Outcome Of Myelodysplastic Syndromes Research Articles

Impact of spliceosome mutation on outcomes of myelodysplastic syndrome and chronic myelomonocytic leukemia patients undergoing allogeneic hematopoietic cell transplantation

IntroductionAllogeneic Hematopoietic cell transplantation (allo-HCT) remains the only curative therapy for myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). The impact of spliceosome mutations on allo-HCT outcome is unclear and further understanding is needed to assess the implications of this class of mutations on risk of relapse, overall survival (OS) and non-relapse mortality (NRM) in order to make decision regarding timing of allo-HCT. We examined the allo-HCT outcomes of MDS/CMML patients based on their spliceosome mutation profile to understand the impact of these mutations on transplant outcomes. ObjectiveTo compare outcomes of MDS/CMML patients with and without spliceosome mutations undergoing allo-HCT. MethodsThis is a single institution, retrospective study of MDS/CMML patients who underwent allo-HCT with myeloablative or reduced intensity conditioning (RIC) regimen at City of Hope from January 2016 to December 2021. Among them, patients who underwent molecular mutation profiling by NGS (Next Generation Sequencing) for a set of genes known to be mutated in myeloid neoplasms are included in this analysis. We compared OS, relapse free survival, NRM and acute/chronic graft versus host disease (GVHD) incidence between the spliceosome-mutated and unmutated groups. ResultsWe identified 258 consecutive MDS/CMML patients who underwent allo-HCT. Of these, 126 (48.8 %) patients had molecular profiling done among whom 57 (45.2 %) patients carried a spliceosome mutation. 84.9 % of patients had MDS and 55.6 % underwent a matched unrelated donor transplant. The median age for the whole cohort was 66 years (range 12–77).78.6 % and 73.7 % received RIC in the spliceosome and non-spliceosome groups, respectively. The 2-year OS for the whole cohort was 66.5 % (95 %CI 0.55–0.75) with a day 100 NRM of 7.1 % and 2-year cumulative incidence of relapse of 20 %. Grade II-IV acute GVHD at day 100 was 36.3 % (95 % CI 0.27–0.44) and any chronic GVHD at 2-years was 48.4 % (95 % CI 0.37–0.58). Patients who carried a spliceosome mutation had a significantly better 2-year survival of 83.8 % vs 55.9 % in the non-spliceosome group (P=0.002) and a better PFS of 73.7 % vs 50.0 % (P=0.007). There was no difference in the cumulative incidence of relapse at 2-years 15.9 % vs 18.5 % (P=0.59) between two groups but the spliceosome group had a significantly lower NRM at 2-years 10.4 % vs 31.5 % (P=0.009). There was no difference in incidence of acute or chronic GVHD between the two groups. ConclusionsAmong patients with MDS or CMML who underwent allo-HCT, our study shows better OS for patients who have spliceosome mutations due to lower NRM compared to those carrying non- spliceosome mutations. This favorable outcome of the spliceosome-mutated patients could have implications for timing of allo-HCT, particularly for patients in the intermediate MDS prognostic risk groups.

The clinical characteristics, gene mutations and outcomes of myelodysplastic syndromes with diabetes mellitus

PurposeDiabetes mellitus (DM) is the second most common comorbidity in myelodysplastic syndromes (MDS). The purpose of the study was to investigate the clinical characteristics of MDS patients with DM.MethodsA retrospective analysis was performed on the clinical data of 890 MDS patients with or without DM. Clinical data, including genetic changes, overall survival (OS), leukemia-free survival (LFS) and infection, were analyzed.ResultsAmong 890 patients, 184 (20.7%) had DM. TET2 and SF3B1 mutations occurred more frequently in the DM group than those in the non-DM group (p = 0.0092 and p = 0.0004, respectively). Besides, DM was an independent risk factor for infection (HR 2.135 CI 1.451–3.110, p = 0.000) in MDS. Compared to non-DM patients, MDS patients with DM had poor OS and LFS (p = 0.0002 and p = 0.0017, respectively), especially in the lower-risk group. While in multivariate analysis, DM did not retain its prognostic significance and the prognostic significance of infection was maintained (HR 2.488 CI 1.749–3.538, p = 0.000).ConclusionsMDS patients with DM have an inferior prognosis which may due to higher infection incidence, with TET2 and SF3B1 mutations being more frequent in those cases.

Impact of Hypomethylating Agents on Cardiovascular Disease Risk Among Patients with Myelodysplastic Syndromes

Introduction: The association between clonal hematopoiesis (CH) and cardiovascular disease (CVD) risk has drawn attention to cardiovascular outcomes in myelodysplastic syndromes (MDS). CVD accounts for 25% of deaths in MDS, potentially via CH-mediated accelerated atherosclerosis from inflammatory vascular responses. We previously demonstrated that MDS was independently associated with increased risk of CVD in older adults from SEER-Medicare. We subsequently hypothesized that treatment with hypomethylating agents (HMA) could reduce CVD risk by ameliorating CH clones and reducing the inflammation. In this study, we aimed to define the impact of HMA on incident cardiovascular events among older adults with MDS. Methods: We identified subjects ≥66 years diagnosed with MDS from 2007 to 2017 in SEER-Medicare. Exclusion criteria including lacking continuous Medicare parts A, B, and D, enrolled in HMO, or incomplete follow-up. Demographics included age, sex, race, rurality, socioeconomic quintile, marital status, and geographic region. Baseline CVD risk factors, defined from ICD-9/10 codes, included hypertension, hyperlipidemia, diabetes, atrial fibrillation, pre-existing cardiac disease, obesity, and smoking. MDS factors, defined using HCPCS codes, ICD-O-3 codes and prescription records, included MDS subtype and histologic risk stratification, transfusion dependence and treatment with hypomethylating agents (HMA), lenalidomide, or erythropoietin-stimulating agents (ESA) as time-varying variables. Incident CVD was defined as new myocardial infarction (MI) and/or ischemic stroke occurring after MDS diagnosis, using published ICD-9/10 algorithms. We controlled for confounding using 2 complementary analytic approaches. First, we assessed the association between HMA use and CVD using propensity score adjusted cause-specific competing risk Cox hazard models with death as competing risk, Second, we used a case-crossover design with conditional logistic regression, in which subjects with CVD served as their own controls, using a 3-month HMA treatment window and a control period 6 months prior to the incident event. Results: We identified a cohort of 15,227 eligible patients with MDS. Of these, 1,125 patients had an MI and/or ischemic stroke within 1 year before MDS diagnoses and were excluded. We analyzed 14,102 MDS patients, with median age 82 years (IQR 77 - 86), who were predominantly male (53.8%), non-Hispanic white (88.6%), and from urban/suburban areas (86.2%). MDS was of low, intermediate, and high histologic risk in 14.7%, 72.8%, and 12.5%, respectively, and 28.6% were transfusion dependent. Pre-existing CVD risk factors at time of MDS diagnosis were present in 12,538 patients, with baseline cardiovascular risk defined as low, intermediate, and high in 11.1%, 32.3%, and 56.6% of the cohort. The cumulative incidences of MI, ischemic stroke and composite CVD events were 11.3%, 10.6% and 20.4%, respectively. The propensity score (PS) conditional probability for being treated with HMA included demographic variables, CVD risk factors, MDS histology and transfusion dependence. Our PS model adequately predicted HMA treatment propensity (AUC 0.76). Cause-specific regression with death as competing risk, adjusted for PS and other MDS-specific treatments (ESA and lenalidomide), showed no significant effect of HMA on the risk of composite CVD events, MI, or ischemic stroke (Table 1). Conditional logistic regression in the case-crossover analysis of 1,907 patients with composite CVD events showed no significant effect of HMA. Results were similar for analysis of patients with MI and ischemic stroke (Table 2). Conclusions: No study has previously investigated the effect of HMA therapy on cardiovascular outcomes in patients with MDS. We demonstrate that HMA therapy is not associated with a significant risk reduction in cardiovascular events among patients with MDS patients from the SEER-Medicare database. These results show that HMA therapy is unlikely to reduce cardiovascular mortality and underscore the need for alternative therapeutic strategies targeting cardiovascular health patients with MDS.

Features of the clinical picture and course of GATA2 deficiency complicated by generalized verrucosis with an outcome in myelodysplastic syndrome in adulthood

GATA2 deficiency is a rare disease belonging to the group of phagocyte birth defects, which is clinically manifested by four syndromes: MonoMac syndrome (myedysplasia and immunodeficiency associated with the development of infections caused by Mycobacterium avium complex); monocyte, dendritic cell, B- and NK-lymphocyte deficiency syndrome; Emberger syndrome, including primary lymphedema with myelodysplasia and sensorineural hearing loss, as well as familial myelodysplastic syndrome and acute myeloid leukemia. The disease is inherited by autosomal dominant type, but in most cases, mutations ofthe germ line of the GATA2 gene occur de novo. The first manifestations of the disease occur in early adulthood, the course of GATA2 deficiency is variable and may differ in individuals in the same family with similar genetic variants. The article presents a clinical case of manifestation of GATA2 deficiency at the age of seven years in the form of development of generalized verrucosis, lymphostasis of the lower limb, generalized tuberculosis with involvement of the abdominal cavity, small pelvis, and chest organs. The examination revealed deficiency of monocytes, B- and NK-lymphocytes, myelodysplastic syndrome with multilineage dysplasia. We present a detailed description of the clinical picture and peculiarities of the course of the primary immunodeficiency state, the results of the examination and treatment.

Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups: Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study.

Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study. We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity). The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), and SRSF2 (16% v 16%; P = .99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P < .001). Among those with a TP53 mutation, OS was similar between TP53single versus TP53multihit (22% ± 8% v 20% ± 6% at 3 years; P = .31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P = .04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P < .001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P = .001). HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.

A Personalized Risk Model for Azacitidine Outcome in Myelodysplastic Syndrome and Other Myeloid Neoplasms Identified by Machine Learning Model Utilizing Real-World Data.

Azacitidine is an approved therapy for higher-risk myelodysplastic syndrome (MDS). However, only 30-40% patients respond to azacitidine, and the responses may take up to six cycles to become evident. Delayed responses and the myelosuppressive effects of azacitidine make it challenging to predict which patients will benefit. This is further compounded by a lack of uniform prognostic tools to identify patients at risk of early treatment failure. Hence, we performed a retrospective analysis of 273 consecutive azacytidine-treated patients. The median overall survival was 16.25 months with only 9% alive at 5 years. By using pre-treatment variables incorporated into a random forest machine learning model, we successfully identified those patients unlikely to benefit from azacytidine upfront (7.99 vs. 22.8 months, p < 0.0001). This model also identified those who required significantly more hospitalizations and transfusion support. Notably, it accurately predicted survival outcomes, outperforming the existing prognostic scoring system. By integrating somatic mutations, we further refined the model and identified three distinct risk groups with significant differences in survival (5.6 vs. 10.5 vs. 43.5 months, p < 0.0001). These real-world findings emphasize the urgent need for personalized prediction tools tailored to hypomethylating agents, reducing unnecessary complications and resource utilization in MDS treatment.

On the basis of sex: outcomes in myelodysplastic syndromes

Sex has long been relevant in patients with myelodysplastic syndromes given there is a higher prevalence1 and poorer prognosis2 among men compared with women. However, this relationship has been traditionally viewed as one that is confounded by disease genetics or caused by differential responses to therapy,3 and not necessarily as an independent prognostic factor. In The Lancet Haematology, the GenoMed4All consortium4 used large European population datasets to challenge this dogma. The authors' data show that male sex is associated with a poorer prognosis in myelodysplastic syndromes than female sex, particularly in patients with low-risk prognostic scores according to the Revised International Prognostic Scoring System (IPSS-R).

Characterization of TP53-Mutated Myelodysplastic Syndromes and Impact of Allelic Status and Concurrent Cytogenetic Abnormalities on Survival Outcomes

BackgroundTP53 mutations (TP53mt) are associated with dismal outcomes in myelodysplastic syndromes (MDS). However, clinical and biological heterogeneity among TP53mt MDS patients (pts) exists, including the prognostic relevance of mono- vs biallelic TP53mt. The newly proposed WHO 2022 and ICC 2022 classifications recognize TP53mt as a unique entity but vary in its definition. We aimed to assess the impact of TP53 allelic status and complex cytogenetics in different clinical subsets of TP53mt MDS. Methods A total of 2355 MDS pts with annotated clinical and molecular data treated at Moffitt Cancer Center were analyzed. We defined MDS with biallelic TP53 inactivation (biTP53) according to the 5th edition of the WHO classification. Biallelic status was determined by VAF ≥50%, 2 or more TP53mt and/or TP53mt with deletion 17/17p abnormalities. Pts were classified into IPSS-R lower risk (LR) and higher risk (HR) strata by merging IPSS-R VL, L and I categories, as well as H and VH groups. Results A total of 490 pts (21%) harbored a TP53mt. Of these, 78% (382) were biTP53 and 22% (108) maTP53. Median duration of follow-up was 4.7 years (4.4-4.9). Pts harboring TP53mt had significantly shorter OS relative to their TP53wt counterparts: median OS 1.2 yrs vs 4 yrs (p<.001). Median OS was worse for the biTP53 subset compared to maTP53: 1.0 yrs (0.9-1.1) vs 1.3 yrs (1.1-1.6; p<.001). Compared to those harboring TP53wt, pts with maTP53 had double the risk of death: HR 2.1 (1.8-2.5). For pts with biTP53 the risk quadrupled: HR 4.0 (3.4-4.7). Both were significant at p<.001. Patients harboring complex (CK) vs non-complex (nCK) karyotypes had inferior mOS of 1.0 yrs (0.9-1.1) vs 2.1 yrs (1.5-2.7; p<.001). Compared to TP53wt, the risk of death was higher for TP53 with CK [HR 4.7 (4.1-5.4)] than for TP53 with nCK [HR 1.5 (1.2-1.8)], both significant at p<.001. Among patients with nCK, allelic state had significant impact on outcomes: mOS for maTP53 was 2.8 yrs (2.0-3.6) vs 1.2 yrs (0.6-1.8) for biTP53 (p<.001; Figure 1). Compared to TP53wt, HR for death for maTP53 was 1.2 (0.9-1.5, p=.21) and for biTP53 was 2.7 (1.9-3.8, p<.001). There was no survival distinction between maTP53 and biTP53 among pts with CK (p=0.780; Figure 1). Both had mOS of 1 yr (0.9-1.2) and were associated with worse outcomes compared to CK TP53wt (p<0.001). Among pts with LR disease, outcomes were significantly worse for those harboring TP53mt: mOS for TP53wt was 5.2 yrs (4.7-5.7) compared to 3.3 yrs (1.6-5.0, p<.001) for maTP53 and 2.1 yrs (0-4.4, p<.001) for biTP53. There were no differences between maTP53 and biTP53 (p=.2). Allelic status remained significant in HR disease (p=.033), where mOS was worse for biTP53 compared to maTP53: 0.9 yrs (0.8-1.0) vs 1.1 yrs (1.0-1.2). Similarly, allelic state had value in pts with <5% and ≥5% blasts. Among pts with <5% blasts, TP53wt mOS was 4.8 yrs (4.3-5.4) vs 2.5 yrs (1.7-3.3) for maTP53 and 1.3 yrs (0.9-1.7) for biTP53 (p=.032). Outcomes were worse among TP53mt pts with ≥5% blasts: mOS for TP53wt was 1.7 yrs (1.6-1.9), with distinction between maTP53 and biTP53: 1.2 yrs (1.0-1.2) and 0.9 yrs (0.8-1.0) respectively (p=.005). For the <5% group, the median VAF in maTP53 was 19.5% and 40% in biTP53. For the ≥5% group, the median VAF in maTP53 was 24% (95) and 47.3% (158) in biTP53. There were no differences in outcomes using 10% blast burden as cutoff. ConclusionTP53mt MDS demarcates a heterogenous group, whose behavior is influenced by allelic status and cytogenetic architecture. TP53mt patients have poor prognosis with ≥5% blasts without distinction from a 10% cutoff. In TP53mt disease, allelic state has strong significance in pts with non-CK, and retains significance independent of IPSS-R strata and myeloblast percentage, albeit with marginal differences. Notably, CK matters independent of allelic status and is invariably associated with worse outcomes. TP53mt with CK should homogenously be considered a biallelic equivalent. This has important implications for future trial design where distinction of allelic state and CK carries relevance. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Transfusion Patterns during Early Follow-up Predict Overall Survival Independently of IPSS-M in Patients with Myelodysplastic Syndromes

Background: The cumulative red blood cells (RBC) transfusion burden is known to impact outcomes in myelodysplastic syndromes (MDS) but doesn't accurately predict prognosis during the early disease phase. Here we aimed to assess the prognostic value of early changes in transfusion patterns in addition to the recent IPSS-M scoring system. Methods: We gathered diagnostic biobank samples from adult patients (pts) with MDS and registered in the Karolinska Institute's biobank (KI) and the National Swedish MDS Biobank (NB) between 2003-2017 and 2013-2017, respectively. DNA targeted sequencing (152 genes) was performed (Bernard et al., NEJM Evid, 2022). Clinical data was retrieved through pts’ charts (KI) and the Swedish cancer registry (NB). Pts were treated according to Nordic/EU guidelines and most common therapies for lower-risk MDS and higher-risk MDS were erythropoietin and azacytidine, respectively. Transfusion data was obtained from the SCANDAT registry. Pts were followed with regards to RBC transfusion until censored due to death, transformation to acute myeloid leukemia (AML-t), allogenic stem cell transplantation (allo-SCT), or end of follow-up on the 31st of August 2018, whichever occurred first. As per the IWG hematological response criteria for MDS (Platzbecker et al., Blood 2019), transfusion states (TS) were categorized every 4 months (m) as transfusion dependent (TD) or transfusion free (TF) during the past 4 m period. Lower-risk MDS (LR) was defined as IPSS-M very low, low and moderate low, and higher-risk MDS (HR) as IPSS-M very high, high and moderate high at diagnosis (Bernard et al., NEJM Evid, 2022). Landmark analyses of overall survival (OS) were performed with the Kaplan-Meier method for estimating probabilities of OS over time. Multivariable analyses were conducted using Cox proportional hazards model. Results: We gathered a cohort of 688 pts with MDS from KI (n=424) and 33 other clinics in Sweden (NB, n=264). Median age at diagnosis was 74 years (y) old (range 19-93). The male:female ratio in the cohort was 1.4. At diagnosis, 63% of the pts were TF. Out of 646 pts evaluable by the IPSS-M score at diagnosis 54% had LR. Most frequently mutated genes in the cohort were TET2, SF3B1, ASXL1, DNMT3A, RUNX1, TET2, TP53 (66% TP53 multihit), U2AF1, STAG2, ZRSR2. Changes between TS (transitions) preferentially occurred within a year after diagnosis (panel A) with a median time for occurrence of transfusion-related transitions of 1.0 y (range 0.33-8.37). Based on this finding, we assessed whether TS at 8 m landmark impacted prognosis. We observed that there was a significant difference in OS since landmark between TF pts compared with TD pts at landmark 8 m and across IPSS-M categories (panel B). LR pts who were TD at 8 m, had a median OS of 3.2 y (95% CI: 2.2-4.0) versus 6.9 y (95% CI: 5.6-8.9) for LR pts who were TF (P<0.0001). Similarly, median OS was 0.8 y (95% CI: 0.6-1.1) in HR and TD pts while it was 2.4 y (95% CI: 2.1-3.1) in HR and TF pts at landmark 8 m (P<0.0001). Interestingly, OS for LR pts who were TD didn't significantly differ from HR pts who were TF at 8 m. Overall, pts TD at 8 m had more gene mutations compared to TF pts (median 5 [1;13] and 4 [1;16], respectively, P=0.0084). Moreover, studying specific genetic subgroups of MDS, TS at 8 m distinguished subsets of pts with adverse or favorable outcomes within SF3B1-mutated LR pts. In this population, the median OS in pts TF at 8 m was 8.4 y (95% CI: 6.5-13.1) compared to 3.2 y (95% CI: 1.7-4.1) for TD pts (P<0.0001). Next, in multivariable analysis, we found that TD at 8 m significantly impacted OS (HR=2.4 [95% CI: 1.9-3.1]), independently of diagnostic IPSS-M score, age, gender and type of MDS (de novo or therapy-related). Conclusion: TS at landmark 8 m, usually after outcome of first-line treatment was evaluated, appears to be a strong and independent predictor of OS in MDS. These findings are of particular importance for the LR group in which it could discriminate subsets with favorable outcomes from those with adverse prognosis. In addition to the IPSS-M calculation at diagnosis, transfusion dependency could be easily used for prognostic reassessment during follow-up. More generally, these results highlight the need of dynamic outcomes prediction tools and/or validation of current prognostic scores in dynamic settings. Finally, multistate modeling of the dataset is being completed and aims to assess how changes of transfusion patterns over time impact prognosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immunohistochemical loss of enhancer of Zeste Homolog 2 (EZH2) protein expression correlates with EZH2 alterations and portends a worse outcome in myelodysplastic syndromes

AbstractEZH2 coding mutation (EZH2MUT), resulting in loss-of-function, is an independent predictor of overall survival in MDS. EZH2 function can be altered by other mechanisms including copy number changes, and mutations in other genes and non-coding regions of EZH2. Assessment of EZH2 protein can identify alterations of EZH2 function missed by mutation assessment alone. Precise evaluation of EZH2 function and gene-protein correlation in clinical MDS cohorts is important in the context of upcoming targeted therapies aimed to restore EZH2 function. In this study, we evaluated the clinicopathologic characteristics of newly diagnosed MDS patients with EZH2MUT and correlated the findings with protein expression using immunohistochemistry. There were 40 (~6%) EZH2MUT MDS [33 men, seven women; median age 74 years (range, 55–90)]. EZH2 mutations spanned the entire coding region. Majority had dominant EZH2 clone [median VAF, 30% (1–92)], frequently co-occurring with co-dominant TET2 (38%) and sub-clonal ASXL1 (55%) and RUNX1 (43%) mutations. EZH2MUT MDS showed frequent loss-of-expression compared to EZH2WT (69% vs. 27%, p = 0.001). Interestingly, NINE (23%) EZH2WT MDS also showed loss-of-expression. EZH2MUT and loss-of-expression significantly associated with male predominance and chr(7) loss. Further, only EZH2 loss-of-expression patients showed significantly lower platelet counts, a trend for higher BM blast% and R-IPSS scores. Over a 14-month median follow-up, both EZH2MUT (p = 0.027) and loss-of-expression (p = 0.0063) correlated with poor survival, independent of R-IPSS, age and gender. When analyzed together, loss-of-expression showed a stronger correlation than mutation (p = 0.061 vs. p = 0.43). In conclusion, immunohistochemical assessment of EZH2 protein, alongside mutation, is important for prognostic workup of MDS.

A Novel Prognostic Scoring Model for Myelodysplastic Syndrome Patients With SF3B1 Mutation.

The outcomes of myelodysplastic syndrome (MDS) patients with SF3B1 mutation, despite identified as a favorable prognostic biomarker, are variable. To comprehend the heterogeneity in clinical characteristics and outcomes, we reviewed 140 MDS patients with SF3B1 mutation in Zhejiang province of China. Seventy-three (52.1%) patients diagnosed as MDS with ring sideroblasts (MDS-RS) following the 2016 World Health Organization (WHO) classification and 118 (84.3%) patients belonged to lower risk following the revised International Prognostic Scoring System (IPSS-R). Although clonal hematopoiesis-associated mutations containing TET2, ASXL1 and DNMT3A were the most frequent co-mutant genes in these patients, RUNX1, EZH2, NF1 and KRAS/NRAS mutations had significant effects on overall survival (OS). Based on that we developed a risk scoring model as IPSS-R×0.4+RUNX1×1.1+EZH2×0.6+RAS×0.9+NF1×1.6. Patients were categorized into two subgroups: low-risk (L-R, score <= 1.4) group and high risk (H-R, score > 1.4) group. The 3-year OS for the L-R and H-R groups was 91.88% (95% CI, 83.27%-100%) and 38.14% (95% CI, 24.08%-60.40%), respectively (P<0.001). This proposed model distinctly outperformed the widely used IPSS-R. In summary, we constructed and validated a personalized prediction model of MDS patients with SF3B1 mutation that can better predict the survival of these patients.

The impact of oral hypoglycemics and statins on outcomes in myelodysplastic syndromes.

Observational studies suggest an anti-neoplastic effect associated with statins, metformin, and dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. We linked the Ontario subset of a prospective Canadian myelodysplastic syndromes (MDS) registry with provincial administrative databases. We assessed the impact of statin/oral hypoglycemic medication exposure on overall survival (OS) using Cox regression analysis, controlling for comorbidities and sociodemographic factors. Five hundred thirty-three patients aged ≥ 66years were included: 49.3% used statins, 18.9% used metformin, 9.0% used sulfonylureas, and 6.4% used DPP4i. Three hundred ninety-five patients were lower-risk based on the International Prognostic Scoring System. On univariate analysis, we identified a marginal improvement in OS in the lower-risk group using DPP4i (HR 0.98, 95% CI 0.95-1.00, P = 0.05), while there was no impact on mortality for higher-risk DPP4i users (HR 1.03, CI 0.99-1.07, P = 0.21). There was no mortality difference for statins (HR 1.00, CI 1.00-1.01, P = 0.93), metformin (HR 1.00, CI 0.99-1.01, P = 0.81), or sulfonylureas (HR 1.00, CI 0.99-1.02, P = 0.43) in the entire cohort, as well as when stratified into lower/higher-risk groups. On multivariable analysis in the lower-risk group, there was no association between DPP4i and OS (HR 0.98, CI 0.95-1.00, P = 0.06). Prospective studies with larger cohorts of patients and longer follow-up are required to further study the impact of DPP4i in MDS.

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.

Dysregulation of immune cell and cytokine signalling correlates with clinical outcomes in myelodysplastic syndrome (MDS).

Myelodysplastic syndromes (MDS) are characterised by ineffective haematopoiesis. Although hypomethylating agents (HMA) have improved survival in higher-risk MDS, most patients eventually succumb to progressive disease. Utilising samples collected prospectively from three MDS clinical trials, we analysed genetic and immunological biomarkers and correlated them with clinical outcomes. A hundred and fifty four samples were analysed from 133 de novo MDS patients for T-cell and myeloid cell immunophenotyping and gene expression analysis. Treatments were with HMA or immunomodulatory drug (IMiD) alone or in combination. We observed differences in immune cell subsets between lower- and higher-risk IPSS groups with NKT cells, MDSCs, intermediate-proinflammatory and non-classical monocytes being higher in the latter group, while naïve CD4+ T cells were reduced. Intermediate-proinflammatory monocytes were increased in non-responders and those failing to achieve at least a haematological improvement. Proinflammatory NKT cells were increased at diagnosis for patients failing to derive clinical benefit after 12months of treatment. Gene expression analysis of paired bone marrow (BM) colony-forming units (CFUs) from diagnosis and 4 cycles post-treatment confirmed that genes involved in cytokine signalling were downregulated in C4 normal colonies. These findings support the central roles of dysregulation in innate immunity and inflammatory signalling in the pathogenesis of MDS which correlated with clinical outcomes post-treatment.

Predictive values of mutational variant allele frequency in overall survival and leukemic progression of myelodysplastic syndromes.

The implication of mutational variant allelic frequency (VAF) has been increasingly considered in the prognostic interpretation of molecular data in myeloid malignancies. However, the impact of VAF on outcomes of myelodysplastic syndromes (MDS) has not been extensively explored. Targeted next-generation sequencing was performed in 350 newly diagnosed MDS cases. The associations of mutational VAF of each gene with overall survival (OS) and leukemia-free survival (LFS) were examined by multivariate Cox regression after univariate analysis. Shorter OS was independently associated with DNMT3A VAF (HR 1.020 per 1% VAF increase; 95% CI 1.005-1.035; p = 0.011) and TP53 VAF (HR 1.014 per 1% VAF increase; 95% CI 1.006-1.022; p = 0.001). LFS analyses revealed that TET2 VAF (HR 1.013 per 1% VAF increase; 95% CI 1.005-1.022; p = 0.003) and TP53 VAF (HR 1.012 per 1% VAF increase; 95% CI 1.004-1.021; p = 0.005) were independently associated with faster leukemic transformation. Furthermore, we established nomograms to predict OS and LFS, respectively,by integrating independent mutational predictors into the revised International Prognostic Scoring System. Our study highlights that VAF of certain genes should be incorporated into routine clinical prognostication of survival and leukemic transformationof MDS.

Improving patient understanding and outcomes in myelodysplastic syndromes - An animated patient guide to MDS with visual formats of learning

ObjectivesPatient education resources that address barriers to health literacy to improve understanding and outcomes in myelodysplastic syndromes (MDS) are limited. The aim of this study was to evaluate the impact and outcomes benefits of An Animated Patient's Guide to Myelodysplastic Syndromes (MDS) cancer educational modules (which includes the ‘You and MDS’ website and YouTube hosted resources) related to MDS education, awareness, understanding and health outcomes. MethodsThis was a retrospective study of learner feedback, metrics, and utilization data from July 2018 to August 2021. We evaluated audience reach (number of visit sessions, unique visitors, page views) and calculated top views by media type (animation, expert video, patient video, and slide show) and top retention videos from the modules. We also assessed the educational impact and utilization through learner feedback surveys. ResultsDuring the study period, ‘You and MDS’ had 233,743 views worldwide of which 104,214 were unique visitors and 78,161 (or 76% unique visitors) were from the United States. Of these, 61% were patients; 29% family members or caregivers; 5% were healthcare providers and 5% represented other groups. Most popular topics viewed among the animations were “Understanding Myelodysplastic Syndromes (MDS)” (40,219 views), “Managing and Treating MDS” (19,240 views), “Understanding Erythropoiesis” (17,564 views.) The most popular expert videos viewed were “What is iron overload, and how it is treated?” (20,310 views), “How serious a cancer is MDS? What is the prognosis for MDS?” (8,327 views), “What is MDS?” (3,157 views). Of participants who completed the online feedback survey, ≥ 95% reported improved knowledge gains and commitments to change. ConclusionsMDS patients using ‘You and MDS - An Animated Patient's Guide to MDS’ and its visual formats of learning represented a wide U.S. and global learner audience. This MDS educational resource had a significant impact on improved understanding among patients, families, and caregivers. Continued efforts should be made to provide patient-effective resources that address health literacy, improve patient understanding, and address educational needs that respond to the concerns of patients to achieve better quality of life and improved health outcomes in MDS.

Identification of Novel Prognostic Biomarkers DDX11 and CHD1 of Allogeneic Hematopoietic Cell Transplantation Outcomes for Patients with MDS: A CIBMTR Comprehensive Genomic Screening

BACKGROUNDMyelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid malignancies characterized by cytopenia and increased risk of progression to acute myeloid leukemia (AML) driven by accumulated somatic mutations in hematopoietic stem cells (HSCs). While recurrent mutations are known to associate with adverse outcomes in myelodysplastic syndrome (MDS), 10% of MDS cases have no known genetic indicators for survival prognosis. Whole genome sequencing (WGS) detects comprehensive mutations on coding and non-coding regions that empowers discovery of novel genetic biomarkers.METHODSWe conducted WGS at 60x read depth on 494 MDS patient subjects and scanned genome-wide for novel somatic biomarkers associated with MDS post allogeneic hematopoietic cell transplantation (allo-HCT) outcomes. Forward and backward stepwise variable selection was performed, and important clinical covariables were integrated into multivariate Cox proportional hazard models for survival outcome association tests. To test for associations with overall survival (OS), we conducted burden tests of somatic variants by summing the number of somatic nonsynonymous (missense, nonsense, splice) mutations per gene and testing for association with OS. For non-coding regions, we applied a sliding window approach, summing somatic mutations within each 10kb window and testing for association with OS. Furthermore, to distinguish potentially novel biomarkers from mutations in known MDS prognostic genes, we re-ran our association analyses considering only those MDS subjects with no known mutations in previously-identified prognostic genes for post allo-HCT survival(including TP53, RAS, JAK2, TET2, EZH2, ETV6, RUNX1, DNMT3A and ASXL1).RESULTSGenome-wide analyses of somatic coding variants on OS identified two statistically significant associations (Figure 1A I); one at TP53 (hazard ratio [HR], 2.19; 95% confidence intervals [CI] 1.48-2.75; P = 1.51e-06) and the other at HCN2 (HR, 5.84; 95% CI 2.38-14.34; P=1.18E-04). When we restricted our analyses to those patients with no mutations in known prognostic genes (N=301), we found one statistically significant candidate at DDX11 (HR, 3.74; 95% CI 1.87-7.47; P=1.83E-04). When we expanded our analyses to include non-coding somatic variants, we observed five additional significant genes (Figure 1A II, IV) including CHD1 (HR, 7.31; 95% CI 3.33-16.08; P=7.45E-07) that was significantly associated with post allo-HCT OS in the patient subset with no known mutations. Meta-analyses of OS using TCGA lymphoma and AML/MDS data provided validation that DDX11 and CHD1 mutations are associated with poor overall survival in hematopoietic malignancies (data not shown).Interestingly, many of the candidates from these analyses (e.g., DDX11, CHD1, RASGRF1 and ARHGEF7) are involved in DNA repair pathways. Gene set enrichment analyses confirmed that our association results are enriched a TP53-centered networks (p value: 0.0042, Figure 1B).Besides the novel candidates, a known MDS prognostic gene TP53 was replicated by our nonbiased screening approach. Co-occurrence of TP53 mutation and complex karyotypes, as well as high VAF of TP53 mutations in our MDS cohort were highly associated with poor post allo-HCT OS (data not shown). MDS patients with TP53, DDX11 and CHD1 mutations were overrepresented in samples with complex karyotypes.CONCLUSIONSOverall, through WGS of samples obtained at the time of allo-HCT, we identified two novel genetic prognostic biomarkers, DDX11 and CHD1 mutations, which were associated with inferior post allo-HCT OS. These results once validated could contribute to personalized risk assessments of post HCT outcomes for MDS patients. [Display omitted] DisclosuresSaber: Govt. COI: Other.

The Impact of Oral Hypoglycemics and Statins on Outcomes in Myelodysplastic Syndromes

The Impact of Oral Hypoglycemics and Statins on Outcomes in Myelodysplastic Syndromes

Lymphocytic Infiltrate and p53 Protein Expression as Predictive Markers of Response and Outcome in Myelodysplastic Syndromes Treated with Azacitidine.

High-risk Myelodysplastic syndromes (MDS) represent therapeutical challenges and are usually managed with hypomethylating agents such as azacitidine. Given the lack of data in the literature concerning azacitidine effects on bone marrow, we retrospectively analyzed 57 high-risk MDS cases in order to identify any changes induced by azacitidine therapy or relevant correlations between therapy response and pre- or post-treatment features. Azacitidine treatment had no significant impact on bone marrow cellularity or morphological dysplastic features. On the contrary, although not statistically significant, we observed a slight decrease in CD34+ and CD117+ blasts and p53+ precursors after treatment. Moreover, pre-treatment IPSS-R cytogenetic score (p = 0.004), lymphocytic infiltrate (p = 0.017) and p53+ elements (p = 0.001) correlated with AML progression; pre-treatment lymphocytic infiltrate was also linked to better response to therapy (p = 0.004), suggesting an anti-tumoral role of bone marrow microenvironment. Post-treatment blast count impacted negatively on overall survival (p = 0.035) and risk of leukemic progression (p = 0.04), while both post-treatment lymphocytic infiltrate and p53+ elements showed significant correlation with treatment response (p = 0.004 and p = 0.003 respectively). Higher post-treatment p53+ elements correlated also with risk of leukemic progression (p = 0.013). Our results suggest the possible role of lymphocytic infiltrate and p53+ elements as predictive markers in MDS treated with azacitidine, disclosing new chapters in the understanding of MDS evolution and treatment.

Common Fetal Hemoglobin Variants Modify Hematological Phenotypes in MDS/MPN/Myeloma Patients Receiving Cytotoxic Drugs

Background: Genetic studies have identified common variants within the HBS1L-MYB intergenic polymorphism (HMIP) region on chromosome 6q, BCL11A on chromosome 2p, and Xmn 1- HBG2 (rs748214) as associated with elevated fetal hemoglobin (HbF) levels and other clinically important human hematological traits. A recent study suggested that HbF is a predictor of outcome in myelodysplastic syndrome (MDS)/acute myeloid leukemia patients receiving decitabine. We set out to evaluate the genotypic significance of HbF and its effect on hematological traits in patients with myeloproliferative neoplasm (MPN), myeloma and MDS treated with HbF-inducing cytotoxic agents to determine potential of the HbF-associated variants for prediction of treatment response in these conditions.Methods: 89 patients - 44 with MPN on Hydroxyurea (HU), 33 with myeloma on Lenalidomide, and 12 with MDS on Azacytidine were recruited from hematology clinics at Brighton & Sussex NHS Trust, UK. Blood samples were obtained from patients with written consent and analyzed for HbF/hematological parameters. 7 common HbF variants (rs6545816 and rs1427407 on BCL11A, rs9494142, rs6920211, rs9494145, and rs66650371 in HMIP, and rs748214) were genotyped on DNA extracted from peripheral blood using Taqman procedure. A subset of the patients (N = 16) (7 MPN, 6 myeloma and 3 MDS patients) had baseline values before starting therapy and had repeat values 3 months after cytotoxic agent initiation. The study was approved by the local and national UK NHS Research Ethics Committee (REC) (reference 14/WA/1078). Statistical analysis to test and graph genetic association of blood traits was performed with linear regression (IBM SPSS Statistics 24) with a genotypic genetic model adjusting for age and sex as covariates and analysis of variance determining genotype effect and mean HbF. Hardy-Weinberg test was performed on all genotype results for quality assurance. Hematological parameters which did not satisfy assumptions of normality were log-transformed.Results: HbF variants genotyped in our hematological malignancy study population had significantly discordant minor allele frequencies (MAF) differing in comparison to MAF from wider British/European population data derived from 1000 Genome project with MDS having greatest MAF discordance (see Fig. 1). Amongst the total hematological malignancy group, HMIP variants were statistically associated with higher baseline and induced HbF levels as well as lower WBC (see Table 1). Amongst MPN patients on HU, rs9494142 (HMIP) was observed as significantly associated with induced HbF levels (p = 0.04) in addition to increased baseline platelet count (p = 0.04) (see Table 1). These variants were seen to affect different hematological parameters at different stages of treatment as observed with HMIP variants rs9494142 and rs6920211 shifting from their regulation of baseline platelet levels to the regulation of induced hemoglobin levels (p = 0.02) 3 months post cytotoxic agent initiation. Amongst the Myeloma group, rs6920211(HMIP) was significantly associated with baseline HbF (p < 0.001). BCL11A variant rs1427407 was strongly associated with induced HbF levels with Lenalidomide (p = 0.002). rs1427407 was also significantly associated with increased platelet count (p = 0.04) negating the thrombocytopenic tendency of Lenalidomide (see Table 1). Xmn 1- HBG2 (rs748214) was not observed to have any statistically significant association with HbF but was associated with decreased hemoglobin (p = 0.03) in Myeloma and increased levels of hemolysis markers (reticulocytes (p = 0.003) and lactate dehydrogenase (p = 0.001)) in MPN patients on HU.Conclusion: Although our sample size is small,the data suggests that the common HbF variants influence HbF and hematological traits in MDS, MPN, and myeloma and that the variants may potentially be involved in disease biology and treatment response in these conditions. The study also suggests HbF acts as a marker for the presence of the genetic variants that influences the hematological response in MDS/AML in the previous study. We hope that this study stimulates a larger prospective genotype-phenotype association studies of these disorders with the HbF variants. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.