Incidence Of Myelodysplastic Syndromes Research Articles

The Efficacy and Prognosis of Advanced Myelodysplastic Syndrome in Children

Pediatric myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell neoplasm with an annual incidence of 1-4 cases/million. The low incidence of advanced MDS in children and poor prognosis attract our attention. However, there are limited reports on the scheme and efficacy of pediatric advanced MDS. In this study, we retrospectively analyzed the efficacy of chemotherapy in pediatric advanced MDS and assessed the prognosis of patients. According to 2016 World Health Organization (WHO) classification of haematolymphoid tumours, 30 newly diagnosed pediatric advanced MDS patients during Dec 2007 to Apr 2022 from our single center were selected as the research object. The clinical data and prognosis were analyzed. The median age of patients is 8 years (range: 1-15years). The median bone marrow blast is 15.75% (range: 5-29.5%), while the median peripheral blood blast is 4% (range: 0-29%). Cytogenetic analysis was available for 29 patients, 69% (20/29) cases had abnormal karyotype. Monosomy 7 (37.9%) was the most common cytogenetic abnormality. Out of the total, 7 patients were treated with CAG/HAG regimen (C: aclarubicin 6mg d1-14, H: homoharringtonine 1mg/m 2d1-14, A: cytarabine 10mg/m 2 q12h d1-14, and G: Granulocyte Colony-stimulating Factor 200mg/m 2 d1-14 ), 8 patients with decitabine (20mg/m 2 d1-5), 11 patients with decitabine and CAG/HAG, 4 patients with AML-like chemotherapy (Daunorubicin+cytarabine+etoposide ) or other. The evaluation of response of therapy was available in 25 patients, 5 cases (20%) in partial remission (PR), 11 cases (44%) in complete remission (CR), 9 cases in(36%)non-remission (NR). The total response rate of chemotherapy is 60%, with CAG/HAG therapy 33%, decitabine therapy 43%, combined CAG/HAG and decitabine therapy 78%, AML-like chemotherapy 100%. The total complete remission rate of chemotherapy is 44%, with CAG/HAG therapy 17%, decitabine therapy 43%, combined CAG/HAG and decitabine therapy 56%, AML-like chemotherapy 67%. Patients receiving CAG/HAG in combination with decitabine had higher response rates compared to CAG/HAG or decitabine alone (OR=17.5, 95% CI 1.2-250.3, P=0.035). With a median follow-up of 20 months (range: 1-158months), 23 patients received HSCT after chemotherapy, and they had a higher 2-year overall survival rate compared to those who did not undergo transplantation (86% vs 0%, p<0.001). Decitabine combined with CAG/HAG improve the response rate of advanced pediatric MDS. Chemotherapy bridged hematopoietic stem cell transplantation significantly improves the prognosis of advanced pediatric MDS.

Risk of Myelodysplastic Syndromes (MDS) in Adolescents and Young Adults with Cancers Treated with Chemotherapy with or without Radiotherapy

Introduction The risk of MDS among adolescents and young adults (AYA) with cancer treated with chemotherapy with or without radiotherapy in the US is not well understood. Method We interrogated NCI's Surveillance, Epidemiology and End Result (SEER)-17 registries to identify patients (pts) between the ages of 15-39 years (AYA) diagnosed with MDS at least one year after diagnosis of a primary unrelated cancer treated with chemotherapy and or radiotherapy over a twenty-year period (January 2000 to December 2020). All cancers, including MDS, were identified using ICD-O-3/WHO-2008 histology codes. We excluded all leukemia and MDS entities from index cancer sites. The risk of MDS was estimated by standardized incidence ratio (SIR), defined as the ratio of observed MDS cases in the AYA pts treated for first cancers to the expected number of MDS cases in the general US population during this period. A referent rate file for MDS incidence in age, gender, race and calendar-year matched US population available in SEER*Stat software (version 8.4.0) was used for SIR calculation. We calculated exact, 2-sided Poisson-based 95% confidence intervals (CIs) about the SIRs. We stratified the risk using 5- calendar year periods, and latency after index cancer diagnosis. SIR and time to MDS development was calculated for six most common index cancers using R(v4.2.2)-software. Result Of a total of 168,078 AYA pts eligible for analysis, with 1,290,803-person years at risk during 2000 to 2020, 66 pts developed MDS during this period. The median age at diagnosis of index cancer and MDS were 34 years (yrs) (interquartile range (IQR), 27-37 yrs) and 38 yrs (IQR, 32-44 yrs), respectively. There were 680% more cases of MDS in the AYA cohort compared to that expected in the matched general US population [SIR (95% CI): 7.80 (6.03-9.92), p<0.05)]. A higher SIR was observed for males (12.19) compared to females (5.82) and among all race/ethnicity, highest among black males [(SIR (95%CI): 18.99 (6.17-44.32), p<0.05]. We analyzed SIR for top-six index cancer sites that contributed to most MDS cases. Lymphomas [Non-Hodgkin (NHL) and Hodgkin (HL)] and breast accounted for 54.5% of all MDS cases. SIR for MDS in pts with NHL was 22.07 (95% CI: 12.61-35.84), in HL pts was 10.75 (95% CI: 4.64-21.18), and in breast cancer pts was 2.79 (95% CI:2.22-7.51). Even though the absolute number of cases was low, pts with brain, as well as bone and joint cancers had highest SIRs for MDS. When stratified by 5-calendar year periods, the SIR of MDS was elevated compared to general population through all periods and was highest during 2000-2005 (27.44; 95% CI: 11.03-56.53), and declined for the subsequent time periods. When analyzed by latency period, the SIR for MDS was highest at 1-3 years after index cancer diagnosis (21.46: 95% CI 13.45-32.50) and then showed a steady decline with increasing latency over a period of 15-20 years but never reached the rates observed in general population (Figure 1). Among the six most common index sites, pts with bone and joint cancer had earliest time to occurrence of MDS, whereas the longest latency to developing MDS was observed in pts with testicular cancer (Figure 2). Conclusion AYA cancer cohort treated with chemotherapy or radiotherapy have nearly 8-fold higher risk of future development of MDS compared to the same age matched general US population. This risk is highest during the initial 1-3 years of diagnosis of index cancer, declines over time, but never reaches the rates in the general population. These findings warrant further investigation to understand the biology behind this observation and have potential treatment and surveillance implications.

Association of weight loss with risk of myelodysplastic syndromes (MDS) in adults with obesity: Insights from the SPLENDID cohort.

e18865 Background: MDS arises from pre-existing somatic mutations or clonal hematopoiesis (CH). A normal body mass index (BMI) is strongly associated with a lower prevalence of CH. We hypothesized that intentional weight loss (IWL) might be associated with lower incidence of MDS and studied this in the context of bariatric surgery (BSx) among adults with obesity. Methods: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adults with BMI ≥35Kg/m2 who had BSx (ages 18-80) during 2004-2017 were included. Each patient (pt) who underwent BSx was matched with propensity score by the nearest-neighbor method to five pts who did not undergo BSx for their obesity, resulting in a total of 30318 pts. MDS diagnosis was made using contemporary WHO criteria and myeloid sequencing mutation data were analyzed. Multivariable cox regression analysis estimated time to MDS as the primary endpoint. Results: 5053 adults with obesity had BSx while 25265 adults underwent nonsurgical (NS) care. Median age and BMI were 46 years (y) and 45kg/m2. The majority were females (77%); and had white (73%) race. Follow-up was over 17y period with median (IQR) of 6.1 (3.8-8.9)y for the entire cohort. BSx-group had 19.2% greater WL at 10-y [mean between-group difference: 24.8 (95% CI, 24.6-25.1) kg]. One patient (male) in the BSx-group vs twenty-four patients (twelve females) in the NS-group developed MDS (incidence rate: 0.03 vs 0.14, per 1000 person-years). A fully adjusted hazard ratio was 0.14 (95%CI 0.02-1.14), which did not reach conventional level of statistical significance (p = 0.066) due to small number of events. A third of MDS pts had high-risk disease per IPSS-R prognostic score (7/20 evaluable pts). 10 (of 11 NS MDS pts with available NGS data) pts had ≥1 nonsynonymous mutations and most pts (6/11) harbored multiple [Median (IQR): 2 (1-3)] high-risk mutations despite a younger median age of the cohort. Conclusions: In this large cohort of adults with obesity, we observed a lower incidence of MDS after IWL achieved with BSx. Higher prevalence of high-risk-MDS mutations in a relatively young NS-cohort with obesity warrants further investigation of effects of IWL on clonal evolution, its clinical relevance, and role of screening in halting progression of CH to MDS via early detection and targeted intervention. [Table: see text]

Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions

Introduction: The incidence of myelodysplastic syndrome and acute myeloid leukemia is significantly increased in children with Down syndrome (DS). Within the revised 2016 WHO edition, these entities are jointly classified as myeloid leukemia associated with DS (ML-DS). Additionally, infants with DS may develop transient abnormal myelopoiesis (TAM) which is histomorphologically similar to ML-DS. While TAM is self-limiting, it is associated with an increased risk of subsequently developing ML-DS. Differentiating TAM and ML-DS is challenging but clinically critical. Methods: We performed a retrospective review of ML-DS and TAM cases collected from five large academic institutions in the USA. We assessed clinical, pathological, immunophenotypical, and molecular features to identify differentiating criteria. Results: Forty cases were identified: 28 ML-DS and 12 TAM. Several features were diagnostically distinct, including younger age in TAM (p < 0.05), as well as presentation with clinically significant anemia and thrombocytopenia in ML-DS (p < 0.001). Dyserythropoiesis was unique to ML-DS, as well as structural cytogenetic abnormalities aside from the constitutional trisomy 21. Immunophenotypic characteristics of TAM and ML-DS were indistinguishable, including the aberrant expression of CD7 and CD56 by the myeloid blasts. Discussion: The findings of the study confirm marked biological similarities between TAM and ML-DS. At the same time, several significant clinical, morphological, and genetic differences were observed between TAM and ML-DS. The clinical approach and the differential diagnosis between these entities are discussed in detail.

10-year nationwide trends in incidence, treatment patterns, and mortality of patients with myelodysplastic syndromes in Denmark

Further temporal data on incidence, treatment patterns, and prognosis for patients with myelodysplastic syndromes (MDS) are needed. This study examined 10-year trends in incidence, treatment patterns, and all-cause mortality in a population-based cohort of 2309 MDS patients using Danish nationwide registries (2010–2019). We computed annual incidence rates overall and according to sex and age-groups. We examined temporal changes in the cumulative incidence of MDS specific treatments initiated within one year from diagnosis and temporal changes in the absolute risk of death and five-year adjusted hazard ratios (aHRs) for death, adjusting for age, sex and comorbidity. The age-standardized incidence rate of MDS per 100,000 person-years increased slightly from 5.3 in 2010 to 6.4 in 2019. Between 2010-2012 to 2016–2017, the use of azacitidine increased overall (8% to 22%), in patients with intermediate risk MDS (12% to 34%), and in patients with high-risk MDS (22% to 50%), while it remained stable (around 5%) for patients with low-risk MDS. The five-year aHR for death in the most recent calendar period compared to the earliest calendar period remained unchanged in patients with low-risk MDS, aHR = 0.90 (95% CI, 0.72–1.12) and in patients with high-risk MDS, aHR = 1.19 (95% CI, 0.89–1.61), while survival improved over time among patients with intermediate risk MDS, aHR = 0.67 (95% CI, 0.48–0.92). In conclusion the incidence of MDS slightly increased during a 10-year period in Denmark. The use of azacitidine increased markedly but five-year overall survival remained unchanged.

Myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a family of myeloid cancers with diverse genotypes and phenotypes characterized by ineffective haematopoiesis and risk of transformation to acute myeloid leukaemia (AML). Some epidemiological data indicate that MDS incidence is increasing in resource-rich regions but this is controversial. Most MDS cases are caused by randomly acquired somatic mutations. In some patients, the phenotype and/or genotype of MDS overlaps with that of bone marrow failure disorders such as aplastic anaemia, paroxysmal nocturnal haemoglobinuria (PNH)and AML. Prognostic systems, such as the revised International Prognostic Scoring System (IPSS-R), provide reasonably accurate predictions of survival at the population level. Therapeutic goals in individuals with lower-risk MDS include improving quality of life and minimizing erythrocyte and platelet transfusions. Therapeutic goals in people with higher-risk MDS include decreasing the risk of AML transformation and prolonging survival. Haematopoietic cell transplantation (HCT) can cure MDS, yet fewer than 10% of affected individuals receive this treatment. However, how, when and in which patients with HCT for MDS should be performed remains controversial, with some studies suggesting HCT is preferred in some individuals with higher-risk MDS. Advances in the understanding of MDS biology offer the prospect of new therapeutic approaches.

MDS-416 Myelodysplastic Syndromes in Morocco: Evolution over 15 Years

Myelodysplastic syndromes (MDS) are defined in the World Health Organization classification of tumors of hematopoietic and lymphoid tissues as a group of clonal hematopoietic cell diseases characterized by cytopenia, dysplasia in one or more of myeloid cell lines, ineffective hematopoiesis, and an increased risk of progression to acute myeloid leukemia (AML). To determine the incidence of MDS in the pediatric hematology and oncology department of hospital 20 August 1953. Descriptive retrospective study made at the Pediatric Hematology and Oncology Department of hospital 20 August 1953 of the CHU Ibn Rochd Casablanca, including all patients with MDS confirmed on myelogram or BOM, diagnosed between January 2014 and December 2018. Patients with CMML, MDS/MPS border syndromes, or AML were excluded from our study. We found 272 patients diagnosed with MDS over the 15-year period from January 2004 to December 2018. The median incidence of MDS in our study was 19 cases/year, the median age was 59.5 years. According to the age groups, we found that 108 patients (or 40%) represented the age group of young adults (31-60 years), 67 patients (or 25%) represented the age group of elderly subjects (61-74 years), 60 patients (20%) represented the age group of very old subjects (over 75 years). The sex ratio (M/F) is 0.74. We noted that 1% of patients were genetically exposed and 16% of patients were exposed to various risk factors. The history of autoimmune diseases was found in 18% of patients in our series. 91% of patients had clinical signs. Therapeutically, we found that 74% of patients received symptomatic treatment. Fifteen patients in our series received specific treatment. Median survival is 5.63 months Conclusions: Myelodysplastic syndromes present a heterogeneous group of clonal hemopathies characterized by peripheral cytopenias and the risk of progression to acute leukemia. Diagnosis is currently based on bone marrow cytology, but the contribution of cytogenetic and molecular biology seems to go beyond prognostic interest (early diagnosis, prediction of therapeutic response). While the treatment of low-risk myelodysplastic syndromes is based on the correction of cytopenias, that of high-risk myelodysplastic syndromes aims to control the leukemic clone.

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications.

Myelodysplastic syndromes (MDS) constitute a very heterogeneous group of diseases with a high prevalence in elderly patients and a propensity for progression to acute myeloid leukemia. The complexity of these hematopoietic malignancies is revealed by the multiple recurrent somatic mutations involved in MDS pathogenesis and the paradoxical common phenotype observed in these patients characterized by ineffective hematopoiesis and cytopenia. In the context of population aging, the incidence of MDS will strongly increase in the future. Thus, precise diagnosis and evaluation of the progression risk of these diseases are imperative to adapt the treatment. Dysregulations of both innate and adaptive immune systems are frequently detected in MDS patients, and their critical role in MDS pathogenesis is now commonly accepted. However, different immune dysregulations and/or dysfunctions can be dynamically observed during the course of the disease. Monitoring the immune system therefore represents a new attractive tool for a more precise characterization of MDS at diagnosis and for identifying patients who may benefit from immunotherapy. We review here the current knowledge of the critical role of immune dysfunctions in both MDS and MDS precursor conditions and discuss the opportunities offered by the detection of these dysregulations for patient stratification.

Incidence of myelodysplastic syndromes in Finland 1997–2016

Myelodysplastic syndromes (MDS) are a diverse group of clonal hematopoietic stem cell diseases that may progress to acute myeloid leukemia. Here, we present incidence of myelodysplastic syndromes based on a nationwide, registry-based study. A total of 1906 MDS cases were reported to the Finnish Cancer Registry during 1997-2016. We analysed the age-standardized incidence rates using the new European standard population, incidence trend and changes in trend by sex, age group and calendar year using Poisson regression and joinpoint regression. The average age-standardized incidence rate was 3.92 per 100,000 person-years. The incidence of MDS increased in a linear-quadratic fashion across 10-year age groups and was higher among men (5.43 versus 3.14 per 100,000). The incidence trend increased during the first 15 years followed by a decline towards the end of the study period. A similar trend was found in subgroups by sex and age. Our results show a similar or slightly higher MDS incidence in Finland as in other Western countries, with an increasing trend, but some decrease in the end. The increasing incidence may reflect improved reporting and coding, or there could be a genuine increase in MDS over time.

A Systematic Literature Review of the Relationship between Serum Ferritin and Outcomes in Myelodysplastic Syndromes.

Anemia is the most common form of cytopenia in patients with myelodysplastic syndromes (MDS), who require chronic red blood cell transfusions and may present high serum ferritin (SF) levels as a result of iron overload. To better understand the potential effects of high SF levels, we conducted a systematic literature review (SLR) to identify evidence on the relationship between SF levels and clinical, economic, or humanistic outcomes in adult patients with MDS. Of 267 references identified, 21 were included. No studies assessing SF levels and their relationship with humanistic or economic outcomes were identified. Increased SF levels were an indicator of worse overall survival and other worsened outcomes; however, the association was not consistently significant. SF levels were a significant prognostic factor for relapse incidence of MDS and showed a significant positive correlation with number of blood units transfused but were not associated with progression to acute myeloid leukemia or the time to transformation. Higher SF levels were also an indicator of a lower likelihood of leukemia-free survival, relapse-free survival, and event-free survival. The SLR suggests that SF levels are associated with clinical outcomes in MDS, with higher levels correlated with number of blood units transfused, frequently indicating worse outcomes.

MDS-259: Myelodysplastic Syndrome in Uzbekistan: A Study of Prevalence

Context: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal diseases of the blood system characterized by cytopenia, signs of impaired myelopoiesis, and a high risk of transformation into acute myeloblastic leukemia (AML). Objective: Study the characteristics of the incidence of MDS among the population of Uzbekistan. Design: Retrospective analysis of the medical records of registered patients with MDS in our center for the period of 2010–2020. Setting: The diagnosis of MDS was verified taking into account the generally accepted criteria according to WHO (2017) on the basis of results of a general specialized clinical examination of patients and laboratory methods. Statistical processing of the data was performed using the “Statistic for Windows, 2017” application package. Main Outcomes Measures: The average number of patients in Uzbekistan amounted to 20.3 new cases per year. In 2010, the primary incidence of MDS was 9 cases per year, 4 cases each in 2011 and 2012, 6 each in 2013 and 2014, and 5 in 2015. Since 2016, the primary incidence of MDS has increased sharply and amounted to 33 new cases in the current year: 39 in 2017, 34 in 2018, and 52 in 2019, while in 2020, 14 new cases were registered in only two months. For 2010–2020, the total number of registered patients with MDS was 206 cases: males - 107, females - 99. The indicator of the primary incidence of MDS for 2016–2020 in comparison with 2010–2015 increased by 5.1 times, and the median age of patients at the time of diagnosis verification was 50.9±4.05 years (men - 50.1±4.2 years, women - 49.6±4.3 years). The highest incidence of MDS was recorded among the age category from 41 to 70 (n = 132); the lowest was among patients under 20 years of age (n=9). Conclusion: An increasing number of new cases in recent years is associated with an improvement in the diagnosis of MDS, which is typical for the category of people in older age groups.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes.

British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes.

Incidence of myelodysplastic syndrome and acute myeloid leukemia in patients receiving poly-ADP ribose polymerase inhibitors for the treatment of solid tumors: A meta-analysis of randomized trials

BackgroundClinical trials demonstrated that PARPi (poly [adenosine diphosphate–ribose]-ADP polymerase inhibitor) therapy is effective in solid tumors. However, long term effects such as therapy-related myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) are poorly described. We sought to quantify whether PARPi therapy is associated with the development of MDS/AML. MethodsMedline, Embase, and Cochrane databases were searched (inception to January 6, 2020) and phase 2 and 3 clinical trials that randomized patients with solid tumors to a PARPi or control therapy were included. The PRISMA guidelines were used to extract data independently by multiple authors. We extracted person-time and number of cases of MDS/AML in the PARPi and control arms of each study and pooled results with a random-effects Poisson regression model. The pooled incidence rate ratio (IRR) for MDS/AML among patients randomized to PARPi therapy was compared to those randomized to a control. ResultsWe identified 14 studies that included 5739 patients. Accounting for intra-study clustering, the risk of MDS/AML was similar in patients who were randomly assigned to receive PARPi compared to controls (IRR 1.32, 95% confidence interval [CI] 0.78–2.26). In the front-line setting, PARPi therapy was associated with developing MDS/AML (IRR 5.43, 95% CI 1.51–19.60). Among patients treated for recurrence, however, the risk of MDS/AML appeared to be similar among patients randomized to PARPi or control treatment. Among studies that included only patients with a BRCA mutation, the risk of MDS/AML was similar in both treatment groups (IRR 0.83, 95% CI 0.45–1.53), but PARPi therapy was associated with MDS/AML in studies with an unrestricted population (IRR 2.43, 95% CI 1.17–5.06). ConclusionThe pooled overall effect was not statistically significant. However, treatment with PARPi was associated with a statistically significant increase in the incidence of MDS/AML among patients receiving front-line cancer therapy and those with limited prior exposure to chemotherapy.

Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database

Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy and acceptable safety in a range of neoplasms, particularly in ovarian cancers. However, some concerns have emerged regarding rare and delayed adverse events including cases of myelodysplastic syndrome and acute myeloid leukaemia, for which data are scarce. The aim of this study was to estimate the risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitors, via a systematic review and safety meta-analysis, and to describe clinical features of PARP inhibitor-related myelodysplastic syndrome and acute myeloid leukaemia cases reported in WHO's pharmacovigilance database (VigiBase). We systematically reviewed randomised controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments (placebo and non-placebo) in adults (age ≥18 years) treated for cancer in MEDLINE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry with ongoing surveillance up to May 31, 2020. The date range for included studies was not restricted. By a stepwise method to capture all available adverse events, we first extracted data on myelodysplastic syndrome and acute myeloid leukaemia cases from ClinicalTrials.gov. If cases were not available, we extracted them from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data. RCTs without available data from ClinicalTrials.gov, publications, or corresponding authors or sponsors were excluded. The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibition versus placebo treatment in RCTs. We used a fixed-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% CIs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitor therapy were extracted on May 3, 2020, and clinical features summarised with a focus on median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death. Our systematic review and safety meta-analysis were registered with PROSPERO, CRD42020175050. Our retrospective pharmacovigilance study was registered on ClinicalTrials.gov, NCT04326023. For our safety meta-analysis, initial searches identified 1617 citations, and 31 RCTs were systematically reviewed for eligibility. 28 RCTs with available adverse events were analysed (18 placebo and ten non-placebo RCTs), with 5693 patients in PARP inhibitor groups and 3406 patients in control groups. Based on the 18 placebo RCTs (n=7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with placebo treatment (Peto OR 2·63 [95% CI 1·13-6·14], p=0·026) with no between-study heterogeneity (I2=0%, χ2 p=0·91). The incidence of myelodysplastic syndrome and acute myeloid leukaemia across PARP inhibitor groups was 0·73% (95% CI 0·50-1·07; I2=0%, χ2 p=0·87; 21 events out of 4533 patients) and across placebo groups was 0·47% (0·26-0·85; I2=0%, χ2 p=1·00; three events out of 2774 patients). All 28 RCTs were rated as having unclear risk of bias. In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukaemia (n=79) related to PARP inhibitor therapy were extracted. In cases with available data, median treatment duration was 9·8 months (IQR 3·6-17·4; n=96) and median latency period since first exposure to a PARP inhibitor was 17·8 months (8·4-29·2; n=58). Of 104 cases that reported outcomes, 47 (45%) resulted in death. PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukaemia versus placebo treatment. These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting. None.

Myelodysplastic syndrome: the other cause of anemia in end-stage renal disease patients undergoing dialysis

In end-stage renal disease (ESRD) patients receiving dialysis, anemia is common and related to a higher mortality rate. Erythropoietin (EPO) resistance and iron refractory anemia require red blood cell transfusions. Myelodysplastic syndrome (MDS) is a disease with hematopoietic dysplasia. There are limited reports regarding ESRD patients with MDS. We aim to assess whether, for ESRD patients, undergoing dialysis is a predictive factor of MDS by analyzing data from the Taiwan National Health Insurance Research Database. We enrolled 74,712 patients with chronic renal failure (ESRD) who underwent dialysis and matched 74,712 control patients. In our study, we noticed that compared with the non-ESRD controls, in ESRD patients, undergoing dialysis (subdistribution hazard ratio [sHR] = 1.60, 1.16–2.19) and age (sHR = 1.03, 1.02–1.04) had positive predictive value for MDS occurrence. Moreover, more units of red blood cell transfusion (higher than 4 units per month) was also associated with a higher incidence of MDS. The MDS cumulative incidence increased with the duration of dialysis in ESRD patients. These effects may be related to exposure to certain cytokines, including interleukin-1, tumor necrosis factor-α, and tumor growth factor-β. In conclusion, we report the novel finding that ESRD patients undergoing dialysis have an increased risk of MDS.

MDS-278: Epidemiology of MDS in Kosovo During 2014–2019

Context: Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders with significant morbidity and high mortality. Population-based data on patients with MDS in Kosovo are scarce. Before and during the transition phase in our country, no statistics have been released on the epidemiological situation on MDS of which we can make any comparisons. This study is important in developing an epidemiologic strategy and improving the knowledge of MDS in Kosovo. Objective: To evaluate the incidence, age, sex, MDS subtype, and treatment in Kosovo during the period of 2014–2019. Design: Cross-sectional retrospective epidemiological study. Setting: The data were collected from the chemotherapy treatment protocol books in the Hematology Clinic. Patients or other participants: We retrospectively analyzed the cohort of 37 patients diagnosed with MDS in the Hematology Clinic - UCCK. Interventions: None. Main outcome measures: No main outcomes because it is an epidemiological study. Results: During the period of 2014–2019, 37 patients were diagnosed with MDS, of whom 24 were men and 13 were women. Male to female ratio was 1.85:1. Median age at diagnosis was 65 years. During 2014, 7 cases were identified or 18.92% of the total cases with an incidence rate 0.39/100000. In 2015, 3 cases were identified or 8.11% with an incidence 0.17/100000; in 2016, 4 cases were identified or 10.81% with an incidence 0.22/100000; in 2017, 8 cases or 21.62% with an incidence 0.44/100000; in 2018, 8 cases or 21.62%, with an incidence 0.44/100000 and in 2019, 7 cases or 18.92% with an incidence 0.39/100000 were identified. Based on 2016 WHO classification, the main subtypes were MDS-EB-2 with 12 (33%) cases, followed by MDS-SLD with 9 (24%) cases, MDS-EB-1 with 6 (16%), MDS-MLD with 5 (14%), MDS-RS with 3 (8%), and MDS-U with 2 (5%). For the majority of patients, the main treatment was erythropoiesis-stimulating agents in 62% of patients, followed by granulocyte colony-stimulating factor in 22% of patients, and drug therapy including Azacitidine in 33%. Twelve (33%) MDS patients progressed to AML. Conclusions: Our study reveals that incidence of MDS in Kosovo is lower than in Western countries. Chi-Square test shows that there is no significant statistical difference (p

The incidence of myelodysplastic syndrome in patients receiving poly-ADP ribose polymerase inhibitors for treatment of solid tumors: A meta-analysis.

3641 Background: Clinical trials have reported improved outcomes with PARPi (poly [adenosine diphosphate–ribose]-ADP polymerase inhibitor) therapy in ovarian, breast, pancreatic and lung cancers. There is concern that PARPi therapy may cause myelodysplastic syndrome (MDS). In this meta-analysis we seek to quantify the risk of MDS among patients treated with PARPi for solid tumor malignancies. Methods: We searched Medline, Embase, and Cochrane databases (up to January 6, 2020) to abstract randomized controlled trials that include a PARPi in the experimental arm in solid tumors. Combinations included PARPi versus (vs.) placebo, PARPi vs. cytotoxic treatment, and PARPi with cytotoxic treatment vs. cytotoxic treatment. We used to time-to-event curves to estimate person-time and calculated the incidence of MDS among all studies. We used random-effects Poisson regression models to estimate pooled incidence risk ratio (RR) for developing MDS. Results: We identified 14 studies, 10 in ovarian, 3 in breast, and 1 in pancreatic cancer patients. Of 5,646 patients, 62.3% received a PARPi alone or in combination with chemotherapy or bevacizumab, and 37.8% received treatment consisting of placebo alone or with chemotherapy or bevacizumab. PARPi were investigated as an upfront treatment in 2,827 patients, and as treatment for recurrence in 2,819 patients. The incidence of MDS was 6.73 cases vs. 3.85 per 1000 person-years in patients receiving PARPi as compared to control corresponding to a 3-year cumulative incidence of 2.0% and 1.1%. Accounting for intra-study clustering, PARPi use was associated with a 60% increase in risk (incidence RR 1.60, 95% Confidence Interval [CI] 0.89-2.87) of MDS compared to control. In the upfront setting, patients randomized to PARPi were twice as likely to develop MDS (RR 2.08, 95%, CI 1.39-3.64). Among patients treated for recurrence, the risk of MDS appeared to be similar among patient randomized to PARPi or control treatment (RR 1.13, 95% CI 0.35-3.64). In studies that compared PARPi in combination with other cytotoxic treatment vs. cytotoxic treatment alone, PARPi was associated with a large risk of MDS (RR 5.08, 95% CI 1.36-19.03). Conclusions: In pooled estimates from randomized controlled trials in solid tumors PARPi treatment appears to be associated with an increased incidence of MDS particularly in the upfront setting and when combined with cytotoxic treatment. Despite pooling 14 randomized trials our estimates remain imprecise due to the rarity of MDS.

Integrating the "Immunome" in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and often include a dysregulation and dysfunction of the immune system. In the context of population aging, MDS incidence is set to increase substantially, with exponential increases in health care costs, given the limited and expensive treatment options for these patients. Treatment selection is mainly based on calculated risk categories according to a Revised International Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of disease progression, it is an ineffective predictor of response to disease-modifying therapies. Redressing these unmet needs, the "immunome" is a key, multifaceted component in the initiation and overall response against malignant cells in MDS, and the current omission of immune status monitoring may in part explain the insufficiencies of current prognostic stratification methods. Nevertheless, integrating these and other recent molecular advances into clinical practice proves difficult. This review highlights the complexity of immune dysregulation in MDS pathophysiology and the fine balance between smoldering inflammation, adaptive immunity, and somatic mutations in promoting or suppressing malignant clones. We review the existing knowledge and discuss how state-of-the-art immune monitoring strategies could potentially permit novel patient substratification, thereby empowering practical predictions of response to treatment in MDS. We propose novel multicenter studies, which are needed to achieve this goal.

Integrated Analysis of Long Non-Coding RNA and mRNA Expression Profile in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies. The incidence of MDS is gradually increasing, but the pathogenesis is still not very clear. Studies have shown that long non-coding RNAs (lncRNAs) play a critical role in both oncogenic and tumor-suppressive pathways. However, the function of lncRNAs in MDS is still unknown. The purpose of this study was to investigate the expression profiles and biological function of the aberrantly expressed lncRNAs and mRNAs in MDS. We downloaded two data sets (GSE4619 and GSE19429) from the Gene Expression Omnibus database and obtained differentially expressed (DE) lncRNAs and DE-mRNAs between MDS cases and healthy controls. Then we performed systematic bioinformatics analysis to know the biological function of DE-lncRNAs and DE-mRNAs in MDS. We identified 40 DE-lncRNAs and 643 DE-mRNAs between MDS cases and healthy controls. Gene Ontology (GO) and pathway analysis revealed that DE-lncRNAs and DE-mRNAs were mainly involved in necroptosis, apoptosis, immunodeficiency, p53 and FoxO signaling pathways. LncRNA-mRNA co-expression and lncRNA functional similarity network showed that twelve down-regulated lncRNAs co-regulated the same target gene and they were similar in function. The comprehensive analysis of lncRNA and mRNA is helpful in understanding the pathogenesis of MDS, and the synergistically down-regulated lncRNAs may contribute to the development of new diagnostic and therapeutic strategies.