Overall Survival In Myelodysplastic Syndromes Patients Research Articles

Prognostic significance of GATA2 in patients with MDS/AML: a systematic review and meta-analysis.

GATA2 deficiency syndrome is a heterogeneous disorder characterized by a high risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML). We conducted a meta-analysis of the literature to explore the prognostic significance of GATA2 mutations in patients diagnosed with MDS/AML, as previous studies have yielded conflicting findings regarding the impact of GATA2 mutations on patient outcomes. We conducted a comprehensive literature search of databases such as PubMed, Embase, the Cochrane Library, and the Web of Science to obtain studies on the prognostic significance of GATA2 mutations in patients with MDS/AML that were published through January 2024. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). The meta-analysis was conducted by choosing either a fixed-effect model or a random-effect model, depending on the variability observed among the studies. A total of 13 cohort studies were included in the final meta-analysis, including 2714 patients with MDS, of whom 644 had GATA2 mutations. The results revealed that GATA2 mutations had an adverse impact on OS (HR = 1.54, 95% CI = 1.08-2.18, P = 0.02) and EFS (HR = 1.32, 95% CI = 1.01-1.72, P = 0.04), but no significant effect on DFS (HR = 1.21, 95% CI = 0.89-1.64, P = 0.23). GATA2 mutations were associated with a significantly shorter OS in MDS patients (HR = 2.56, 95% CI = 1.42-4.06, P = 0.002) but not in AML patients (HR = 1.08, 95% CI = 0.92-1.26, P = 0.37). Our meta-analysis revealed that GATA2 mutations are associated with unfavourable outcomes in patients with MDS/AML. Furthermore, patients harbouring these mutations should be prioritized for aggressive therapeutic interventions.

Platelet Count Doubling after One Course of Demethylated Drug Therapeutic Predicts the Treatment Response and Efficacy of Patients with Myelodysplastic Syndrome

To investigate the predictive value of platelet doubling (platelet count doubling) after one course of hypomethylating agents (HMA) on the treatment response and efficacy of myelodysplastic syndrome (MDS). Clinical and pathological data of 75 patients who received HMA in our hospital from January 2017 to March 2022 were collected and analyzed. All patients were divided into two groups according to whether their platelet count doubled after one course of treatment, including platelet doubling group and non-doubling group, and statistical analysis was performed to compare the treatment response and efficacy between the two groups. In addition, platelet count changes were compared between azacitidine and decitabine therapy. Compared with the non-doubling platelet count group, the ORR of the doubling platelet group was significantly better after 3 courses of treatment (P =0.002), and there was a statistically significant difference in the number of HI between the two groups (P =0.005). In addition, the median survival time (MST) was 26 months in the platelet doubling group and 11 months in the non-doubling group (P =0.001). The overall survival (OS) and 1- and 2-year survival rates of the platelet doubling group were also significantly better than those of the non-doubing group. Multivariate COX analysis showed that platelet count doubling was an independent predictor of OS in MDS patients after 1 course of treatment (P =0.013). There was no significant difference in the response rate of platelet count doubling between MDS patients treated with azacitidine and decitabine (33.3% vs 23.8%, P >0.05). Platelet count doubling after one course of treatment can be used as a predictor of response rate and survival of demethylated drug therapy in MDS patients. In addition, there was no significant difference in the response rate of platelets in MDS patients treated with azacitidine or dicetabine.

High BM plasma S100A8/A9 is associated with a perturbed microenvironmentand poor prognosis in myelodysplastic syndromes.

S100A8/A9 is a proinflammatory protein and plays an essential role in the pathogenesis of myelodysplastic syndromes (MDS) via the S100A8/A9-Toll-like receptors axis. While S100A8/A9 levels have been used as biomarkers in many inflammatory diseases, their clinical relevance has not been conclusively resolved in MDS. To address this, we used an enzyme-linked immunosorbent assay to quantify S100A8/A9 heterodimers in bone marrow (BM) plasma from 215 MDS patients and compared S100A8/A9 levels across patients with various disease risks and genotypes. S100A8/A9 levels correlated with ASXL1 variant allele frequencies significantly. Moreover, mutant ASXL1 with concurrent RUNX1, STAG2, ZRSR2, or EZH2 mutations was associated with higher S100A8/A9 levels. We further showed that higher S100A8/A9 independently predicted inferior leukemia-free survival and overall survival in MDS patients, irrespective of age, Revised International Prognostic Scoring System subgroups, and known detrimental mutations. Lastly, through deep-sequenced transcriptomic analysis, we demonstrated that higher S100A8/A9 in the BM intimated a perturbed microenvironment with enhanced myeloid-derived suppressor cell-mediated tumor immune escape signal, altered metabolism, and impairment in the functions and quantities of CD8+ T cells and NK cells. S100A8/A9 in the BM microenvironment may be a potential biomarker in the prognostication of MDS and target for novel therapy.

Association of systemic inflammatory and autoimmune manifestations with myelodysplastic syndromes: A systematic review and meta-analysis.

Systemic inflammatory and autoimmune manifestations (SIAMs) are frequently reported in Myelodysplastic syndromes (MDS). Studies focused on the impact of SIMAs on survival outcomes of MDS remains controversial. We performed this systematic review and meta-analysis to determine the association of SIAMs with overall survival, median survival, rate of acute myeloid leukemia transformation and mortality of MDS. An electronic search was conducted in 4 databases without any language restrictions, including PubMed, EMBASE, Medicine and Cochrane library up to April 30, 2021. The 18 studies included a total of 4603 MDS patients, of which 1175 (25.5%) patients had SIAMs. MDS patients with SIAMs had a statistically shorter overall survival compared with patient without SIAMs (Hazard ratio, 2.43; 95% confidence interval [CI], 1.34-4.41; P < .01). Our results were most compatible with no effect of SIAMs on median survival, rate of acute myeloid leukemia transformation and mortality (Median survival ratio, 1.16; 95% CI, 0.91-1.47; Odds ratio, 0.96; 95% CI, 0.63-1.45 and 1.2; 95% CI, 0.84-1.7, respectively). In this systematic review and meta-analysis, SIAMs appeared to have an adverse effect on overall survival of MDS patients. This finding suggested that SIAMs may be a potential independent prognostic factor for MDS.

Prognostic Value of Thrombocytopenia in Myelodysplastic Syndromes After Hematopoietic Stem Cell Transplantation.

Prolonged isolated thrombocytopenia (PT) is a common complication affecting the outcome of stem cell transplantation. In this study, we undertook a real-world study of 303 myelodysplastic syndrome (MDS) patients who received allogeneic hematopoietic stem cell transplantation (HSCT) between December 2007 and June 2018. 28.4% of MDS patients suffered from PT after HSCT. Survival analysis indicated that PT was associated with worse overall survival (OS) in MDS patients. The 2-year and 5-year OS in MDS patients with PT after HSCT were 49% and 47%, significantly worse than that of 68% and 60% in patients without PT (P=0.005). For RFS, patients with PT did not have an increased risk of disease relapse (P=0.964). After multivariate adjustment, PT was proved to be the independent risk factor associated with the worse OS (HR 1.49, 95% CI 1.00-2.21, P =0.048). We further analyzed risk factors associated with the occurrence of PT in MDS patients. Multiple logistic regression identified grade II-IV aGVHD, extensive chronic GVHD, hemorrhagic cystitis, and CMV activation as significant risk factors for developing PT. Among these variables, the Odds Ratio (OR) of grade II-IV aGVHD was the highest (P =0.001, OR: 2.65, 95% CI: 1.51-4.64). These data indicated the prognostic value of PT in MDS after HSCT. The identification of risk factors for PT may help improve patient management and lead to the design of effective treatment strategies.

Platelet Doubling After First Decitabine Cycle Predicts Response and Survival of Myelodysplastic Syndrome Patients.

Although the effect of decitabine on myelodysplastic syndrome (MDS) has been demonstrated, merely a proportion of patients respond to therapy, and no well-recognized predictors have been identified. This study was conducted to investigate the effectiveness of decitabine in real-world clinical practice, and determine the predictive factors of response and overall survival (OS) in MDS patients. Clinical and pathological data were collected from 94 patients and analyzed. These patients were reclassified according to the 2016 World Health Organization classification criteria, and restratified by International Prognostic Scoring System prognostic scores. The response evaluation was performed according to the 2006 modified International Working Group response criteria. In this study, 62% of patients responded to decitabine. Among these patients, 15 patients (16%) obtained complete remission (CR), 15 patients (16%) obtained marrow CR with hematologic improvement (HI), 20 patients (21%) obtained marrow CR without HI, and 8 patients (9%) only obtained HI, and no patient botained partial remission. The OS of the responders was significantly longer than that of non-responders (67 months vs. 7 months, P<0.001). The OS in patients with and without platelet doubling was significantly different in both the low/intermediate and high/very high risk groups (P=0.0398 and P=0.0330). The multivariate analysis revealed that platelet doubling after the first decitabine cycle is an independent predictor of response and OS in MDS patients (P=0.002 and P=0.008). Decitabine is effective for treating MDS patients in real-world clinical practice. Furthermore, platelet doubling after the first decitabine cycle can be used as a predictor of response and survival in MDS patients.

Independent Prognostic Value of Flow Cytometry (FCM) in Myelodysplastic Syndromes (MDS) - Composition of a Prognostic FCM-Score for Overall Survival

Independent Prognostic Value of Flow Cytometry (FCM) in Myelodysplastic Syndromes (MDS) - Composition of a Prognostic FCM-Score for Overall Survival

High PRAME expression is associated with poor survival and early disease progression in myelodysplastic syndromes with a low bone marrow blast percentage

We investigated the clinical implications of preferentially expressed antigen in melanoma (PRAME) expression in bone marrow cells of 116 patients with myelodysplastic syndromes (MDS). Quantitative RT-PCR was carried out to examine the PRAME expression level. High PRAME expression was observed in MDS patients classified into higher revised International Prognostic Scoring System (IPSS-R) risk categories (Very high and High) with a high bone marrow blast percentage (5% or higher). Kaplan-Meier analysis demonstrated that high PRAME expression is significantly associated with a poorer overall survival (OS) in MDS patients with a low bone marrow blast percentage (less than 5%) (log-rank test p = .0014) and those classified into lower IPSS-R risk categories (Very Low, Low, and Intermediate) (log-rank test, p = .0035). In contrast, there was no significant association between PRAME expression and OS in MDS patients with a high bone marrow blast percentage or those classified into higher IPSS-R risk categories. In addition, high PRAME expression was associated with early disease progression in MDS patients with a low bone marrow blast percentage. This study suggested PRAME expression to be a prognostic factor in MDS.

Impact of obesity on survival of patients with myelodysplastic syndromes

ABSTRACT Background: Obesity has been associated with increased incidence of myelodysplastic syndromes (MDS). Recently intriguing data in mouse models suggested that obesity increases survival in animals with MDS. Methods: This was a retrospective analysis using the Moffitt MDS database. Obesity was defined by using body mass index (BMI), whereby a BMI ≥ 30 was regarded as obese. Results: Among 3089 MDS patients with known BMI, 963 patients (31%) were categorized as obese. There were no differences in baseline characteristics between patients with BMI ≥ 30 and those with <30. The median OS for patients with BMI ≥ 30 was 34 months compared to 37 months for those with BMI < 30 (p 0.04). For patients with lower-risk MDS median OS was 52 months versus 57 months, respectively, (p 0.08) while for higher-risk patients median OS was 17 months for both groups. The rate of AML transformation was 36% for patients with BMI ≥ 30 compared to 32% for those with BMI < 30 (p 0.009). There was no difference in response to azacitidine. In multivariable analysis, BMI was associated with inferior OS. For patients < 45 years old, the median OS was 25 months for patients with BMI ≥ 30 compared to 116 months for those with BMI < 30 (p 0.034). Conclusions: Obesity is associated with inferior overall survival (OS) in MDS patients in less than 65 years old and lower MDS risk. Impact of obesity on the outcome of MDS is being explored in both mice and human. Here we reported the impact of obesity on OS in MDS patients. Obesity is associated with inferior OS in MDS patients particularly younger age groups and lower MDS risk.

LOC101928834, a novel lncRNA in Wnt/β-catenin signaling pathway, promotes cell proliferation and predicts poor clinical outcome in myelodysplastic syndromes.

Long non-coding RNAs (lncRNAs) play important roles in hematological malignancies. We have previously identified several differentially expressed lncRNAs in myelodysplastic syndromes (MDS) by microarray analysis. In the present study, we explored the regulatory circuitry, potential functions, clinical and prognostic relevance of these lncRNAs in MDS by developing a lncRNA regulation network. We identified a novel lncRNA, LOC101928834, which was significantly up-regulated in the bone marrow of patients with MDS and acute myeloid leukemia (AML). We further evaluated the clinical relevance of LOC101928834 in 89 MDS and 110 AML patients and found that higher level of LOC101928834 expression was associated with higher white blood cell count, higher blast percentage, the subtype of refractory cytopenia with excess blasts (RAEB) and shorter overall survival in MDS patients. Receiver operating characteristic (ROC) curve analysis showed that LOC101928834 expression could discriminate MDS-RAEB patients from control with an area under the receiver-operating curve (AUC) of 0.9048. Moreover, functional analysis showed that LOC101928834 promoted cell proliferation and cell cycle progression, and activated Wnt/β-catenin signaling pathway in vitro. In conclusion, LOC101928834 expression is correlated with clinical and biological features of MDS and may serve as a novel diagnostic and prognostic biomarker.

Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hi conventional dendritic cells.

The use of immunotherapy to treat patients with myelodysplastic syndromes (MDS) shows promise but is limited by our incomplete understanding of the immunologic milieu. In solid tumors, CD141Hi conventional dendritic cells (CD141Hi cDCs) are necessary for anti-tumor immunosurveillance and the response to immunotherapy. Here, we found that CD141Hi cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141Hi cDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141Hi cDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141Hi cDCs, we found fewer numbers of progenitors committed to DC differentiation in the MDS bone marrow and these progenitors expressed lower levels of interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi cDC differentiation. To rescue impaired CD141Hi cDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141Hi cDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu. Epigenetic regulation of CD141Hi cDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.

Prognostic significance of SF3B1 mutations in patients with myelodysplastic syndromes: A meta-analysis.

Splicing factor 3B subunit 1 (SF3B1) is a complex takes part in intron splicing of pre-mRNA and mutations within it have been reported frequently in myeloid malignancies including myelodysplastic syndromes (MDS). However, its prognostic value has been controversial. Hence, we aimed this meta-analysis to investigate the prognostic effect of SF3B1 mutations in patients with MDS. Several electronic databases were searched in of EMBASE, PubMed, the Cochrane Library and Web of Science (published up to November 2017) to obtain eligible studies. The pooled Hazard Ratio (HRs) and 95% confidence interval (CI) for overall survival (OS) and leukemia-free survival (LFS) as the primary and secondary endpoint, respectively, were chosen and extracted to determine the prognostic impact of SF3B1 mutations and to compare SF3B1 mutations to those with wild-type. Nine cohort studies with a total of 2259 patients were obtained, and the pooled HRs for OS was 0.93 (95% CI: 0.56-1.52, p-value = 0.78) and revealed no significant effect on overall survival of MDS patients by random effect models. Our meta-analysis suggested that SF3B1 has no impact on OS of patients with MDS, however, an adequately designed prospective study with a large number of patients with different type of SF3B1 mutations is needed to confirm these results. Additionally, Begg's and Egger's tests did not show any publication bias.

Understanding the Association between Transfusion Status (TS) and Overall Survival (OS), and Other Clinical Outcomes in Patients with Myelodysplastic Syndromes (MDS) from the Physicians' Perspective: A Pilot Survey

Introduction: Approximately 50% of patients with myelodysplastic syndromes (MDS) are anemic at initial diagnosis, with many becoming transfusion dependent. Based on several clinical trial analyses and observational studies, transfusion dependence is associated with worse outcomes in patients with MDS (e.g. overall survival [OS], hematologic improvement, etc.) compared with transfusion independence. However, no studies have examined the physicians' perspective with regard to the relationship between transfusion dependence and outcomes in MDS. The current study investigates physicians' understanding of the impact of transfusion status (TS) on OS and other clinical outcomes. Methods: Data were derived from a brief 5-minute web-based physician survey via the M3 Global Research physician panel. Physicians had to be a hematologist/oncologist or hematologist to participate in the survey. In total, 100 physicians completed the survey across the EU5 countries (France, Germany, Italy, Spain, and United Kingdom; n = 15 in each country) and the USA (n = 25). The survey asked physicians for their opinion on the impact that TS has on OS, as well as on other clinical outcomes, such as hematologic improvement or serum ferritin level. Both items were ranked with a 7-point Likert scale ranging from 0 "very low impact" to 7 "very high impact". Physicians were also asked to rate their level of certainty for each of these assessments, with a 7-point Likert scale ranging from 0 "not at all certain" to 7 "completely certain". Lastly, respondents were asked to select from several options regarding what they based these decisions upon in terms of their sources of knowledge of the relationships between TS and OS or other outcomes (respondents could choose more than one option). All results were described descriptively with frequency counts and percentages. Results: A total of 80 hematologist/oncologists and 20 hematologists completed the survey. A majority (85%) of physicians selected a score ≥ 5 (7 being "very high impact") on the item "In your opinion, what is the impact of TS on OS in MDS patients, holding other characteristics constant (e.g. disease severity, comorbidities)?". A total of 84% of physicians selected a score ≥ 5 (7 being "completely certain") on the certainty of their answer, with 8% reporting being "completely certain". Similarly, 87% of physicians selected a score ≥ 5 on the item "In your opinion, what is the impact of TS on other clinical outcomes (e.g. hematologic improvement, serum ferritin level) in MDS patients, holding other characteristics constant (e.g. disease severity, comorbidities)?". Some 85% of physicians selected a score ≥ 5 on the certainty of their answer, with 15% reporting being "completely certain". A majority (79%) of respondents reported using their clinical experience with their own patients as the basis for their assessment of the association between TS and OS or other clinical outcomes. More than half (57%) of physicians reported basing their assessment on knowledge of the literature, and 24% reported using the opinions of their colleagues or others in the field. These findings were numerically similar across the EU5 countries and the USA. Conclusions: In this global pilot survey, almost all physicians reported TS as having more than a moderate level of impact on OS and other clinical outcomes in patients with MDS; almost all physicians also reported more than a moderate level of certainty to their perceptions of these relationships between TS and OS or other clinical outcomes. Physicians' own clinical experience was the key driver in understanding the association between TS and OS or other clinical outcomes. Physicians' level of knowledge and confidence was similar across geographical areas. Disclosures Gupta: Kantar: Employment; Celgene Corporation: Consultancy. Li:Celgene Corporation: Consultancy; Sun Pharma: Consultancy; BMS: Consultancy; Novartis: Consultancy; Asclepius Analytics: Employment. Schroeder:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kulasekararaj:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy. Matos:Celgene Corporation: Consultancy; Kantar: Employment. Berk:Kantar: Employment; Celgene Corporation: Consultancy. Tang:Celgene Corporation: Employment, Equity Ownership. Grisolano:Celgene Corporation: Consultancy; Kantar: Employment.

Intermittent Transfusion Independence Is Associated with Improved Overall Survival in Patients with Transfusion Dependent MDS

Intermittent Transfusion Independence Is Associated with Improved Overall Survival in Patients with Transfusion Dependent MDS

Decitabine: An effective and safe treatment for myelodysplastic syndrome and acute myeloid leukemia

Decitabine is reported to be valuable in treating multiple malignant blood diseases. However, the application of decitabine in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) has not been fully examined. Thus, our study aimed to investigate the clinical efficacy and safety of decitabine in treating such patients. Clinical data of MDS or AML patients treated with decitabine were retrospectively analyzed. All the patients were regularly followed up, and the risk factors affecting clinical efficacy were also detected. A total of 36 patients (MDS, n = 27; AML, n = 9) were included in the study. The response rate of MDS patients was 55%, and there were three cases (15%) of complete remission (CR), three cases (15%) of marrow CR, and five cases (15%) of hematologic improvement. It was about three cycles to achieve the best efficiencies. Gender, age, percentage of blasts in bone marrow, International Prognostic Scoring System risk group, and cytogenetic factors were not associated with response rate. The median overall survival of MDS patients was 8 (1-44) months. Agranulocytosis (P = 0.037) and severe anemia (P = 0.044) were the independent factors for prognosis. The complete response rate of AML was 33.3%. From the investigation, infection was the most common complication in our cohort, especially lung infection with the incidence of 27.8%. Our data demonstrated that decitabine was effective and relatively safe in treating MDS and AML. Patients with agranulocytosis and severe anemia were prone to have poor survival, which should be monitored in clinical practice.

Impact of Red Cell Distribution Width on Dysplasia and Clinical Outcome in 66 Patients with Myelodysplastic Syndrome without Increased Blasts

Both clonal hematopoiesis as defined by genomic alteration and morphological cell dysplasia is a hallmark of pathology of myelodysplastic syndrome (MDS). Studies showed that, red cell distribution width (RDW), a quantitative non-subjective index of red cell anisocytosis, has diagnostic significance in anemia associated with MDS.Our recent study showed that increase of RDW has close association with dyserythropoiesis and also shorter overall survival (OS) in refractory anemia (Leuk Res 2018;67:56-59). To explore the clinical significance of RDW in MDS without increased blasts, we examined the details of correlation between RDW and morphological dysplasia which characterize MDS.We retrospectively analyzed 101 MDS patients, including 66 patients without increased blasts (blasts in the bone marrow of less than 5% and the peripheral blood of 1% or less). RDW was calculated using automated blood cell analyzer. Dysplasia was assessed according to the WHO 2008 classification by different two investigators. 100 cells (at least 25 cells) of myeloid and erythroid series were counted. At least 25 cells of megakaryocyte were also counted. Karyotype of bone marrow cells was analyzed by using routine G-band technique and categorized according to MDS cytogenetic scoring system. Correlations of RDW and clinical variables were analyzed. Based on previous study, MDS patients was divided into two groups, RDW-H (RDW was 15% or more, 48 cases) and RDW-L (RDW was lower than 15%, 18 cases). Comparisons of dysplasia or OS between these two groups were analyzed.In MDS without increase of blasts, weak inverse correlation was found between RDW and hemoglobin (rs = −0.31, P = 0.01). RDW was correlated with the presence of ring sideroblasts (RS) in the bone marrow (rs = 0.40, P = 0.001), and also weakly correlated with budding of nucleus of erythroblasts (rs = 0.33, P = 0.007). Dysgranulopoiesis was less observed than either dyserythropoiesis or dysmegakaryopoiesis (P <0.001, P <0.001). RDW was not significantly different between groups with karyotype risk category (P = 0.08).Table showed the subtype of MDS, details of morphological dysplasia. Between two groups, RDW-H showed significantly higher percentages of dyserythropoiesis, dysgranulopoiesis, and dysmegakaryopoiesis.The increased RDW (≥15.0%) was associated with shorter OS (P = 0.02) (hazard ratio, 1.15e + 9 (95% confidence interval = 2.49-2.49)) (Figure). In contrast, there was no association between RDW and OS in MDS patients with increased blasts.Earlier studies showed increase of RDW was evident in refractory anemia with ring sideroblasts (RARS) which showed erythrocyte anisocytosis called dimorphism. Revised WHO classification (2017) defined MDS-RS with single lineage dysplasia (MDS-RS-SLD) which is characterized with specific mutation of splicing factors, such as SF3B1 and with favorable prognosis. This classification also defined MDS-RS with multi lineage dysplasia (MDS-RS-MLD) which has additional dysplasia in myeloid and/or megakaryocyte lineage in addition to RS. Pathology of MDS-RS-MLD is still to be remained.Our findings partly agree the earlier observations, showing close association between red cell anisocytosis evaluated with increase of RDW and the presence of RS. Furthermore, RDW-H group contained MDS with dysplasia of myeloid and/or megakaryocyte lineage not limited to the erythroid dysplasia(s) with RS. RDW could discriminate MDS-MLD with poor prognosis from MDS-SLD with favorable prognosis.To explore the significance of RDW in MDS, it is necessary to study large number of patient combined with genetic analysis. Nevertheless, RDW is potentially simple and useful laboratory parameters in clinical practice in MDS, representing hematopoietic defect (ineffective hematopoiesis), associated with iron metabolism and hemoglobin synthesis in MDS. DisclosuresNo relevant conflicts of interest to declare.

Prognostic value and clinical feature of SF3B1 mutations in myelodysplastic syndromes: A meta-analysis.

SF3B1 gene mutations are the most frequent mutations found in myelodysplastic syndromes (MDS), and the prognostic implication of these mutations remains controversial. We conducted a meta-analysis of studies assessing the prognostic impact and clinical feature of SF3B1 mutations in MDS patients. The overall hazard ratio for overall survival (OS) was 0.90 (95% confidence interval 0.60-1.35, P = 0.61) in MDS patients with SF3B1 mutations compared to those without. Lower leukemia-free survival was associated with SF3B1 mutations. Subgroup analyses showed that Asian cohorts and Illumina HiSeq 2000 methods were significantly associated with OS. Furthermore, SF3B1 mutations were significantly correlated with a lower level of blast cells and a high level of platelet counts and bone marrow ring sideroblasts. Thus, the current meta-analysis suggests that SF3B1 mutations have no significant impact on the OS of MDS patients, and the hematologic parameters of SF3B1 mutations identify a distinct subset of MDS patients with homogeneous features.

Prognostic role of TET2 deficiency in myelodysplastic syndromes: A meta-analysis.

Tet methylcytosine dioxygenase2 gene (TET2) is one of the most frequently mutated gene in myeloid neoplasm, but the prognostic role of TET2 aberrations in myelodysplastic syndromes (MDS) remains unclear. Therefore, we performed a meta-analysis. Fourteen eligible studies with 1983 patients were included in this meta-analysis. Among these, 2 studies evaluated the impact that the TET2 expression level had on the prognosis. The combined hazard ratios (HR) estimated for overall survival (OS) was 1.00 (95%CI: 0.74 to 1.37; p=0.989) when comparing those with TET2 mutations with those without. Among the patients treated with hypomethylating agents (HMAs) or hematopoietic stem cell transplantation (HSCT), the pooled HR for OS was 1.02 (95% CI: 0.77-1.35, p=0.89) and 1.54 (95%CI: 0.69 to 3.44; p=0.29), respectively. We also conducted an analysis of the response rate to HMAs, and the OR was 1.73 (95%CI: 1.11 to 2.70; p=0.016). Additionally, subgroup analyses showed the pooled HR for OS was 0.93(95%CI: 0.44 to 1.98; P=0.849) in WHO-classified CMML patients and 1.02(95%CI: 1.02 to 3.46; p=0.042) in studies evaluated TET2 expression level. The analysis suggested TET2 mutations had no significant prognostic value on MDS. However, the response rates to HMAs were significantly different between those with and without TET2 mutations, and the low expression level of TET2 gene was significantly associated with a poor OS in MDS patients.

TET2 mutations in myelodysplastic sydndromes (MDS)

The ten-eleven translocation 2 (TET2) gene encodes the protein methylcytosine dioxygenase which catalyses the conversion of methylcytosine to 5-hydroxymethylcytosine and plays a key role in both DNA demethylation and myelopoiesis. Mutations in the TET2 gene have been reported in 10–26% of myelodysplastic syndromes (MDS) cases. The impact of these mutations on overall survival of MDS patients and their likelihood to transform to secondary acute myeloid leukaemia (AML) still needs to be clarified. A cohort of 55 MDS patients who were diagnosed between 2013 and 2016 were screened retrospectively for mutations in the hotspots LCX1 and LCX2 (exons 4, 7, 8, 9 and 11) by Sanger sequencing as previously described by Jankowska et al.1 Seven TET2 mutations were found in six of 55 MDS patients (10.9%). Among these 55 MDS patients, 23 (40%) patients were on azacitadine, 14 (25.4%) patients were on transfusions, 15 (27.2%) patients received no treatment, one patient had a transplant, one patient was on myelosuppressant and one patient received erythropoeitin. Identification of these mutations can help refine and confirm the diagnosis of myelodysplasia, resulting in better patient management. Moreover, recent studies suggest that TET2 mutations may be associated with response to DNA hypomethylating agents2 and further validation of this biomarker is worthwhile.

Driver Somatic Mutations and Transplantation Decision Making in Patients with Myelodysplastic Syndrome

▪The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various somatic mutations are associated with different phenotypes and clinical outcomes. The only curative treatment for MDS patients is allogeneic hematopoietic stem cell transplantation (HSCT) which is considered as a therapeutic option until the age of 65-70 in eligible patients. Whether the genetic basis influences the outcome of HSCT is currently unclear. Recently, we observed that mutations on ASXL1, RUNX1 and TP53 genes are independent predictors of relapse and overall survival in MDS patients after HSCT, and that the integration of these mutations into currently available predictive models increases the capability to capture prognostic information at individual patient level (Della Porta MG et al. J Clin Oncol, 2016 in press).In this study, we explored the possibility of developing a clinical/molecular predictive model to specifically estimate the outcome after HSCT in patients with MDS or acute myeloid leukemia evolving from MDS (MDS/AML). We studied 401 patients undergoing allogeneic HSCT for primary MDS or MDS/AML between 1997 and 2013 and reported to the GITMO registry. We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms.In multivariable analysis with probability of relapse as endpoint the following factors showed independent prognostic value: percentage of marrow blasts (>10% vs. ≤10%, HR 1.43, P=0.04), cytogenetic risk according to IPSSR (poor/very poor vs. very low/low/intermediate risk, HR 1.85, P=.002), disease status at transplant (refractoriness to induction chemotherapy vs. complete remission, HR 2.4, P<.001), type of conditioning (reduced intensity vs. standard conditioning, HR 1.35, P=.034) and mutational status of ASLX1/RUNX1/TP53 genes (present vs absent, HR 1.49, P=.021). Recipient age (>40 vs. ≤40 years, HR 1.68, P=.001), comorbidity risk according to HCT-CI (high vs. low/intermediate risk 2.10, P<.001) type of conditioning (reduced intensity vs. standard conditioning, HR 0.53, P=.033) and HLA matching (≤7/8 vs. 8/8 match, HR 1.97, P=.001) were significant risk factors for transplant-related mortality (TRM).Based on regression coefficients, we developed a clinical/molecular model predictive for the risk of relapse after transplantation in MDS and MDS/AML. Accordingly, a score value of 1 was assigned for each of the following risk factors: marrow blasts >10%, poor/very poor cytogenetic risk according to IPSSR, refractoriness to induction chemotherapy, and driver mutations in ASLX1/RUNX1/TP53 genes. A relapse risk index was calculated as the sum of these weighted scores, and was then categorized into 4 risk groups: low (score=0), intermediate (score=1-2), high (score=3), and very high (score=4). The cumulative incidence of relapse was estimated by a competing risks approach with TRM. In patients receiving standard conditioning, 5-year probability of survival after allogeneic HSCT was 61%, 43%, 39% and 19% for low, intermediate, high and very high risk (P<.001), while cumulative incidence of relapse were 9%, 19%, 24% and 35%, respectively (P=.001). In patients receiving reduced intensity conditioning, 5-year probability of survival was 55%, 42%, 33% and 15% for low, intermediate, high and very high risk (P=.003), while cumulative incidence of relapse were 12%, 25%, 39% and 58%, respectively (P<.001).This model serves as a proof of concept that the integration of somatic mutations significantly increase the capability to capture prognostic information in MDS and MDS/AML patients receiving allogeneic HSCT, and may provide a basis for improving clinical decision-making. Possible interventions in patients with high risk of disease relapse after HSCT according to genotype may include the anticipation of the transplant procedure in early disease phase, the use of innovative conditioning regimens to increase the probability to eradicate MDS clone, and prophylaxis of disease recurrence after transplantation by donor leukocyte infusions and targeted/novel therapies DisclosuresCiceri:MolMed SpA: Consultancy.