Refractory Anemia With Excess Blasts Research Articles

Novel Clinically Useful Inhibitor of Mediator Complex, RVU120, Relives Differentiation Block in MDS/AML

Background: Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemias (AML) are characterized by a block in hematopoietic differentiation that can often be traced to aberrant stage-specific transcription. The kinase module of the mediator complex, consisting of CDK8, its paralog CDK19, Cyclin C, MED12, and MED13, have been identified as a molecular switch that regulates gene expression. A variety of cancers have exploited this mechanism to maintain stemness and an undifferentiated state. RVU120 is a first-in-class, specific, and selective inhibitor of CDK8/19, currently in Phase Ib clinical trial in patients with AML or High-Risk MDS (HR-MDS) (NCT04021368). RVU120 has been shown to stimulate erythroid differentiation in transformed CD34+ cord blood (CB) cells and in CD34+ cells from Diamond-Blackfan Anemia (DBA). To evaluate the further therapeutic potential of CDK8/19 inhibition, we confirmed aberrant expression of mediator complex components and erythroid-stimulating activity in a collection of CD34+ primary samples of AML and MDS. Results: We investigated the expression of mediator complex components in a large database of MDS CD34+ marrow samples and age-matched controls. Our findings revealed that MED12, a critical component of the mediator complex, was significantly overexpressed in MDS samples from refractory anemia with excess blasts (RAEB), a higher risk subset of MDS(p=0.018) (Fig A). Furthermore, we observed that this overexpression of MED12 was associated with a higher rate of transformation to AML. To delve deeper, we examined the expression of MED12 in sorted leukemic stem cells from primary AML samples and found significantly elevated levels in Long Term Hematopoietic Stem Cells from AML samples with both normal karyotype and complex karyotypes compared to healthy controls. Next, we conducted an evaluation of the efficacy of the mediator kinase module inhibition in MDS-derived cell line (MDS-L). Inhibition of CDK8/19 with RVU120 led to increased erythroid differentiation in this model which confirmed our observations in transformed CD34+ CB cells in CB cells, these phenotypic changes were correlated with the inhibition of CDK8-dependent phosphorylation marker S726 on STAT5 and a profound increase in the expression of genes involved in erythroid commitment and hemoglobin metabolism. In order to confirm therapeutic potential of CDK8/CDK19 inhibition in MDS and AML, we performed colony-forming assay on primary samples of MDS and AML (n= 15). The treatment with RVU120 resulted in increased erythroid differentiation in a majority of samples, evident from an augmented number of colonies. Detailed analysis indicated changes in the expression of erythroid differentiation markers, including increased CD71 and Glycophorin A expression on colonies, as assessed by FACS analysis (Figure B, shows representative sample). Conclusion Our data highlight that inhibition of the overexpressed mediator complex proteins can alleviate the differentiation blocks seen in MDS/AML. These results provide a compelling rationale for further developing the CDK8/19 inhibitor RVU120 for transfusion- dependent MDS/AML patients.

Prognostic Impact of Conditioning Intensity on Outcomes after Allogeneic Transplantation for MDS with Low Blasts

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes in patients with myelodysplastic syndromes (MDS). The blast percentage in MDS is one of the important factors to utilize allo-HSCT, and the other disease-related factors, such as transfusion dependency and chromosomal risk, are crucial to consider whether patients harboring MDS with less than 5% of marrow blasts (MDS-Lo) undergo to allo-HSCT. However, the prognostic impacts of conditioning intensity in MDS-Lo patients are still unclear. We here conducted a nationwide retrospective study to clarify the prognostic factor and investigate the optimal conditioning intensity for MDS-Lo. Methods In this study, patients diagnosed as the other than refractory anemia with excess blasts (RAEB)-1 and -2 according to the WHO classification (marrow blasts <5% and peripheral blood blasts <1%) were considered to be MDS-Lo. The clinical data of 1,229 de novo MDS-Lo patients (i) who had stayed MDS-Lo from diagnosis to transplantation and (ii) who underwent their initial allo-HSCT between January 2001 and December 2020 were collected from the Transplant Registry Unified Management Program of the Japan Society for Hematopoietic Cell Transplantation. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS), chronic graft-versus-host disease (GVHD)-free survival (CRFS), and GVHD- and relapse-free survival (GRFS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR) and non-relapse mortality (NRM), using cumulative incidence curves to accommodate competing events. Results In a total of 1,229 patients, 651, 397, and 181 patients received myeloablative conditioning (MAC), reduced-intensity conditioning (RIC), and non-myeloablative conditioning (NMAC) groups, respectively. The estimated 3-year OS rates were 63.3%, 61.0%, and 69.7% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year CRFS rates were 41.1%, 43.9%, and 47.2% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year GRFS rates were 27.5%, 33.4%, and 35.4% in MAC, RIC, and NMAC groups, respectively; the estimated 3-year CIR were 11.9%, 14.2%, and 16.0% in MAC, RIC, and NMAC groups, respectively; and the estimated 3-year NRM were 29.8%, 31.0%, and 24.7% in MAC, RIC, and NMAC groups, respectively. The multivariate analyses revealed four factors affecting lower OS: older recipient's age (Hazard ratio (HR) [95% confidential interval], 1.70 [1.28-2.24]; P<0.001 for 40-59 years)(HR, 2.32 [1.71-3.15]; P<0.001 for 60 years or older), performance status 2-4 at HSCT (HR, 1.84 [1.32-2.57]; P<0.001), the history of infection before HSCT (HR, 2.12 [1.55-2.89]; P<0.001), and high number of red blood cell (RBC) transfusion before HSCT (HR, 1.65 [1.35-2.02]; P<0.001). These factors also negatively affected CRFS, GRFS, and NRM. In addition, poor cytogenetic risk group was associated with worse OS (HR, 1.66 [1.32-2.09]; P<0.001), CRFS (HR, 1.48 [1.22-1.80]; P<0.001), and GRFS (HR, 1.36 [1.14-1.64]; P=0.001) but not CIR. There was no significant difference of OS, CRFS, GRFS, CIR, and NRM in either RIC or NMAC group compared to MAC group. We next performed the subgroups analysis based on the prognostic factors. The subgroup analysis for the comparison between MAC and RIC regimens showed the better OS of MAC regimen among patients with low number of RBC transfusion (HR, 1.33 [1.01-1,75]; P=0.039). The subgroup analysis for the comparison between RIC and NMAC regimens revealed the better OS of NAMC regimen among patients aged <40 years (HR, 0.43 [0.19-0.96]; P=0.038), no history of infection (HR, 0.67 [0.50-0.91]; P=0.009), and good cytogenetic risk (HR, 0.54 [0.38-0.83]; P=0.004). Conclusion This study showed the prognostic factors on the post-transplant outcomes among MDS-Lo patients, and no significant difference of conditioning intensity in the entire population. Furthermore, we found the factors (the number of RBC transfusion, patient's age, the history of infection, and cytogenetic risk) potentially affecting the selection of conditioning intensity. These findings would improve the management for transplant candidates with MDS-Lo.

Clinical Outcomes in Patients With Refractory Anemia With Excess Blasts (RAEB) Who Receive Hypomethylating Agents (HMAs)

BackgroundWe sought to understand the clinical effectiveness associated with use of hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) for patients with refractory anemia with excess blasts (RAEB; an established proxy for higher-risk myelodysplastic syndromes/neoplasms) in contemporary and representative real-world settings. Patients and methodsWe used the Surveillance, Epidemiology and End Results (SEER)-Medicare database, a linkage of cancer registry and Medicare claims data, to identify patients aged ≥ 66 years diagnosed with RAEB, between 2009 and 2017 in the United States, and who received AZA or DEC as first-line therapy. Outcomes measured were overall survival (OS), event-free survival (EFS), and incidence of progression-related acute myeloid leukemia (AML). ResultsOf 973 eligible patients, 738 (75.8%) received AZA and 235 (24.2%) received DEC; 6.4% received hematopoietic cell transplantation during follow-up. In the overall population, median OS was 13.9 months (95% confidence interval [CI]: 12.9-15.0), median EFS was 5.2 months (95% CI: 4.9-5.7), and 38.0% of patients progressed to AML. Incidences of AML progression and death were 25.6% and 29.9%, respectively, at Year 1, and 34.3% and 44.8%, respectively, at Year 2. There were no significant differences in clinical benefits between AZA and DEC. ConclusionMedian OS with both HMAs remained significantly shorter than in the AZA-001 clinical trial, highlighting how patient outcomes vary between clinical and real-world settings. Further research is required to understand why these disparities exist.

Effect of Two Conditionings on Relapse in Myelodysplastic Syndrome and Secondary Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

Background The relapse rate remains high in patients with myelodysplastic syndrome (MDS)-refractory anemia with excess blasts (RAEB) and secondary acute myeloid leukemia evolving from MDS (sAML) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). We investigated whether the addition of granulocyte colony-stimulating factor (G-CSF) and decitabine to busulfan plus cyclophosphamide (BuCy) conditioning would reduce relapse in this population. Methods We did an open-label, randomised phase 3 trial at six hospitals in China. Eligible patients (aged 14-65 years) had a diagnosis of MDS-RAEB or sAML, were willing to undergo allo-HCT, and had an Eastern Cooperative Oncology Group performance status of 0-2 and HCT-comorbidity index of 0-2. Patients were randomly assigned 1:1 to receive G-CSF and decitabine plus BuCy (G-DAC-BuCy) or BuCy conditioning. Randomisation was done with permuted blocks (block size four) and implemented through an interactive web-based randomisation system. The primary endpoint was the 2-year cumulative incidence of relapse (CIR) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02744742. Findings Between April 18, 2016 and September 30, 2019, 202 patients were enrolled and randomly assigned to receive G-DAC-BuCy (n=101) or BuCy conditioning (n=101). Median follow-up was 32.4 (range, 1.0-64.5) months after randomization. The 2-year CIR was 10.9% (95% CI: 5.8-17.9%) and 24.8% (16.8-33.5%) in the G-DAC-BuCy and BuCy groups (HR=0.387, 95% CI: 0.190-0.786; P=0.011). Within 100 days post-transplantation, the most common grade 3-4 adverse effects (AEs) in the G-DAC-BuCy and BuCy groups were infections (34 [33.7%] and 32 [31.7%]), acute graft-versus-host disease (30 [29.7%] and 30 [29.7%]), and gastrointestinal toxicity (28 [27.7%] and 29 [28.7%]). Eleven patients in the G-DAC-BuCy and 13 in the BuCy group died of AEs. Interpretation G-DAC-BuCy conditioning can prevent relapse compared with BuCy conditioning and is well tolerated, suggesting its potential to become a standard conditioning in patients with MDS-RAEB and sAML undergoing allo-HCT.

P779: OPTIMIZING TREATMENT OUTCOMES FOR CHILDREN WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background: Myelodysplastic syndrome (MDS) are rare clonal hematopoietic disorders in children. Risk stratification system for adults is unfit for children. Refractory anemia with excess blasts(RAEB), acute myeloid leukemia with myelodysplasia-related changes(AML-MRC), monosomy 7 and complex karyotype always indicate poor prognosis. Hypomethylating agent (HMA) improved survivals of high-risk MDS in adults, and decitabine as part of conditioning regimen for allogenetic hematopoietic stem cell transplantation(allo-HSCT) was associated with favorable outcomes. However, these findings have not been tested in pediatric cohorts broadly. Aims: To evalute the efficacy and safety of hypomethylating agents as a part of pre-transplant treatments and contidioning regimens in children with higher-risk MDS. Methods: Patients from 1 to 14 years of age who were diagnosed with higher-risk MDS and underwent allo-HSCT consecutively between February 2019 and August 2020 in Pediatric Blood Diseases Center were enrolled. All identified patients were retrospectively reviewed with a collection of clinical data, laboratory test results, and outcome. Results: We reviewed 18 pediatric patients with higher-risk MDS, including 7 with RAEB, 8 with AML-MRC, and 3 with refractory cytopenia of childhood with monosomy 7. Regardless of initial diagnosis, monosomy 7 is the most common cytogenetic aberration (8/18, 44.4%). Next-generation sequencing (NGS) was performed on 15 specimens and the most frequent detection of mutation gene was SETBP1, followed by ETV6. Before transplantation, ten patients received monotherapies or combined chemotherapies with HMA, two patients received AML-like chemotherapies, and nine of those achieved bone marrow complete remission. The stem cell sources came from matched sibling donor (n=1), haploidentical donor (n=11), and unrelated cord blood (n=6), respectively. Low-dose decitabine-containing myeloablative conditioning regimens were administered in all cases. About 50% of patients (n=9) experienced Grade II- IV acute graft versus host diseases post-transplant. The cumulative incidence of transplantation-related mortality (TRM) was 11.1%. During a median follow-up of 10.5 (range, 2–36) months after transplantation, 15 of 18 patients were alive. At time of last follow-up, all survivors had resolution of hematologic disorder without relapse. Summary/Conclusion: In summary, administration of hypomethylating agents to allogeneic SCT resulted in excellent outcomes in children with higher-risk MDS.

P766: CLINICAL OUTCOMES IN PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROMES RECEIVING HYPOMETHYLATING AGENTS: A LARGE POPULATION-BASED ANALYSIS

Background: Myelodysplastic syndromes (MDS) are a spectrum of hematopoietic neoplasms characterized by variable degrees of cytopenias and risk of progression to acute myeloid leukemia (AML). Although the hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DEC) are widely used to treat higher-risk (HR)-MDS in the United States (US), questions remain about their longer-term clinical benefits. Aims: To understand the survival outcomes and progression-related events of patients (pts) treated with AZA or DEC for HR-MDS in the US. Methods: Older adults (≥66 years old) diagnosed with refractory anemia with excess blasts (RAEB), an established proxy for HR-MDS, between January 2009 and December 2017, were included from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. The index date was date of HMA initiation. Pts who received AZA or DEC, had ≥12 months (mo) of continuous enrollment prior to the index date, and who did not receive a stem cell transplant (SCT) prior to the index date were included. Overall survival (OS) from the index date to death was estimated using Kaplan–Meier methodology. Baseline platelet and red blood cell (RBC) transfusion dependence (TD) were defined as ≥2 transfusion episodes in the 8 weeks prior to the index date; baseline transfusion use (TU) was defined as one transfusion episode in the 8 weeks prior to the index date. A competing risk analysis was used to assess the incidence of progression to AML, with death as the competing event. Results: Of 973 pts with HR-MDS treated with HMA, 75.8% received AZA and 24.2% received DEC. Median time from diagnosis to HMA initiation was 1.2 mo (interquartile range [IQR]: 0.6–2.6). Median treatment duration was 5.7 mo (IQR: 2.3–11.5) overall (5.8 mo [IQR: 2.6–11.8] for AZA and 5.0 mo [IQR: 1.9–11.0] for DEC). At baseline, 13.8% of pts had platelet TD/TU, 29.9% had RBC-TD and 27.0% had RBC-TU. Only 6.4% of pts received SCT during follow-up. Median follow-up from the index date until death or censoring was 13.8 mo (IQR: 6.2–25.3). Median OS (mOS) was 13.9 mo (95% confidence interval: 12.9–15.0). There was no significant difference in mOS for pts treated with AZA vs DEC (13.4 vs 15.2 mo, respectively; p=0.22). Pts with RBC-TD/TU had shorter mOS vs those with RBC-transfusion independence (TI) (10.7 vs 18.6 mo, respectively; p<0.0001). Similarly, pts with platelet TD/TU had shorter mOS vs those with platelet TI (8.4 vs 14.9 mo, respectively; p<0.0001). There were no statistically significant differences in OS by the route of AZA administration, insurance category, county metropolitan status, or county poverty level. Overall, 38.0% of HMA-treated pts progressed to AML; median time from HMA initiation to AML progression was 8.2 mo (IQR: 3.5–15.1). Cumulative incidences of AML and death were 25.7% and 30.7%, respectively, at Year 1 and 34.3% and 45.8%, respectively, at Year 2, with the rates of progression slowing over time. Summary/Conclusion: Compared with previously published literature from the SEER-Medicare database (Zeidan Br J Haematol 2016; mOS: 11 mo [AZA] and 12 mo [DEC] in pts diagnosed with HR-MDS between 2004 and 2011), pts with HR-MDS treated with HMA have improved mOS, but OS remains substantially worse vs the landmark AZA-001 trial (Fenaux Lancet Oncol 2009; mOS: 24.5 mo). The incidence of death and AML progression was highest in the first year after initiation of therapy. SCT rates remain very low among pts with HR-MDS, further emphasizing the urgent need for novel treatment options for pts with HR-MDS.

Incidence and survival estimates for patients with myelodysplastic syndrome in the early 21st century: no evidence of improvement over time

We examine changes in population level incidence and survival of patients diagnosed with myelodysplastic syndrome (MDS) in the United States in 2001–2016. Data were extracted from the Surveillance, Epidemiology, and End Results (SEER)-18 database. Period analysis was used to calculate one-, two-, and five-year survival. The incidence peaked at 5.6 per 100,000 in 2010 then decreased to 3.9 by 2016, with a decrease in the diagnoses of refractory anemia (RA) and RA with ringed sideroblasts (RARS) and a relative increase in RA with excess blasts (RAEB). Overall, one-, two-, and five-year relative survival decreased over time, going from 74.3%, 60.9%, and 42.3%, respectively, in 2008–2010 to 70.9%, 55.9%, and 37.6%, respectively, in 2014–2016. When survival was examined by histology, patients with RA/RARS and RAEB had similar survival expectations in 2008–2010 versus 2014–2016 and a decrease was observed for 5q-MDS. Our results highlight the need for new treatment options in MDS.

Treatment Utilization and Characteristics Among Patients with Higher-Risk Myelodysplastic Syndromes According to Hypomethylating Agent Use

Introduction: Hypomethylating agents (HMAs) are standard of care treatment for patients with higher-risk myelodysplastic syndromes (HR-MDS) who are ineligible for stem-cell transplantation or intensive chemotherapy. Until recently, approved HMAs included intravenous or subcutaneous azacitidine and decitabine, which should be administered for a minimum of 4-6 cycles to elicit response in the absence of progression or unacceptable toxicity. In real-world clinical practice, underutilization of HMA therapy has been documented; however, prior estimates have utilized data preceding 2016. The study objectives were to understand recent treatment utilization and characteristics among patients newly diagnosed with HR-MDS in the United States (US).Methods: This retrospective observational study utilized the IQVIA PharMetrics ® Plus database which comprises adjudicated claims for more than 190 million unique patients across the US. Adult patients newly diagnosed with HR-MDS from July 1, 2016 through December 31, 2019 were included. Patients had ≥1 inpatient claim or ≥2 outpatient claims >60 days apart with diagnosis codes for high grade MDS lesions and/or refractory anemia with excess blasts (RAEB), and continuous enrollment for 6 months prior to and ≥180 days following the index date (index date = first diagnosis claim). Patients had a variable follow-up period up to 1 year post-index, and were followed through June 30, 2020. Patient characteristics at baseline, and treatment utilization based on observed MDS-related therapy (HMAs and supportive care), over the variable follow-up period were evaluated.Results: A total of 371 patients were included; the mean age of patients at baseline was 69.2 years and 57.7% were male. Of these, 61 (16.4%) patients received no HMA and no supportive care over the variable follow-up period following diagnosis. Half (n=182, 49.1%) received no HMA but received supportive care, and the remainder (n=128, 34.5%) received HMA therapy over the variable follow-up period; 45 (12.1%) received decitabine as the first HMA in a mean of 89.2 days from diagnosis, and 83 (22.4%) received azacitidine as the first HMA in a mean of 51.1 days from diagnosis (Table). Patients receiving no HMA therapy but with supportive care were older (mean age 70.6 years; 45.6% aged ≥75 years) and had higher comorbidity burden (mean Charlson Comorbidity Index [CCI] 2.5) than the other cohorts (mean age 66.6-68.8 years; 24.4-37.7% aged ≥75 years; CCI 1.2-2.0). For example, a higher proportion of patients receiving no HMA therapy but with supportive care had baseline renal disease (21.4%) compared to the other cohorts (4.9-15.6%). Patients receiving no HMA or supportive care in this study had a similar mean age compared to those who received HMAs (68.8 vs 66.6-68.0 years), but tended to have lower comorbidity burden (CCI 1.2 vs 1.9-2.0).Conclusions: In this real-world study using contemporary data, utilization of HMA therapy among patients with HR-MDS in the US was low, with only around one-third of patients receiving HMAs. Patients who did not receive HMAs but received supportive care tended to be older and have higher comorbidity burden than those who received HMAs, suggesting potential barriers for physicians in prescribing HMAs to older, frailer patients. [Display omitted] DisclosuresZeidan: Pfizer: Other: Travel support, Research Funding; Jazz: Consultancy; Jasper: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Consultancy; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; BeyondSpring: Consultancy; Astex: Research Funding; Astellas: Consultancy; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Divino: IQVIA: Current Employment, Other: IQVIA received funding for this study from Epstein Health in connection with this study. DeKoven: IQVIA: Current Employment, Other: IQVIA received funding for this study from Epstein Health in connection with this study. Shah: IQVIA: Current Employment, Other: IQVIA received funding for this study from Epstein Health in connection with this study. Wang: IQVIA: Current Employment, Other: IQVIA received funding for this study from Epstein Health in connection with this study. Bey: Taiho Oncology: Current Employment. Salimi: Taiho Oncology: Current Employment. Epstein: Epstein Health: Current Employment; Fate Therapeutics: Other: Holds leadership position; Veracyte: Other: Holds leadership position; Illumina: Other: Holds leadership position; Merck: Consultancy; Radius Health: Consultancy; Halozyme: Consultancy; Intra-Cellular Therapies: Consultancy; Taiho Oncology: Consultancy; Otsuka: Consultancy.

Long-Term Survival of Older Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agent Therapy: A Large Population-Based Analysis

Introduction: The approval of hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) were major milestones in improving the clinical outcomes of patients with higher-risk myelodysplastic syndromes (MDS). In the landmark AZA-001 randomized trial, the median overall survival (OS) and the 2-year OS rates were 24.5 months and 50·8%, respectively, in the AZA arm, compared to 15 months (p=0·0001) and 26·2%, respectively, in conventional care regimen arms. However, long-term OS rates with HMAs have not been formally assessed due to limited follow-up duration of most clinical studies. To address this question, we analyzed Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data to assess longer term survival for MDS patients treated with HMAs and who did not undergo transplantation.Methods: In this retrospective cohort study, we used ICD-O-3 codes to identify MDS patients in SEER-Medicare who were diagnosed between 2004-2009 and initiated HMA before 12/31/2009. We defined patients with refractory anemia with excess blasts (RAEB) as a proxy for higher-risk MDS. Patients were followed until death or December 31, 2013, whichever came first. Our selection strategy allowed at least 4 years of potential follow-up for every patient to optimize reliability of long-term survival assessment. Patients were ≥66 years at diagnosis, had continuous Medicare Parts A and B coverage, and received ≥10 days of HMA therapy. Patients who underwent allogeneic stem cell transplantation (n=14) were excluded [Figure 1]. The Healthcare Common Procedural Coding System codes in Medicare claims identified treatments including HMAs and transfusion of red blood cells (RBC) and platelets during an 8-week period preceding the first HMA treatment. Cycles of HMA therapy were defined by at least 4 individual days of HMA use and a gap of at least 2 weeks between cycles. We measured OS from first day of HMA. Kaplan-Meier methods and log-rank test were used to analyze unadjusted survival, while the Cox proportional hazards models were used to study adjusted survival. Two-sided statistical tests with p-value <0.05 to indicate statistical significance.Results: We identified 1,187 eligible MDS patients [Figure 1], including 336 patients (28.3%) with RAEB.The median age at diagnosis was 77 (interquartile range [IQR] 72-81) years, and 63.8% were males. AZA was used in 936 patients (78.9%) while 251 patients (21.1%) received DAC. In total, 72.6% and 49.5% of patients received ≥4 and ≥ 6 cycles of HMA therapy, respectively, with no significant differences in these proportions between the AZA and DAC treated groups. The median OS for the entire cohort was 14 months (95% CI: 13-15 months), and the 5-year OS probability was 12% (95% CI: 10%-14%). The median OS for patients in the RAEB cohort (n=336) was 11 months from HMA initiation (95% CI: 10-12 months). The 5-year OS probability for RAEB patients was a dismal 4% (95% CI: 2%-6%). In a multivariate survival analysis, the choice of HMA was not associated with increased probability of survival among RAEB patients (DAC vs. AZA, HR = 0.96, 95% CI: 0.70-1.31, P=0.78, Figure 2) while RBC or platelet transfusions were associated with increased risk of death.Conclusions: In this large retrospective study of 1,187 HMA-treated older patients with MDS, who had ≥ 4 years of follow-up from time of initiation of HMA therapy and who did not undergo transplantation, we observed a dismal 5-year OS probability rate of 4% (95% CI 2%-6%) for the RAEB cohort. We did not find significant difference in the probability of long-term survival as based on the type of HMA received among patients with RAEB. These results argue against the presence of a significant survival tail (or plateau) for patients higher-risk MDS after receiving HMAs. These results confirm the suboptimal performance of HMAs for treatment of MDS in the real-world setting and provide rationale for strong consideration of alternative management strategies including clinical trials for all patients with MDS. [Display omitted] DisclosuresMa:Incyte Corp.: Consultancy. Huntington:Janssen: Consultancy; Pharmacyclics: Honoraria; Celgene: Consultancy, Other: Travel. Podoltsev:CTI biopharma/Baxalta: Consultancy; Alexion: Consultancy; Ariad: Consultancy; Incyte: Consultancy. Zeidan:Takeda: Speakers Bureau; AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Otsuka: Consultancy.

Effect of Azacitidine on CD4+CD25+Foxp3+ Regulatory T Cell on Immunity in Myelodysplastic Syndrome Survivors

Background: Immune editing is recognized as important in various pathogenic processes. We previously showed that regulatory T cell (Treg) levels were elevated in MDS with a poor prognosis and that Treg levels decreased with Azacitidine (AZA) treatment and became equivalent to that in the untreated group. In this study, we examined changes in the number of circulating Tregs, T cells, and NK cells in the peripheral blood of patients with MDS treated with AZA, and we evaluated the clinical significance of these findings with survival.Patients and Methods: Patients with MDS and with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) according to the WHO 2008 classification who were initially treated between January 2015 and December 2016 and followed up for more than 6 months were enrolled in the study. AZA was given intravenously at a dose of 75 mg/m2 daily for either 5 or 7 consecutive days every 4 weeks. The response was assessed using the IWG response criteria for MDS. A total of 50 patients with AML-MRC (n=11), refractory anemia with excess blasts (RAEB) (n=8), refractory cytopenia with multilineage dysplasia (RCMD) (n=28), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (n=12), and refractory anemia with ring sideroblastis (RARS) (n=1) were included in the study. The IPSS was classified as low (n=15) intermediate-1 (n=13), intermediate-2 (n=10), and high (n=13). Twenty-six patients did not require treatment, including a transfusion (untreated group). Twenty-two patients were treated with AZA (AZA group). The remaining patients received conventional chemotherapy. After obtaining informed consent, blood was drawn from all of the patients at initial diagnosis. In the 22 patients treated with AZA, blood was also drawn after 6 completed treatment cycles. CD4+CD25+Foxp3+ Treg cells, CD3+CD4+ T cells, CD3+CD8+ T cells, and CD3-CD56+ NK cells were analyzed using flow cytometry, and the absolute numbers of these cells were calculated. Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and compared by the log-rank test for univariate analysis.Results: The median age was 74 years (range: 44-93 years), and 35 of the patients were male. The median period of observation was 391 days. In the AZA group, 10 patients died (AZA-ineffective group), and 12 had either a CR, PR, or HI (AZA-effective group). The 2-year OS of the AZA group was 43.7%. The absolute number of Tregs and Treg% values before treatment were not significantly different between the AZA group and the untreated group. The Treg levels in peripheral blood before treatment in the AZA-effective (0.80±0.39%) tended to be lower than that in the AZA-ineffective (1.29±0.82%) group (p=0.076). The CD8+ T cell counts before treatment were moderately higher in the AZA-effective group compared to that in the AZA-ineffective group (385.5 ± 129.0 vs. 195.5 ± 70.0 /μL, p<0.01). Similarly, the CD3-CD56+ NK cell counts before treatment differed significantly between the AZA-effective group (197.4 ± 138.8 /μL) and the AZA-ineffective group (82.3 ± 36.7 /μL) (p=0.015). In a univariate analysis, the MDS patients with elevated NK cells survived longer than the group with reduced NK cells (p=0.013). In a multivariate analysis, the lower percentage of Treg cells and the higher percentage of CD8+T cells before treatment were independent factors for OS (HR, 4.80; p=0.085, HR, 4.13; p=0.040, respectively). In the AZA group, the percentage of CD8+T cells before treatment associated with OS (HR, 39.24; p=0.018). After treatment, the AZA group had an increase in the NK cell counts, which tended to associate with survival (HR 4.29; p=0.067).Conclusions: The number of Tregs in MDS cases requiring treatment was higher than that in MDS cases for which treatment was unnecessary. The prognosis of the patients with high CD8+ T cells counts was better. In contrast, there was an increase in the number of NK cells after AZA treatment, which was found to be associated with an improved prognosis. These results suggest that an immunological mechanism associated with the prognosis of MDS may be enhanced by treatment with AZA. Further examination of this mechanism and of the influence of AZA on the immunological effect are required. DisclosuresNo relevant conflicts of interest to declare.

Direct Medical Costs Associated With Treatment Nonpersistence in Patients With Higher-Risk Myelodysplastic Syndromes Receiving Hypomethylating Agents: A Large Retrospective Cohort Analysis

BackgroundSuboptimal use of hypomethylating agents (HMAs) among higher-risk myelodysplastic syndrome (HR-MDS) patients can translate into worse health outcomes and economic burden. We estimated the direct medical costs associated with HMA treatment nonpersistence among HR-MDS patients. Patients and MethodsUsing the Surveillance, Epidemiology, and End Results–Medicare linked database, a retrospective cohort of patients diagnosed with refractory anemia with excess blasts (RAEB), a diagnosis that substantially overlaps with HR-MDS, between January 2011 and December 2015 was analyzed. Patients who had ≥ 1 year of continuous Medicare enrollment before diagnosis and who did not receive stem cell transplant or lenalidomide in the follow-up period were included. Patients receiving HMAs were stratified into HMA persistent (≥4 HMA cycles) and HMA nonpersistent (<4 cycles or a gap of ≥ 90 days between cycles) groups. Healthcare resource use and costs during the follow-up period were reported descriptively as total and per patient per month (PPPM). Weighted generalized linear models (GLM) were used to compare estimated healthcare resource use and costs between HMA groups. ResultsAmong the 664 patients with RAEB, 295 (44.4%) were HMA nonpersistent and 369 (55.6%) HMA persistent. On the basis of weighted GLM analysis, the HMA nonpersistent group incurred significantly (P < .05) higher total PPPM costs compared to the HMA persistent group ($18,039 vs. $13,893), particularly for hospitalization ($3,375 vs. $2,131), and emergency room ($5,517 vs. $2,867) costs. ConclusionThere is a substantial economic burden associated with early discontinuation of guideline-recommended HMA therapy in RAEB patients. The study findings necessitate closer care management in this population in order to improve outcomes and reduce healthcare spending.

The Direct Medical Costs of Treatment Discontinuation Among Higher-Risk Myelodysplastic Syndrome Patients Receiving Hypomethylating Agents

Introduction: Non-persistence to treatment with hypomethylating agents (HMA) in higher-risk myelodysplastic syndrome (HR-MDS) patients can result in loss of response or ability to achieve a primary response. HMA treatment is recommended to be given to HR-MDS patients for least 4-6 treatment cycles to elicit a clinical response and premature termination is likely to result in poor outcomes and considerable healthcare spending. The study objective was to assess direct medical costs associated with HMA treatment non-persistence among HR-MDS patients. Methods: Using a retrospective cohort design, MDS patients with refractory anemia with excess blasts (RAEB) were analyzed using 2010-2016 Surveillance, Epidemiology and End Results-Medicare linked database. RAEB diagnosis is considered to substantially overlap with HR-MDS and has been used as a surrogate for HR-MDS. The study cohort included RAEB patients diagnosed between 01/2011 and 12/2015. Patients were included if they had ≥ 1 year of continuous Medicare enrollment prior to diagnosis and did not receive stem cell transplant or lenalidomide in the follow-up period. HR-MDS patients receiving HMAs were stratified into HMA persistent (receiving 4 or more HMA cycles without any gap of ≥90 days between cycles) and HMA non-persistent (receiving less than 4 cycles or a gap of ≥90 days between cycles) groups. Healthcare resource use (HCRU) and associated direct medical costs incurred during the follow-up period were described as per-patient-per-month (PPPM). To account for baseline differences between HMA persistent and non-persistent groups, propensity score-based inverse probability of treatment weights (IPTW) were calculated. Weighted HCRU and costs (PPPM) were further estimated using generalized linear models (GLMs). Costs were inflated to 2019 USD using medical component of consumer price index. Results: There were 664 patients identified with RAEB, of which 295 (44.4%) patients were classified in the HMA non-persistent group and 369 (55.6%) patients in the HMA persistent group. HMA persistent and non-persistent groups were similar in baseline demographic and clinical characteristics; however, non-persistent HMA users were older at diagnosis and a lower proportion of patients were married. Results from weighted GLM analysis indicated higher PPPM resource utilization in HMA non-persistent patients compared to HMA persistent patients specifically for hospitalizations (Incident rate ratio [IRR], 1.543, 95% Confidence interval [CI]: 1.181 - 2.018]), ER visits (IRR= 1.322, 95% CI: 1.146 - 1.524), SNF use (IRR = 2.158, 95% CI: 1.308 - 3.560), home health (IRR = 1.335, 95% CI: 1.039 - 1.714] and hospice care use (IRR = 2.555, 95% CI:1.972 - 3.309) (Table 1). Further, HMA non-persistent patients had significantly (P&amp;lt;0.05) higher total PPPM costs than HMA persistent patients ($18,039 vs. $13,893, p&amp;lt;0.05); particularly for hospitalizations ($3,375 vs. $2,131), and ER costs ($5,517 vs. $2,867) (Figure 1). Conclusions: A significant proportion of HR-MDS (RAEB) patients discontinue guideline-recommended HMA treatment. Non-persistence with HMA treatments was associated with substantial cost burden. The study findings call for closer care management by healthcare providers to ensure HMA treatment is completed as scheduled (unless directed otherwise by the provider) to manage outcomes and healthcare spending. Disclosures Joshi: Pharmerit International: Current Employment. Kale:Pharmerit International: Current Employment. Corman:Pharmerit International: Current Employment. Hill:Taiho Oncology: Current Employment, Current equity holder in publicly-traded company. Wert:Taiho Oncology: Current Employment, Current equity holder in publicly-traded company. Zeidan:Otsuka: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Astex: Research Funding; CCITLA: Other; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

Clinical Impacts of Germline DDX41 Mutations on Myeloid Neoplasms

DDX41 was identified as a causative gene for late-onset familial myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While DDX41 is thought to be one of the most frequent targets of germline mutations responsible for sporadic cases with AML/MDS and other myeloid neoplasms, the entire spectrum of pathogenic DDX41 variants and their effect size therein are still to be elucidated, and so was the clinical picture of DDX41-mutated myeloid neoplasms. In this study, through an international collaboration, we investigated DDX41 variants in a total of 5,609 sporadic cases with different myeloid neoplasms from different ethnicities, using next generation sequencing. Mutations in the major driver genes commonly mutated in AML/MDS were also examined. Frequencies of germline DDX41 variants were compared between sporadic cases with myeloid neoplasms and healthy individuals (n=13,906). We also characterized genetic/clinical features of DDX41-mutated myeloid neoplasms. We identified a total of 208 (3.6%) patients with DDX41 variants, of whom approximately 50% had both germline and somatic mutations, whereas 37% and 13% had either germline or somatic mutations alone, respectively. Somatic mutations were found in 58% of patients with germline mutation, which was significantly higher than those without (0.21%) (P&amp;lt;0.0001). No somatic mutation was identified in healthy individuals. Among 174 germline variants, truncating and missense mutations were found in 93 and 81 cases, respectively, whereas only 1.9% of somatic mutations were truncating (P&amp;lt;0.0001). Among 21 cases with somatic mutations alone, 4 had multiple somatic mutations and an additional 4 had loss-of-heterozygosity of the DDX41 locus (5q35.3), including 3 with uniparental disomy and 1 with deletion. Thus, 8 out of 21 cases with somatic mutation alone were suspected to have biallelic DDX41 mutations. Germline DDX41 variants showed a conspicuous ethnic diversity; the most frequent germline variants were A500fs in Japan, D140fs in USA, Q41* in Germany, G218D in Italy, M1I in Sweden, S21fs in Thailand. The M1I variant was also seen in other European countries, but not in Japan or Thailand, while no A500fs mutation was found in Europe. Among the Japanese population, significant enrichment in myeloid neoplasms was observed not only for truncating variants, such as A500fs (odds ratio (OR)=12.1) and E7X (OR=11.0) but also for missense variants, including Y259C (OR 14.3) and E256K (OR 7.81), frequently accompanied by a somatic DDX41 mutation (Figure 1). Patients with germline and/or somatic DDX41 variants were significantly older than those without (P=0.00076) and more prevalent in male than female (OR=3.14; P&amp;lt;0.0001). DDX41 variants were significantly more frequent in MDS (4.7%) and AML (2.9%), compared with other myeloid neoplasms (0.58%). Among AML, mutations were more frequent in AML with myelodysplasia-related changes (P&amp;lt;0.00001). Patients with MDS having both germline and somatic mutations were more likely to classified in refractory anemia with excess blasts (RAEB), compared with those with germline or somatic alone (P=0.029). DDX41 variants were significantly associated with lower WBC and granulocyte counts. Most frequently co-occurring mutations included those in ASXL1, SRSF2, TET2, CUX1, and DNMT3A, of which only CUX1 mutations were statistically significant. Overall, no difference was observed in overall survival (OS) between DDX41-mutated and unmutated cases. However, among RAEB cases, DDX41 variants were associated with a significantly longer OS (P=0.0039). In summary, the majority of DDX41-mutated cases had a germline variant, although a minority had somatic mutations alone. Pathogenic DDX41 alleles have a large ethnic diversity, where not only truncating variants but also missense variants are associated with an increased risk of the development of myeloid neoplasms. Disclosures Kanda: Chugai Pharma: Honoraria, Research Funding; Merck Sharp &amp; Dohme: Honoraria; Mundipharma: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Mochida Pharmaceutical: Honoraria; Daiichi Sankyo: Honoraria; Shionogi: Research Funding; Meiji Seika Kaisha: Honoraria; Sanofi: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Ogawa:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Co., Ltd.: Research Funding.

Under-use of Hypomethylating Agents in Patients With Higher-risk Myelodysplastic Syndrome in the United States: A Large Population-based Analysis

BackgroundRecent data suggest significant underutilization of hypomethylating agents (HMAs) that are recommended treatments for patients with myelodysplastic syndromes (MDS) with refractory anemia with excess blasts (RAEB). The study objective was to assess the degree of HMA use and predictors of HMA underuse in this population. Patients and MethodsThis was a retrospective study including patients diagnosed with the RAEB form of MDS between January 2011 and December 2015 using the Surveillance, Epidemiology, and End Results-Medicare linked database. Patients were excluded if they had < 1 year of continuous enrollment before diagnosis or received stem cell transplant or lenalidomide during the follow-up period. HMA non-peristence was defined as use of < 4 cycles (3-10 HMA days/28 days) of HMAs or a gap of ≥ 90 days between consecutive cycles. Patients were characterized as HMA never-users, HMA–persistent users, and HMA–non-persistent users. Descriptive statistics were used to summarize patient characteristics. Multivariable logistic regression was used to assess predictors of HMA underuse and persistence. ResultsOf the 1190 patients, 526 (44%) were never-users, 295 (25%) were non-persistent users, and 369 (31%) were persistent users. Age at diagnosis (eg, 66-70 years vs. ≥ 80 years; odds ratio [OR], 2.36; 95% confidence interval [CI], 1.56-3.56), marital status (single vs. married; OR, 0.67; 95% CI, 0.51-0.89), National Cancer Institute comorbidity index (≥ 3 vs. 0-1; OR, 0.62; 95% CI, 0.46-0.83), and performance status (poor vs. good; OR, 0.67; 95% CI, 0.51-0.87) were significantly associated with HMA underuse. ConclusionSeveral demographic and clinical factors were associated with underuse of HMAs. There is need for a better understanding of suboptimal HMA use and its relationship with clinical response.

The impact of transfusion burden and comorbidities on the prognosis of patients with myelodysplastic syndromes

PurposeEarly comorbidity detection has been reported to be associated with treatment-related outcomes in several diseases. Two main goals of the present study were to investigate both the impact of comorbidities and transfusion frequencies on the survival and quality of life of patients with myelodysplastic syndromes (MDS). MethodsOne hundred and four MDS patients with a median International Prognostic Scoring System (IPSS) score of 0.5 (range: 0–3) were included in the study. Almost half of the patients had more than one comorbidity. ResultsMedian short form health surveys (SF)-36 mental and physical scores were 42.1 (range: 20.6–66.1) and 38.7 (range: 18–59.7), respectively. Mean scores of the Eastern Cooperative Oncology Group (ECOG) performance scales at diagnosis and during recruitment were 1.0 (1.4 ± 1.0) and 2.0 (1.8 ± 1.1), respectively. The mean Charlson Comorbidity Index (CCI) score was 1.0 (1.4 ± 1.5). In the model that was constructed using variables with a p value < 0.100 in the univariate analysis, factors that predicted death were refractory anemia with excess blasts (RAEB) and ECOG scores at recruitment. When ECOG was removed from the model, RAEB and CCI at diagnosis moved to the forefront as mortality predictors. ConclusionThis study demonstrated that both CCI and ECOG performance status had an impact on survival in MDS patients who had low IPSS scores. ECOG stood out as a better and more practical predictor of survival than CCI, especially after considering its (ECOG) ease of use.

Epigenetic changes in FOXO3 and CHEK2 genes and their correlation with clinicopathological findings in myelodysplastic syndromes

Objectives/backgroundMyelodysplastic syndromes (MDSs) are a heterogeneous disease in terms of clinical course and response to therapy. Epigenetic changes are the primary mechanism of MDS pathogenesis. FOXO3 and CHEK2 genes play significant roles in normal cellular mechanisms and are also known as tumor suppressor genes. We aimed to clarify the correlation of epigenetic changes in these genes with clinicopathologic findings in MDS. MethodsA total of 54 newly diagnosed MDS patients referred to Shariati and Firouzgar Hospitals (Tehran, Iran) were included in the study from 2013 to 2015, comprising the following cases: 26 with refractory cytopenia with unilineage dysplasia, 10 with refractory cytopenia with multilineage dysplasia, four refractory anemia with excess blasts-1 (RAEB-1), 11 refractory anemia with excess blasts-2 (RAEB-2), and three MDS associated with isolated deletion (5q-). Risk groups were determined according to the Revised International Prognostic Scoring System (IPSS-R). The methylation status of CHEK2 and FOXO3 promoters were determined by methylation-sensitive high-resolution melting analysis of sodium bisulfite-converted DNA. Expressions of CHEK2, FOXO3, and GAPDH were measured by quantitative real-time polymerase chain reaction and fold changes were calculated using the ΔΔCT method. ResultsStatistical analysis revealed no promoter methylation of CHEK2 and FOXO3 in healthy control specimens. FOXO3 promoter methylation was associated with high-risk World Health Organization subgroups (p = .017), high-risk IPSS-R (p = .007), high-risk cytogenetics (p = .045), and more than 5% blasts in bone marrow (p = .001). CHEK2 promoter methylation was correlated with more than 5% blasts in bone marrow (p = .009). ConclusionsPromoter methylation of CHEK2 and especially FOXO3 is associated with adverse clinicopathological findings and disease progression in MDS.

Nationwide epidemiological survey of familial myelodysplastic syndromes/acute myeloid leukemia in Japan: a multicenter retrospective study

Although several pedigrees of familial myelodysplastic syndromes/acute myeloid leukemia (fMDS/AML) have been reported, the epidemiology and clinical features has been poorly understood. To explore the epidemiology of this entity, we performed a retrospective nationwide epidemiological survey in Japan using questionnaire sheets. The questionnaire was sent to 561 institutions or hospitals certified by Japanese Society of Hematology, unearthing the existence of 41 pedigrees of fMDS/AML. Among them, we obtained the clinical information of 31 patients in 20 pedigrees. The median age of the initial diagnosis was 51 years (range 9–88 years) and the WHO classification 2008 ranged from refractory anemia (RA) to AML. Focusing on the familial MDS patients, refractory anemia with excess blasts (RAEB)-2 was the largest group (27.3%). The median overall survival (OS) of fMDS and fAML in this study were 71.6 and 12.4 months, and the five-year OS were 61.3 and 50%, respectively.

Hypomethylating agent (HMA) therapy use and survival in older adults with Refractory Anemia with Excess Blasts (RAEB) in the United States (USA): a large propensity score-matched population-based study

Hypomethylating agents (HMA) showed overall survival (OS) benefits in patients with higher-risk myelodysplastic syndromes (HR-MDS) in clinical trials. We conducted a retrospective cohort study of Surveillance, Epidemiology, and End Results (SEER)-Medicare data of patients ≥66 years diagnosed with refractory anemia with excess blasts (RAEB), a proxy for HR-MDS, in 01/2001–04/2004 (pre-period) or 01/2006–12/2011 (post-period). Association between post-period diagnosis and OS was examined using propensity scores (PS)-matched samples. Among 1876 RAEB patients, median OS was 9 months and 30.8% received HMAs (3.6% in pre-period; 43.0% in post-period) with no association between post-period diagnosis and OS. In the top PS quartile, post-period diagnosis was associated with a 74% lower risk of death (Hazard ratio [HR] = 0.26, 95%-CI: 0.10–0.69, p = 0.007), while outcomes were worse in the lowest PS quartile (HR = 2.80, 95%-CI: 1.06–7.36, p = 0.037). HMA lead to a 3-month OS benefit for patients most likely to receive HMA but not for unselected RAEB cohort.

Clinical features of the children with malignancy-associated hemophagocytic syndrome in Beijing

Objective To investigate the clinical features, treatment and prognosis of the children with malignancy-associated hemophagocytic syndrome (MAHS) in Beijing in recent decade. Methods The clinical data of the patients with MAHS under 18 years old from July 2007 to February 2018 collected by the Society of Beijing hemophagocytic syndrome were analyzed retrospectively. Results There were 46 patients under 18 years old with MAHS in all(male 27, female 19). The patients with MAHS took up 8.9% of the patients with hemophagocytic lymphohistiocytosis (HLH)(46/519 cases) from the area during that period.The median age of onset had 13.5 years (0.9-18.0 years). Thirty-five patients had lymphoma (76.0%), 9 cases had leukemia (19.6%), 1 case had myelodysplastic syndrome with refractory anemia with excess blast(RAEB-T), and 1 case had Epstein-Barr virus(EBV) associated lymphoproliferative disease (borderline tumor stage). All the patients had a fever.A half of them suffered from hepatosplenomegaly and 7 patients(15.2%) had neurological symptoms.The common laboratory abnormalities included cytopenias, hemophagocytosis in bone marrow (81.8%, 36/44 cases), elevated serum ferritin (87.8%, 36/41 cases), and elevated sCD25 (100.0%, 15/15 cases), decreased nature killer(NK) activity (61.1%, 11/18 cases), and plasma EBV-DNA positive (57.9%). Four patients did not receive treatment, the rest were treated by several chemotherapy protocols including the HLH-94/2004 protocol.Five patients (10.8%) received the allogeneic hematopoietic stem cell transplantation, and 1 case received the splenectomy therapy.The mortality was 58.7%.Four heterozygous mutations of SH2D1A, UNC13D and PRF1 genes were found in 2 patients. Conclusions MAHS in children progresses rapidly, with poor prognosis, and it is often complicated with EBV infection.The children with MAHS may develop genetic defects similar to primary hemophagocytic syndrome.Nowadays, there is no standard treatment for MAHS, so the individualized treatment is to be explored. Key words: Malignancy-associated hemophagocytic syndrome; Child; Clinical features; Treatment

Anabolic Steroids in Myelodysplastic Syndromes: A Systematic Review

Background Anabolic steroids, such as danazol, have been used for years in the treatment of myelodysplastic syndromes (MDS). Their successful use has been documented in aplastic anemia, hypoplastic MDS, and immune thrombocytopenia, among other hematologic conditions. In patients with low-risk MDS, available treatment options are limited. Danazol is frequently used to improve symptoms and modify the disease course; however, its efficacy and optimal dosing schedule are unclear. Methods We conducted a systematic review of the literature to identify studies that used anabolic steroids, including danazol, in the treatment of MDS. In accordance to guidelines, our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under ID CRD42019121467. We included case series with more than 15 patients, observational studies (cohorts and case control), and randomized trials where anabolic steroids were used to treat MDS. Following PRISMA guidelines, 2 independent reviewers assessed the studies obtained through the search strategy. Discrepancies were resolved by a third reviewer. Due to the heterogeneity of the findings, no meta-analysis was performed. Results A total of 1000 studies were identified through our search. After removing duplicates and undergoing Level 1 screening by 2 reviewers, 69 full text articles were assessed. Thirteen studies were included in the final review as the other studies did not meet inclusion criteria. Of these, 3 were retrospective cohorts, 8 prospective cohorts, and 2 randomized trials. A total of 366 patients with MDS were exposed to anabolic steroids throughout the studies with diverse outcomes reported. FAB classification was used by most of the studies to categorize MDS, with one exception that used the 2008 WHO classification. Diagnoses included refractory anemia, refractory anemia with ring sideroblasts, refractory anemia with excess blasts (RAEB), RAEB in transformation, and chronic myelomonocytic leukemia. All but 2 studies used danazol as their intervention, with the exceptions using other anabolic steroids as well as danazol. Dosage varied across studies with the majority aiming for a dose of danazol 600mg daily. Patient characteristics and interventions are summarized in Table 1. The intervention was sustained for at least 1 month and up to 12 months across studies. Outcomes reported are diverse with positive and negative studies identified. Unfortunately, outcomes are not comparable due to the presence of different response definitions with different hematologic improvement cutoffs. Reports of response were highly variable, with studies showing 5 - 75% response rates depending on their study response definitions. Multiple studies reported a trend in platelet count improvement. Response duration was not specified by all studies and was highly variable across the reports. Response definitions and outcomes are shown in Table 2. No significant adverse effects to danazol were reported in any of the studies reviewed. No specific analysis of benefit throughout the different MDS groups was reported in any of the studies. Conclusion Our systematic review highlights the significant lack of data and irregular results across studies. The heterogeneity of included populations, MDS classification, response criteria, and interventions, do not allow for evidence based recommendations regarding the use of danazol or anabolic steroids in MDS patients. Given the limited treatment options for low-risk MDS patients, particularly in low and middle income countries, further well designed studies are needed. Disclosures No relevant conflicts of interest to declare.