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Background Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments. Methods We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination. Results The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity. Conclusions These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.

The treatment of patients with refractory and/or relapsed (R/R) high-risk myelodysplastic syndrome (HR-MDS) remains a daunting clinical challenge. Venetoclax is a selective BCL-2 inhibitor, which combined with hypomethylating agents (HMAs), increased responses and prolonged survival in unfit and previously untreated AML. We performed a retrospective study of patients with R/R HR-MDS receiving combination azacytidine (AZA) plus 15-days duration of venetoclax (VEN-15d) in order to determine their efficacy and toxicity in this context. We showed that the overall response rate (ORR) was 57.2% (20/35) and the median over survival (OS) was 14 months in R/R MDS. The most common treatment-emergent adverse events were peripheral blood cytopenias and infectious complications. Our retrospective study showed that the real-world experience of treating R/R MDS with AZA plus VEN-15d highlights an encouraging response rate with myelosuppression being the major toxicity. Of note, VEN-15d with AZA may salvage patients failing to respond optimally to HMAs and reduce the disease-burden for subsequent allo-SCT in our analysis. These data of combination AZA plus VEN-15d in R/R MDS warrant further prospective evaluation in clinical trials. This article is protected by copyright. All rights reserved.

Purpose To explore the relevance of cytogenetic or molecular genetic abnormalities to clinical variables, including clinical and laboratory characteristics and prognosis in Chinese patients with myelodysplastic syndromes (MDS). Methods A total of 634 consecutive patients diagnosed with MDS at The First Affiliated Hospital, Zhejiang University School of Medicine from June 2008 to May 2018 were retrospectively included in this study. All patients had evaluable cytogenetic analysis, and 425 patients had MDS‐related mutations sequencing. Results 38.6% of patients displayed abnormal karyotypes. The most common cytogenetic abnormality was +8 (31%). Sole +8 was related to female (p = 0.002), hemoglobin >10 g/dL (p = 0.03), and, This study aimed to explore the relevance of cytogenetic or molecular genetic abnormalities to clinical variables, including clinical and laboratory characteristics and prognosis in patients with myelodysplastic syndromes (MDS) and showed that cytogenetic changes had a potential correlation with molecular genetic abnormalities and both had significant influence on the prognosis of MDS.

Chronic myelomonocytic leukemia (CMML) is a rare disease of elderly people characterized by the presence of sustained peripheral blood monocytosis, overlapping features of myeloproliferation, and myelodysplasia. We present a large retrospective study of 156 CMML patients in China. Mean age at diagnosis was 68 years old (range 23‐91). According to the CMML‐specific prognostic scoring system (CPSS), 10 patients (8.3%) were low risk, 27 patients (22.5%) were intermediate‐1 risk, 72 patients (60%) were intermediate‐2 risk, and 11 patients (9.2%) were high risk. A total of 90 patients (57.7%) received hypomethylating agents (HMAs) treatment, 19 patients (12.2%) received chemotherapy and 47 patients (30.1%) received the best supportive care. Seventeen patients (10.9%) underwent allogeneic hematopoietic stem cell transplantation (allo‐SCT) after HMAs treatment or chemotherapy. With a median follow‐up of 35.3 months, overall response rate (ORR) was 69.5% in the HMAs ± chemotherapy group, 79.5% in the HMAs monotherapy group, 60.0% in the HMAs + chemotherapy group, and 37.5% in the chemotherapy group. HMAs monotherapy group had prolonged OS compared with the chemotherapy group (23.57 months vs. 11.73 months; p = 0.035). Patients who achieved ORR had prolonged OS (25.83 months vs. 8.00 months; p, Our retrospective study showed an advantage of HMAs therapy in CMML with an overall response rate of 65.9%‐79.5% compared with chemotherapy. The patients who respond to HMAs treatment have increased survival benefit compared to those who did not respond to HMAs treatment. HMAs monotherapy group had prolonged OS than the chemotherapy group.

Patients with lower‐risk myelodysplastic syndromes (LR‐MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter‐individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS‐relevant genes in 159 patients with LR‐MDS using next‐generation sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P = .001), RUNX1 (P = .031), EZH2 (P = .049), TP53 (P = .016), SRSF2 (P = .046), JAK2 (P = .040), and IDH2 (P = .035). We also found significantly shorter OS in patients with an adjusted TET2 variant allele frequency (VAF) ≥18% versus those with either an adjusted TET2 VAF, Shorter OS was associated with mutation status of ASXL1, EZH2 and JAK2, as well as TET2 VAF ≥18%. A novel prognostic scoring system based on the IPSS and the presence/absence of the four independent mutational factors further stratified LR‐MDS patients into three prognostically different groups. Integration of IPSS with mutation status/burden of certain MDS‐relevant genes may improve the prognostication of patients with LR‐MDS and could help identify those with worse‐than‐expected prognosis for more aggressive treatment.

Background and aim Despite the high incidence of tuberculosis infection (TBI) in patients with hematological diseases, there were few researches on TBI in MDS patients. We retrospectively analyzed the characteristics of MDS patients with TBI in our center to improve the clinical diagnosis and treatment of these patients.Methods Primary MDS patients diagnosed between 2014 and 2019 at the First Affiliated Hospital of Zhejiang University were retrospectively reviewed, TBI was diagnosed by positive culture(s) or acid fast bacilli on modified Ziehl-Neelsen staining on clinical samples as well as compatible symptoms and signs.Results Thirty-four of 1347 MDS patients were diagnosed with TBI, nine patients had blast＜5%, twelve patients were MDS with excess blast-1(MDS-EB1), and the rest 13 patients were MDS with excess blast-2 (MDS-EB2). Ten patients had lower risk (low and intermediate) and 24 patients had higher risk (high and very high) according to revised international scoring system (IPSS-R). Moreover, fifteen patients were classified into synchronous group (defined as TBI occurring within 3 months of MDS diagnosis), and the rest 19 patients were non-synchronous group (defined as TBI developed after MDS more than 3 months). Patients in synchronous group have higher rate of persistent fever (11/15 vs. 7/19, p=0.03), higher risk classification ( 14/15 vs. 8/19, P=0.002 ), and higher tendency to transform to acute myeloid leukemia (AML) (8/15 vs. 4/19, P=0.04 ) than those in non-synchronous group. The median time to AML was significantly shorter in synchronous group (7.68 months vs. 23.83 months, PConclusion TBI is not uncommon among patients with MDS, patients with synchronous TBI and MDS progress faster and have shorter OS, which may be associated with genetic susceptibility and lack of active therapy.

The clinical relevance of variant allele frequency (VAF) of recurrent mutations in myelodysplastic syndromes (MDS) has been increasingly reported. However, the prognostic value of mutational VAF across the genetic spectrum of MDS has not been extensively evaluated. In this study, we profiled the mutational spectrum of 382 newly diagnosed MDS patients using targeted next-generation sequencing. Exploratory analysis found that mutational VAF of some genes including TET2, TP53, and SF3B1 had significant associations with patient survival. Specifically, TET2 VAF ≥ 32% (HR 1.69, P = 0.025) and TP53 VAF ≥ 27% (HR 3.58, P < 0.001) were independently associated with shorter overall survival (OS). In contrast, SF3B1 VAF ≥ 15% had an independent association with better prognosis (HR 0.52, P = 0.048). In addition, high TET2 VAF was associated with an increased response to hypomethylating agents relative to low TET2 VAF (P = 0.009). Patients with high TP53 VAF more often possessed complex karyotypes than those with low VAF (P = 0.034). And patients with high SF3B1 VAF were more frequently classified as MDS with ring sideroblasts (MDS-RS) category than those with low VAF (P = 0.012). Meanwhile, we found that for some other genes like EZH2 and NRAS, once their mutations appeared, it meant poor survival regardless of mutational VAF. These findings suggest that mutational VAF of certain genes should be considered into the routine prognostic prediction and risk stratification of MDS patients.

AIM The aim of this study was to evaluate the clinical and molecular characteristics of myelodysplastic syndrome (MDS) patients with monosomal karyotype (MK). METHODS Eighty MDS patients with MK diagnosed between January 2010 and December 2018 were included in the retrospective study. Seventy-three had complex karyotype (CK) and 46 had very CK (vCK, ≥ 5 abnormalities). Clinical information was collected, and a panel of 37 genes, on which mutations have been previously reported to be associated with MDS patients, was analyzed by next-generation sequencing. Genetic and biological features and their association with survival were evaluated. RESULTS Monosomy 5, 7, and 17 were the most frequent and mainly occurred in patients with vCK. While median overall survival (OS) for all patients was 12.8 months with 95% CI 9.1-16.5, patients with vCK had shorter OS (8.4 months with 95% CI 3.9-12.8) than those with non-vCK (16.1 months with 95% CI 11.5-20.8) (P = .02). At least one gene mutation was detected in 76 patients (95%), TP53 mutations were detected in 57 patients, and their median OS was significantly shorter than those without TP53 mutations (9.5 months with 95% CI 7.5-11.5 vs 26.1 months with 95% CI 8.0-44.2, P

According to 2008 WHO classification RARS is regarded as less than 5% blasts and more than 15% ring sideroblasts in the bone marrow. In 2016 WHO classification MDS-RS is revised as more than 15% ring sideroblasts or more than 5% ring sideroblasts in the presence of the SF3B1 mutation. In our study, we classified intracellular iron in bone marrow into four types according to the size and quantity of iron granules. We found that there was a significant difference between SF3B1-mutant and SF3B1-wild-type MDS patients in intracellular iron III, intracellular iron IV and ring sideroblasts. We defined intracellular iron (III + IV + RS)%×100 as 'Iron score'. We suggest that the patients carrying SF3B1 mutation with Iron score ≥10 will extend the subtype of MDS-RS, in addition to the current WHO classification criteria. This study gives us a new insight into the relation of SF3B1 mutation and intracellular iron in lower-risk MDS.

Patients with lower-risk myelodysplastic syndromes (LR-MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter-individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS-relevant genes in 159 patients with LR-MDS using next-generation sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P=0.001), RUNX1 (P=0.031), EZH2 (P=0.049), TP53 (P=0.016), SRSF2 (P=0.046), JAK2 (P=0.040), and IDH2 (P=0.035). We also found significantly shorter OS in patients with a TET2 variant allele frequency (VAF) ≥18% versus those with either a TET2 VAF Figure Disclosures No relevant conflicts of interest to declare.