haematological and solid organ malignancies secondary to both the underlying disease and the associated treatment. The introduction of purine analogues into treatment paradigms has seen increased rates of therapy related myelodysplasia reported and it remains unclear yet on the impact the targeted novel therapies play in the development of secondary cancers. We review the rates of secondary malignancy in the chronic lymphoproliferative disorders with a particular focus on the role of the purine analogues in the development of therapy related MDS. [ABSTRACT FROM AUTHOR]

Azacitidine (AZA) maintenance following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may reduce relapse risk and improve survival. Given logistic and toxicity-related challenges, identifying subgroups appropriate for this approach is an unmet need. Using data from two centers, we retrospectively compared event-free survival (EFS) and overall survival (OS) of AML and MDS patients who received AZA maintenance (n = 59) with historic controls (n = 90). Controls were selected according to the following criteria: no death, relapse, or Grade III–IV acute GVHD for 100 days after transplant. In multivariable analysis, AZA maintenance yielded significantly improved EFS (p = 0.019) and OS (p = 0.011). Outcomes differed according to regimen intensity. For reduced-intensity transplant, EFS (p = 0.004) and OS (p = 0.004) were significantly improved and equivalent to myeloablative transplant. A significant benefit following myeloablative transplant was not observed. Within the limitation of its retrospective nature, this study suggests that AZA maintenance improves outcomes following reduced-intensity HCT, comparable to myeloablative HCT. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and adverse effects of venetoclax(VEN) in combination with hypomethylating agents(HMAs) in acute myeloid leukemia(AML) or myelodysplastic syndrome(MDS). Clinical studies were identified from the Cochrane Library, PubMed, Embase, Google Scholar, and ClinicalTrials.gov. Overall complete remission (CR) and overall response rate (ORR) were used to evaluate the efficacy of VEN in combination with HMAs for AML/MDS, the incidence of the 4 most common grade 3–4 adverse events was used to evaluate safety. We identified 13 studies that included a total of 1059 patients. 7 cohort studies and 5 non-randomized controlled trials(NRCTs) were analyzed by random-effects model, and subgroup analyses showed the pooled overall CR rate of 62% (95% CI 57-67%, I2 = 3%) for the new-diagnosed(ND) AML group, 39% (95% CI 30-48%, I2 = 28%) for relapsed/refractory(R/R)-AML, and 61% (95% CI 50-71%, I2 = 25%) for MDS, respectively. There was only one randomized controlled trial(RCT) that showed a CR rate of 66.4% in the patients who received azacitidine(AZA) plus VEN. A total of 8 studies reported adverse events, with cytopenia and infection being the most common grade 3–4 adverse events. The addition of VEN to HMAs may provide significant clinical benefit for AML/MDS patients, where response rates are better in MDS and ND-AML than in R/R-AML, but attention should be paid to the possible increased risk of febrile neutropenia. [ABSTRACT FROM AUTHOR]

This study reviewed patient characteristics, management, and medical costs of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs) in Spanish hospitals. Data were extracted from the Spanish Ministry of Health records via a claims database containing patient records from 192 private and 313 public hospitals between 1997 and 2015 for AML, and 2008 and 2015 for MDS. Direct medical costs at the hospital level were calculated based on mean medical procedure costs determined per the Spanish Ministry of Health. Records for 39,568 patients with AML and 33,091 with MDS were analyzed. The median age of AML patients was 65 years (interquartile range (IQR) = 27) and of MDS patients was 81 years (IQR = 12). In terms of disease management, 58% and 83% of admissions were due to emergencies for patients with AML and MDS, respectively; median length of hospital stay was 14 days (IQR = 25) for AML and seven days (IQR = 9) for MDS. There was an increase in allogeneic hematopoietic stem cell transplantations over time for patients with AML or MDS. Mean annual direct medical costs of AML and MDS, respectively, were €66,422,245 and €42,635,313 for total costs, and €30,775 and €10,312 per patient. Of the total costs, transplantations contributed total annual costs of €15,843,982 and €2,705,791 for patients with AML and MDS, respectively. This study provides novel data to assist decision makers in allocating resources. AML and MDS represent a significant burden for the National Spanish Healthcare System, with substantial costs incurred in secondary care, principally associated with the increasing number of transplantations. [ABSTRACT FROM AUTHOR]

Thrombocytopenia remains a challenge in myeloid malignancies, needing safer and more effective therapies. JNJ-26366821, a pegylated synthetic peptide thrombopoietin (TPO) mimetic not homologous to endogenous TPO, has an in-vitro EC50 of 0.2 ng/mL for the TPO receptor and dose dependently elevates platelets in volunteers. We demonstrate that JNJ-26366821 increases megakaryocytic differentiation and megakaryocytic colony formation in healthy controls and samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). JNJ-26366821 had no effect on proliferation of malignant myeloid cell lines at doses up to 1000 ng/mL and malignant patient-derived mononuclear cells showed no increased cell growth or leukemic colony formation capacity at concentrations between 0.2 ng/mL and 10 ng/mL. Furthermore, JNJ-26366821 did not enhance in-vivo engraftment of leukemic cells in an AML xenotransplantation murine model. Our results show that JNJ-26366821 stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clones in MDS/AML and provides the rationale for clinical testing of JNJ-26366821 in myeloid malignancies. [ABSTRACT FROM AUTHOR]

For most patients with higher-risk myelodysplastic syndromes (HR-MDS) the hypomethylating agents (HMA) azacitidine and decitabine remain the mainstay of therapy. However, the prognosis mostly remains poor and aside from allogeneic hematopoietic stem cell transplantation no curative treatment options exist. Unlike acute myeloid leukemia, which has seen a dramatic expansion of available therapies recently, no new agents have been approved for MDS in the United States since 2006. However, various novel HMAs, HMA in combination with venetoclax, immune checkpoint inhibitors, and targeted therapies for genetically defined patient subgroups such as APR-246 or IDH inhibitors, have shown promising results in early stages of clinical testing. Furthermore, the wider availability of genetic testing is going to allow for a more individualized treatment of MDS patients. Herein, we review the current treatment approach for HR-MDS and discuss recent therapeutic advances and the implications of genetic testing on management of HR-MDS. [ABSTRACT FROM AUTHOR]

Mutations in the tumor suppressor gene TP53 are detected in 5–10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. TP53 mutations have been associated with complex karyotypes, therapy-related malignancies, lower response rates to cytotoxic chemotherapy, and an overall adverse prognosis. In this single-center retrospective study, we analyzed the clinicopathologic characteristics and outcomes of 83 patients with TP53-mutated myeloid malignancies treated at Yale Cancer Center between 9/2015 and 5/2019. Complex karyotypes (n = 75; 90%) and therapy-related malignancies (n = 32; 39%) were common. Median overall survival (OS) was 7.6 months. Intensive chemotherapy did not improve OS compared to lower-intensity treatment for AML patients. Patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT) had a significantly longer median OS, despite relatively limited follow-up. In conclusion, our data confirm the limited efficacy of intensive chemotherapy approaches for TP53-mutated patients with myeloid neoplasms and suggest that a minority of patients achieve long-term survival with alloHSCT. [ABSTRACT FROM AUTHOR]

Gemtuzumab ozogamicin (GO) remained available to US clinicians through an open-label expanded-access protocol (NCT02312037) until GO was reapproved. Patients were aged ≥3 months with relapsed/refractory (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndrome, or acute promyelocytic leukemia (APL), and had exhausted other treatment options. Three hundred and thirty one patients received GO as monotherapy for R/R AML (n = 139), combination therapy for R/R AML (n = 183), or treatment for R/R APL (n = 9). Corresponding treatment discontinuations occurred in 68, 39, and 33% of patients. All-causality grade 5 AEs occurred in 52, 22, and 22% of patients in the monotherapy, combination, and APL groups, respectively. Corresponding grades 3 and 4 treatment-related AEs were reported in 60, 55 and 78% of patients. Hepatotoxicity occurred in five patients: veno-occlusive disease (n = 4) and drug-induced liver injury (n = 1). GO was generally well tolerated in patients with R/R AML or APL. Most frequent treatment-related grade ≥3 AEs were hematologic AEs. Clinicaltrials.gov identifier: NCT02312037 [ABSTRACT FROM AUTHOR]

Optimal conditioning chemotherapy for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains uncertain. Myeloablative regimens such as fludarabine/busulfan are favored over reduced-intensity fludarabine/melphalan (Flu/Mel); however, it is not known if Flu/Mel is inferior. We analyzed hematopoietic cell transplantation recipients with AML and MDS who received fludarabine with once-daily intravenous busulfan targeted to either area under the curve (AUC) 5300 µM*L/min (Flu/Bu 5300) (n = 246) or AUC 3500 µM*L/min (Flu/Bu 3500) (n = 81), or Flu/Mel (n = 69). Flu/Bu regimens were compared separately to Flu/Mel. After 2-year follow-up, no differences in overall or relapse-free survival were found between Flu/Bu 5300 or 3500 versus Flu/Mel though relapse rates were significantly higher; 33.1% (p = 0.024), 44.6% (p = 0.002), versus 19.4%, respectively. Flu/Bu 5300 (p = 0.008) and Flu/Bu 3500 (p < 0.001) groups were prognostic for relapse compared to Flu/Mel. Flu/Mel yields lower relapse rates and similar survival benefit when compared to Flu/Bu 3500 or 5300 µM*L/min. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) is increasingly employed for diagnosis, risk stratification, and management of patients with myelodysplastic syndrome (MDS). We aimed to describe beliefs and practice patterns among providers who treat MDS patients with respect to the utility of NGS in diagnosis, risk stratification, prognosis, and treatment decisions at various points along the disease trajectory, response assessment, and development of institutional guidelines for MDS-specific molecular profiling. Using a 23-question web-based survey in May–June 2018, we identified a widespread use of molecular profiling with MDS-specific panels (N = 53; 39%) and general panels including MDS-related genes (N = 63; 47%), with the majority done at diagnosis (92%). We found substantial variations in genes tested in assays, providers beliefs, practices, testing logistics, and interpretation of results, and recognized multiple challenges limiting a wider utilization of molecular profiling. High-quality data are needed to develop evidence-based guidelines for the role of NGS in the care of MDS patients. [ABSTRACT FROM AUTHOR]

For over a decade the hypomethylating agents (HMA) azacitidine and decitabine have been the mainstay of therapy for myelodysplastic syndrome (MDS). There is a critical need to improve frontline therapy, given that only up to half of high-risk MDS patients will respond to HMA therapy, and responses are short-lived. Currently, a key strategy has been to combine HMAs with other novel agents to improve patient outcomes. While synergy of agents is the goal of combination therapy, combinations often come at the cost of increased side effects that are often intolerable in this vulnerable population. The purpose of this review is to critically examine clinically relevant HMA combinations and discuss the future of MDS management. [ABSTRACT FROM AUTHOR]

Our aim is to investigate the clinical characteristics of low- and intermediate-risk myelodysplastic syndrome (MDS) with pure red cell aplasia (PRCA). We retrospectively reviewed the patients of low- and intermediate-risk MDS patients who had been diagnosed with PRCA in our hospital between January 2010 and December 2019. There were 6 low- and intermediate-risk MDS patients with PRCA in our study, 1 male and 5 females, with a median age of 63.5 (50-75) years. It accounted for 7.7% (6/78) of all diagnosed PRCA cases and 1.67% (6/359) of diagnosed MDS cases during the same period. All patients were treated with multiple drugs, including recombinant human erythropoietin, cyclosporine, glucocorticoids, androgen, sirolimus, intravenous immunoglobulin and decitabine. Two patients achieved complete remission, two patients achieved partial remission and became blood transfusion independent. Two patients had no response and one patient died. Low- and intermediate-risk MDS with PRCA was difficult to treat, but the prognosis was good. [ABSTRACT FROM AUTHOR]

Population level survival of patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) is inferior to clinical trials. Using SEER-Medicare data, we identified 2086 MDS patients diagnosed in 2004–13, aged ≥66 years at diagnosis, and receiving ≥1 HMA cycle after 2005. We used multivariate logistic regression and Cox proportional hazards models to assess the impact of provider experience on persistent HMA therapy and overall survival (OS), respectively. Median number of HMA cycles was 4 and median OS was 10 months. Thirty-two percent of patients were treated by providers with ≥1 prior HMA initiation in the last 2 years and were more likely to receive ≥4 cycles of HMA therapy (OR = 1.29, 95% CI = 1.06–1.57; p =.01). No significant association was found between MDS or HMA initiation volume and survival. In conclusion, while HMA initiation volume was associated with persistent HMA treatment, neither MDS nor HMA initiation volumes were associated with OS in older MDS patients. [ABSTRACT FROM AUTHOR]

To systematically evaluate the efficacy and safety of iron chelators for transfusion-dependent patients with MDS. Thirteen cohort studies with 12,990 patients diagnosed with MDS were included in this study. According to m eta-analysis results transfusion-dependent MDS patients with secondary iron overload had a longer (HR = 0.52, 95%CI = 0.43–0.62, P < 0.001). Further subgroup analysis revealed a longer LFS (HR = 0.84, 95%CI = 0.76–0.93, P = 0.001) in MDS patients receiving iron chelators than in MDS patients not receiving iron chelators (HR = 0.52, 95%CI = 0.43–0.62, P < 0.001) and in patients with lower-risk MDS (HR = 0.50, 95%CI = 0.43–0.59, P < 0.001). Subgroup analysis of DFX showed that compared with patients not treated with iron chelators, the group receiving DFX monotherapy had significantly increased OS (HR = 0.43, 95%CI = 0.27–0.69, P < 0.001). In terms of tolerance, meta-analysis of binary variables in CAEs indicated that the occurrence of CAEs was significantly reduced by ICT (RR = 0.64, 95%CI = 0.57–0.71, P < 0.001). [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the value of Wilms' tumor 1 mRNA (WT1) expression in the differential diagnosis of childhood myelodysplastic syndrome (MDS) and aplastic anemia (AA). Methods: This study compared WT1 expression levels in children of MDS and AA to evaluate its value in differential diagnosis. Results:WT1 overexpression rate and mean WT1 expression level were significantly higher in MDS compared to AA (P = 0.000 and P = 0.013, respectively). Patients with RCC and normal cytogenetics exhibited significantly greater portion of patients exposing WT1 overexpression, compared to all AA subtypes (P = 0.001, P = 0.000 and P = 0.001, respectively). ROC curve analysis revealed that WT1 expression could differentiate between RCC with normal cytogenetics and non-severe AA. Based on a cut-off value of 1.45%, WT1 expression provided a sensitivity of 23.2% and a specificity of 100%. Discussion: In the present study, WT1 overexpression rate was gradually decreased in RAEB group, RCC group and AA subtypes, and the mean WT1 expression level of the MDS patients was significantly higher than that of the AA group. It is very difficult to differentiate between RCC with normal cytogenetics and NSAA in children. Our results showed significant differences in WT1 overexpression rate between these two groups. When we set the cut-off value as 1.45%, WT1 expression levels could be used to differentiate between cases of RCC with normal cytogenetics and NSAA in children. Conclusion:WT1 expression might be useful for distinguishing between myelodysplastic syndrome and aplastic anemia in children. [ABSTRACT FROM AUTHOR]

The addition of lenalidomide (LEN) to azacitidine (AZA) may further improve the outcomes of acute myeloid leukemia (AML) patients as well as patients with high-risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) patients although the evidence for this combination treatment is still relatively limited. This meta-analysis aimed to evaluate efficacy and adverse effects of AZA plus LEN for the treatment of patients with high-risk MDS, AML or CMML. The current study systematically identified all cohort studies of patients with AML and/or MDS and/or CMML who received AZA in combination with LEN that reported the overall complete remission (CR) rate and/or overall response rate (ORR). A DerSimonian–d random–effects model with double arcsine transformation was used for the pooled rates and 95% confidence interval (CI) of the all outcomes. A total of 10 studies with 406 patients were identified and included into the meta-analysis. The pooled CR rate after the treatment with AZA-plus-LEN regimen was 33.0% (95% CI, 27.7%–38.7%, I2 = 18%) while the pooled ORR was 49.9% (95% CI, 38.4%–61.5%, I2 = 72%). Nonetheless, adverse events including grade 3–4 neutrophil toxicity events, platelet toxicity events and febrile neutropenia were common with AZA-plus-LEN regimen. The current study may serve as a preliminary data to suggest that the addition of LEN may offer incremental benefit to patients with high-risk MDS, AML and CMML. However, randomized-controlled studies that directly compare the efficacy and adverse events of AZA-plus-LEN regimen versus AZA monotherapy are still needed. [ABSTRACT FROM AUTHOR]