Myelodysplastic Syndromes Registry Research Articles

Comparison of cytomorphology and histomorphology in myelodysplastic syndromes.

Gold standard for the establishment of the diagnosis of myelodysplastic syndromes (MDS) are cytomorphological features of hematopoietic cells in peripheral blood and bone marrow aspirates. There is increasing evidence that bone marrow histomorphology not only aids in the diagnosis of MDS but can provide additional prognostic information, particularly through assessment of fibrosis and cellularity. However, there is only sparse data on direct comparison between histological and cytomorphological findings within the same MDS patient cohort. Therefore, we performed such an analysis under exceptionally well-standardized conditions. We reexamined biopsy material of 128 patients from the Düsseldorf MDS registry who underwent bone marrow trephine biopsy (in addition to bone marrow aspiration) at the time of diagnosis, addressing the following items: a. Analysis of concordance of diagnoses made by histology and cytomorphology b. Analysis of additional information by histology with regard to the diagnosis and prognosis. The respective biomaterials were available at our institution and had been processed according to unchanged protocols between 1992 and 2010. Fresh histopathological sections were obtained from the tissue blocks, stained under identical conditions and re-assessed by a designated expert pathologist (C.B.) without knowledge of the previous histopathological report or the respective cytomorphological diagnosis. The latter, likewise, was uniformly made by the same expert cytomorphologist (U.G.). Histopathology of bone marrow trephine biopsies reliably captured the diagnosis of MDS. Assignment to the diagnostic WHO subgroup was not entirely concordant with cytomorphology, mainly due to incongruences between the proportion of CD34-positive cells on histopathology and the cytomorphological blast count. Histopathology provided additional diagnostic and prognostic information with high diagnostic and prognostic significance, such as fibrosis. Likewise, histopathology allowed more reliable estimation of bone marrow cellularity.

Infectious Complications in Patients with Myelodysplastic Syndromes: A Report from the Düsseldorf MDS Registry.

Despite notable advancements in infection prevention and treatment, individuals with hematologic malignancies still face the persistent threat of frequent and life-threatening complications. Those undergoing chemotherapy or other disease-modifying therapies are particularly vulnerable to developing infectious complications, increasing the risk of mortality. Myelodysplastic syndromes (MDS) predominantly affect the elderly, with the incidence rising with age and peaking at around 70 years. Patients with MDS commonly present with unexplained low blood-cell counts, primarily anemia, and often experience varying degrees of neutropenia as the disease progresses. In our subsequent retrospective study involving 1593 patients from the Düsseldorf MDS Registry, we aimed at outlining the incidence of infections in MDS patients and identifying factors contributing to heightened susceptibility to infectious complications in this population.

Validation of a novel algorithm with a high specificity in ruling out MDS.

A previously published web-based App using Gradient-boosted models (GBMs) of eight laboratory parameters was established by Oster et al. to facilitate diagnosis or exclusion of myelodysplastic syndromes (MDS) in patients. To validate their algorithm, we compared 175 anemic patients with MDS diagnosis from our German MDS Registry with 1378 non-MDS anemic patients who consulted various specialties in the Düsseldorf university hospital. Based on hemoglobin level, leukocyte and platelet count, mean corpuscular volume, absolute neutrophil count, absolute monocyte count, glucose and creatinine, plus the patients' gender and age, we could not reproduce a high negative predictive value (NPV), but confirmed a useful specificity of 90.9% and a positive predictive value (PPV) of 77.1%. 1192 of 1378 controls were correctly categorized as "probably not MDS (pnMDS)" patients. A total of 65 patients were wrongly classified as "probable MDS (pMDS)," of whom 48 had alternative explanations for their altered laboratory results. In a second analysis, we included 29 patients with chronic myelomonocytic leukemia (CMML) resulting in only one label as possible MDS, suggesting that highly proliferative bone marrow disorders are correctly excluded. The possibility of reliably excluding MDS from differential diagnosis based on peripheral blood lab work appears to be attractive for patients and physicians alike while the confirmation of MDS diagnosis still requires a bone marrow biopsy.

Single-Hit TP53mut Is Associated with Poor Outcomes in Therapy-Related but Not De Novo Myelodysplastic Syndromes: Importance of Clinical History

BACKGROUND: Recent World Health Organization (WHO) classifications (5 th edition), International Consensus Classification (ICC) recognized TP53-mutated ( TP53mut) myeloid neoplasms (MNs) as a distinct subcategory, acknowledging their uniformly poor outcomes. However, there are critical differences between the two guidelines in how TP53 allelic status is assigned. Both WHO-5 and ICC acknowledged the poor outcome of multi-hit TP53mut but excluded single-hit TP53mut. These changes are driven by a pivotal study demonstrating favourable outcome of single-hit TP53mut, however this study predominantly included de novo myelodysplastic syndromes (MDS) cases (Bernard et al. Nat Med 2020). In contrast, we previously reported poor outcome of TP53mut therapy-related myeloid neoplasm (t-MN) irrespective of the allelic status of TP53 (Hiwase et al Blood 2022andShah et al BCJ 2023). Finally, the ICC removed the subcategory of “therapy-related,” substituting it with diagnostic qualifiers instead. The WHO has grouped t-MN with secondary MN and renamed it as “myeloid neoplasm post cytotoxic therapy,” with the assertion that only multi-hit T P53mut MDS occurring post-cytotoxic therapy have poor outcome compared with single-hit. METHODS: We analyzed one of the largest international cohorts of TP53mut MN (n=544) with full characterization of TP53mut allele status utilizing uniform ICC criteria and similar large numbers of de novo and t-MN cases managed at Mayo Clinic Enterprise (USA) and South Australian MDS Registry, Adelaide (Australia) with clinical, integrated genomic profiling, and long-term follow-up. RESULTS: In our cohort of TP53mut MN (n=544), 475 (87.3%) MN had TP53mut variant allele frequency (VAF) of ≥10% and thus satisfied ICC criteria for TP53mut MN. Majority of TP53mut t-MN presented with MDS (bone marrow (BM) blasts 0-9%) compared de novo MN (62% vs. 48%; P=0.0012). While acute myeloid leukemia (AML) (BM blasts ≥20%) were more prevalent in TP53mutde novo MN compared to t-MN (38% vs. 24%; P= 0.001) and there was no difference in frequency of MDS/AML (BM blasts 10-19%) between the two cohorts (14% vs. 14%; P=0.8) ( Figure 1A). Majority of TP53mut were observed in the DNA-binding domain in t-MN and de novo MN (95% vs. 96.2%; P=0.48). However, mutations in Tetramer Domain were more frequent in t-MN (4.3% vs. 0.3%; P=0.002), whereas those in the TAD2 domain were more frequent in de novo TP53mut MN (2.4 vs. 0%; P =0.006). Integrating the mutation, conventional G-banding cytogenetic, copy number variation (CNV), FISH, and SNP array analysis, TP53mut MDS (BM blast 0-9%; n=260) were classified as multi-hit (n=179, 68.9%) or multi-equivalent (n=35, 13.5%) and single-hit (n=46, 17.7%) (Arber et al. Blood 2022). Striking enrichment of multi-hit/multi-hit equivalent was observed in TP53mut t-MDS compared to de novo MDS (91% vs. 72%; P<0.0001). While single-hit TP53mut were prevalent in de novo MDS compared to t-MDS (28% vs. 9%; P<0.0001). Importantly, median overall survival (OS) of single-hit was significantly longer than multi-hit de novo MDS (25.4 vs. 7.2 months; P=0.0002). In contrast to this we did not observe OS difference between single-hit and multi-hit TP53mut t-MDS (11.6 vs. 10.9 months; P =0.73) ( Figure 1B). CONCLUSION: Our study based on a large international cohort of T53mut MN provides compelling evidence that in contrast to de novo MDS, single hit TP53mut t-MDS is associated with poor outcome. Our data supports the consideration of single hit t-MDS as a multi-hit equivalent.

The Absolute Monocyte Count at Diagnosis Affects Prognosis in Myelodysplastic Syndromes Independently of the IPSS-R Risk Score.

The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well studied. Therefore, we investigated its potential prognostic value in a cohort from the Düsseldorf MDS registry in relationship to the revised international prognostic scoring system (IPSS-R). An AMC below the population's median (<0.2 × 109/L) was associated with several adverse disease features such as lower haemoglobin levels, lower count of neutrophils and platelets, and a higher percentage of blasts in the bone marrow. MDS patients with an AMC < 0.2 × 109/L had a significantly higher risk of progression into acute myeloid leukemia (AML). In a univariate, proportional hazards model the effect of the AMC as a continuous variable was modelled via p-splines. We found a U-shaped effect with the lowest hazard around 0.3 × 109/L. Accordingly, an AMC within the last quartile of the population (0.4 × 109/L) was associated with a reduced overall survival independently of IPSS-R, but not with the risk of secondary AML. Considering monocytopenia as a risk factor for AML progression in MDS may provide an additional argument for allogeneic transplantation or the use of hypomethylating agents in patients who are not clear candidates for those treatments according to current prognostic scoring systems and/or recommendations. Further studies are needed to assess the prognostic impact of the AMC in the context of prognostic scoring systems, considering the molecular risk profile, and to identify the mechanisms responsible for the higher mortality in MDS patients with a subtle monocytosis.

Impact of Frailty on Health Care Resource Utilization and Costs of Care in Myelodysplastic Syndromes.

The role of frailty in affecting survival in myelodysplastic syndromes (MDS) is increasingly recognized. Despite this, a paucity of data exists on the association between frailty and other clinically meaningful outcomes including health care resource utilization and costs of care. We linked the Ontario subset of the prospective Canadian MDS registry (including baseline patient/disease characteristics) to population-based health system administrative databases. Baseline frailty was calculated from the 15-item MDS-specific frailty scale (FS-15). Primary outcomes were public health care utilization and 30-day standardized costs of care (2019 Canadian dollars) determined for each phase of disease (initial, continuation, and terminal phases). Negative binomial regression was used to assess the association between frailty and health care costs with Poisson regression to explore predictors of hospitalization. Among 461 patients with complete FS-15 scores, 374 (81.1%) had a hospitalization with a mean length of stay of 10.6 days. Controlling for age, comorbidities, Revised International Prognostic Scoring System, and transfusion dependence, the FS-15 was independently associated with hospitalization during the initial (P = .02) and continuation (P = .01) phases but not the terminal disease phase (P = .09). The mean 30-day standardized cost per patient was $8,499 (median, $6,295; interquartile range, $2,798-$11,996), largely driven by cancer clinic visits and hospitalization. On multivariable analysis, the FS-15 was independently associated with costs of care during the initial disease phase (P = .02). We demonstrate an association between frailty and clinically meaningful outcomes including hospitalization and costs of care in patients with MDS. Our results suggest that baseline frailty may help to inform patients and physicians of expected outcomes.

Activation of Distinct Inflammatory Pathways in LR-MDS Is Determined By Genetics

Background Dysregulated innate immune signaling has been identified as a driver of the complex pathophysiology of myelodysplastic syndromes (MDS), predominantly in low risk (LR)-MDS (Basiorka et al., Blood 2016). The pharmacological targeting of inflammation may therefore help to retard disease development. However, since MDS is a heterogeneous disease, a personalized approach is likely to be necessary, requiring a more detailed knowledge of distinct inflammatory patterns and their variation between genetically defined subgroups of LR-MDS patients (Winter et al., J Clin Oncol 2020). Aims The aim of this work was to describe inflammation states in the bone marrow of LR-MDS patients (IPSS-R ≤ 3.5) compared to controls with and without clonal hematopoiesis of indeterminate potential (CHIP) and to high-risk (HR)-MDS patients (IPSS-R ≥ 4). Methods Cryopreserved bone marrow mononuclear cells (BM-MNCs) and corresponding bone marrow plasma samples from non-CHIP controls (n = 15), CHIP individuals (n = 12) and patients with LR-MDS (n = 47) or HR-MDS (n = 14) were obtained from the MDS registry and the BoHemE study (NCT02867085) at the University Hospitals in Dresden and Leipzig. Targeted expression analysis of 11 inflammasome-related genes (S100A9, NLRP3, PYCARD, CASP1, IL1B, IL18, NLRP1, NLRC4, AIM2, CASP3, CASP4) and multiplex cytokine measurements were performed. To investigate heterogeneity in the LR-MDS cohort, a principle component analysis (PCA) was performed and a cumulative gene expression score was calculated as summed log2 fold changes (mean non-CHIP = 0) of all 11 mRNA expression values for each sample. Furthermore, BM-MNCs of selected non-CHIP (n = 3) and CHIP (n = 3) individuals as well as LR-MDS (n = 14) and HR-MDS (n = 5) patients were FACS-sorted for hematopoietic stem and progenitor cells (HSPCs), monocytes, monocytic and polymorphonuclear myeloid-derived suppressor cells (MDSCs) and lymphocytes. The expression of IL1B, IL18, S100A9, NLRP3, PYCARD, CASP1 and NLRC4 was assessed in each population by qRT-PCR. Finally, colony forming assays were used to assess the effect of the IL-1β-neutralizing antibody canakinumab (100 µg/ml) on the hematopoietic potential of healthy CD34+ HSPCs pre-cultured with CD14+ monocytes from patients with SF3B1-mutated (n = 3) or del(5q) (n = 3) LR-MDS. Results The expression of inflammasome-related genes in the bone marrow increased from non-CHIP through CHIP to LR-MDS individuals, with overall levels of inflammasome-related gene expression being 40% higher in LR-MDS than in non-CHIP controls (p = 0.002). The precise signature of inflammation gene expression varied widely within LR-MDS patients. A PCA identified two separable inflammation states with low (cluster 1, n = 24) and high (cluster 2, n = 23) inflammation patterns (Figure 1), with CASP1, PYCARD and NLRC4 contributing most to the PCA dimensions. The clusters were associated with distinct clinical features and disease genotypes: more than 80% of the SF3B1 mutations were found in cluster 1, while all del(5q) cases were in cluster 2 (Figure 1). Compared to del(5q) samples, those with SF3B1-mutation showed lower expression of IL-1β at both mRNA (3.9-fold decrease, p = 0.0005) and protein level (8.3-fold decrease, p = 0.03). Targeted gene expression analysis of sorted cell populations revealed distinct contributions to the differential patterns of inflammation. IL1B, NLRP3, NLRC4 and S100A9 were expressed in all disease states predominantly by monocytes and monocytic MDSCs, consistent with a dominant role for monocytic cells in determining the inflammatory bone marrow environment. However, IL18 mRNA levels were highest in HSPCs. Compared to untreated controls, canakinumab augmented the colony forming activity of healthy HSPCs pre-cultured with monocytes from SF3B1-mutated MDS (+70%, p = 0.002). The effect in co-cultures with del(5q) MDS-derived monocytes was weaker (+56%, p = 0.188), showing that canakinumab efficacy in this assay does not depend on IL-1β expression level alone. Conclusion We conclude that inflammation patterns in LR-MDS are heterogeneous, highlighting the need for personalization of targeted anti-inflammatory therapies currently entering clinical trials. Our analysis suggests that high resolution studies of gene expression in specific populations or single cells will further resolve a spectrum of inflammation states relevant to prognosis and personalized therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Cytomorphology and Histopathology in Myelodysplastic Syndromes (MDS)

Introduction: Bone marrow cytomorphology, cytogenetics and molecular analyses are essential tools for diagnosing a myelodysplastic syndrome. MDS are characterized by dysplastic features of hematopoietic cells and may also show an increased blast cell count. Histopathology can provide additional information on bone marrow fibrosis and cellularity. We analysed correlations and differences between cytomorphological and histopathological findings at diagnosis. Patients and methods: In the Duesseldorf MDS registry, we identified 127 patients with detailed information available on bone marrow cytomorphology, blast count, blood cell counts and clinical features, who also had a bone marrow core biopsy taken at the time of diagnosis. From their formalin-fixed, paraffin-embedded histopathology specimens new sections and stains were made and evaluated by one reviewing pathologist (SB) who assessed a predefined set of features. The pathologist had no knowledge of the cytomorphological findings, except for the information that the specimen was from a "patient with myelodysplastic syndrome". Statistical analyses were performed by SPSS. Procedures were in accordance with the current version of the Helsinki Declaration. Informed consent was obtained from all patients included in the study. Results: The estimation of the percentage of CD34-positive cells by histopathology differed significantly from the cytomorphologically assessed medullary blast count, with a trend towards histopathological underestimation of blast cells (figure 1). Assessment of dysmegakaryopoiesis by histopathology identified 44 cases with dysplastic features, which were deemed inconspicious by cytomorphology. Histopathology yielded a significant positive correlation (p=0.002) between cellularity and degree of dysmegakaryopoiesis, and these two features were also correlated with higher-risk WHO subtypes. Fibrosis and dysmegakaryopoiesis were negatively correlated. Bone marrow cellularity seemed to be overestimated by cytomorphology compared with histopathology. The percentage of erythropoietic cells did not correlate well between cytomorphological and histopathological review. Neither WHO subtype nor medullary blast count showed an association with the proportion of erythropoiesis, regardless of the mode of evaluation. All patients with expanded erythropoiesis also showed signs of dysmegakaryopoiesis. There was no case of cytomorphologically diagnosed MDS that was not confirmed by histopathology, and 48% of MDS diagnoses were identical as to their WHO subtype. However, in 66 cases (52%), the WHO type diagnosed by histopathology differed from the WHO type diagnosed by cytomorphology. The discrepancy was mainly due to differing estimates of medullary blast counts. In our cohort, the degree of fibrosis positively correlated with bone marrow cellularity, a finding that appeared counterintuitive to clinical experience. Increased cellularity also correlated with higher-risk MDS subgroups. Prognosis in terms of overall survival was influenced by the following parameters: Cytomorphologically assessed medullary blast count, bone marrow cellularity, fibrosis, and percentage of erythropoiesis, the latter assessed by histopathology. Patients with of grade 2 or 3 fibrosis had an inferior outcome (figure 2). Conclusions: In our study, histopathology was fully congruent with bone marrow cytology as far as making a diagnosis of MDS is concerned. Histopathology, though, often underestimated the blast count and showed difficulty in identifying the correct MDS type according to the WHO classification. Histopathology is also at a disadvantage regarding evaluation of single cell morphology, with the exception of assessing certain aspects of dysmegakaryopoiesis. A clear advantage of histopathology is its exclusive capability of gauging bone marrow fibrosis and cellularity, both of which are relevant for the diagnosis and prognosis of MDS. We conclude that cytomorphology and histopathology should both be harnessed to optimize the characterization of a patient's myelodysplastic syndrome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cause of death and excess mortality in patients with lower-risk myelodysplastic syndromes (MDS): A report from the European MDS registry.

Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS.

Lessons from the European and Israel National MDS Registry

On behalf of the Israeli MDS working group and EUMDS Registry/ XIII Eurasian Hematology Oncology Congress (EHOC) 2022. The myelodysplastic syndromes (MDS) are a group of clonal stem cell diseases with cytopenias and a tendency to transform to leukemia. Despite the progress, there is still lack of real world data about the disease. In 2008, top European experts launched the EUMDS Registry. In this project, including 19 countries and 150 sites, epidemiological, clinical and lab data on newly diagnosed MDS patients, are collected and analyzed. As of today, 3300 patients have been recruited. In 2012, the Israel MDS group joined the project. We have contributed data on 360 patients, # 4 in the contributors. This project led to more than 100 abstracts in international meetings and 40 publications in first line journals. We will mention some of these studies. de Swart et al. summarized data on the first 1000 patients, validated the IPSS-R prognostic classification, showing its superiority on IPSS (de Swart L. BJH 2015). Another study, focusing on Quality of life (QoL) of LR-MDS patients revealed that these patients suffer from depression, anxiety, pain, discomfort and mobility difficulties, compared to controls (Stauder R, Leukemia 2018) The effects of Erythroid Stimulating Agents (ESAs,) was evaluated: Garelius et al. showed that ESA administration delays RBC transfusion dependency (Garelius HK. J Intern Med 2017). Since in most countries ESA is given to transfusion-dependent MDS patients, it might change the paradigm. Recently, we demonstrated that ESA treatment, is associated with improved outcomes and overall survival (Garelius HK. EHA 2022; submitted). Since prognostic factors are often determined at disease presentation, it was important to develop dynamic parameters. We showed that a rapid decline > 25% in the platelet count within 6 months is an adverse prognostic marker (Itzykson R. Bl Adv 2018) A study focusing on the mutational status was presented at ASH 2021 showing that LR-MDS patients can be grouped into 3 clusters, with a correlation to the clinical status (Malcovati L. ASH 2021) The Israeli group, independently and as a part of the EUMDS, was involved in several projects. Oster et al. suggested a non-invasive calculator to assess the probability of or excluding MDS diagnosis, based on patient characteristics, avoiding BM examination (Oster HS. Bl Adv 2021). We also investigated the correlation between Hb level and QoL. This correlation was found to be partial, and the decrease in QoL was not linear. This suggests that other factors other than Hb might play a role in determining QoL (Haring Y. ASH 2021). We recently presented data on lymphoid aggregates in BM biopsies, suggesting a possible association with poor prognosis (Book-Rabinowitz. Int MDS Symposium, Toronto 2021; submitted). In summary , the EUMDS registry is a platform of a scientific project, and an example of international collaboration. Such projects, especially in relatively uncommon diseases, allow collection of enough data to allow meaningful conclusions that might change paradigm and improve patient care. We call all participants of this meeting to join us and improve the quality of this wonderful important project.

High transferrin saturation predicts inferior clinical outcomes in patients with myelodysplastic syndromes.

Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 μg/L, 501-800 μg/L, >800 μg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 μg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.

P771: PROGNOSTIC CHARACTERISTICS OF PATIENTS WITH MDS WITH ABERRATIONS OF CHROMOSOME 5. DATA FROM THE DÜSSELDORF MDS REGISTRY

Background: Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders with a wide spectrum of biological and clinical features. Up to 20% of MDS patients present with aberrations of chromosome 5, either as isolated del(5q) or combined with other aberrations. Patients with a medullary blast count < 5% and isolated del(5q), or with one additional aberration except anomalies of chromosome 7, are diagnosed as MDS del(5q), a defined entity according to the WHO 2016 classification. They have a favorable prognosis compared to other types of MDS, although profound anemia, chronic transfusion dependency and the risk of disease progression into AML present clinical challenges. Aims: We analyzed the prognostic impact of karyotype complexity in MDS del(5q). Methods: From the Düsseldorf MDS registry we retrieved 499 patients with MDS or CMML according to WHO 2016, who showed any kind of del(5q). Biological and clinical parameters such as karyotype, IPSS-R and type of treatment were evaluated. Survival and progression to AML was calculated using Kaplan-Meier-plots. Cox regression analysis was performed to identify disease-related prognostic factors. Patients were followed up until Dec 31th 2021. Results: 58% of the patients were female, median age was 67 years. Median medullary blast count was 4% (0-19%), and median survival in the entire group was 28 months. For assessing the natural course of disease, we screened for patients with non-intensive treatment only (best supportive care, lenalidomide, low-dose Ara-C, hydroxyurea). Separation by medullary blast count (< 5%, 5-9% or ≥ 10%) was associated with significantly different median survival times, ranging from 63 months in the first group to 3 months in patients with ≥ 10% medullary blasts (p < 0.001). Survival was also affected by the cytogenetic risk group according to IPSS-R. Patients in the low-risk group (median survival 72 months) differed significantly from patients in the very high risk group (median survival 5 months) (p < 0.001). A similar trend was observed according to karyotype complexity represented by number of aberrations apart from del(5q). Median survival of patients with an isolated del(5q) was 86 months, while patients with a complex karyotype (del(5q) and ≥3 additional aberrations) had a median survival of 5 months. Biological risk factors were assessed using Cox regression analyses. Considering overall survival as endpoint, medullary blast percentage, cytogenetic risk group, and complexity of the karyotype had a significant impact on survival (p < 0.001). In the entire patient cohort, as well as among patients receiving non-intensive treatment, the rate of AML progression was significantly influenced by karyotype complexity (p < 0.001). While the median time to AML progression in both isolated del(5q) and del(5q) combined with one aberration had not been reached at the end of the observation period, the median time to AML progression for patients with del(5q) as part of a complex karyotype was 31 months in the entire cohort and 14 months in the low-intensity treatment group. Image:Summary/Conclusion: Both the IPSS-R cytogenetic risk group and the complexity of the 5q- karyotype showed prognostic impact in patients with del(5q). This was true for overall survival as well as risk of AML progression. Regardless of therapy or medullary blast count in patients with del(5q), the risk of AML progression increased dramatically with increasing complexity of the 5q- karyotype.

P747: LR-MDS IS CHARACTERIZED BY DIFFERENTIAL EXPRESSION OF INFLAMMASOME-RELATED GENES IN SPECIFIC CELL POPULATIONS

Background: Myelodysplastic Syndromes (MDS) are a group of hematopoietic neoplasms characterized by clonal expansion of hematopoietic stem and progenitor cells (HSPC) and peripheral blood cytopenia. MDS can develop from clonal hematopoiesis of indeterminate potential (CHIP) and progress through low-risk (LR) to high-risk (HR)-MDS and further to acute myeloid leukemia (AML). Recent findings emphasize the role of sterile inflammation in the bone marrow (BM) as a driver of neoplastic progression. Our previous analysis of whole BM mononuclear cells (BM-MNC) has revealed distinct expression patterns of inflammasome-related genes, including IL1B and IL18, to be associated with LR-MDS subgroups and clinical features. This raises the prospect of interrupting disease evolution at an early stage by targeted, personalized anti-inflammatory therapy. The development and stratification of such therapies will ultimately require more detailed knowledge of the variety and consequences of inflammation networks in MDS bone marrow. Aims: Our objective was to assess inflammasome-related gene expression levels in individual cell types in the BM of CHIP, LR-MDS and HR-MDS individuals as well as non-CHIP controls in order to determine a) which cell types contribute to the expression of inflammasome-related genes and b) whether specific disease states are associated with consistent patterns of cell-specific gene expression. Methods: Cryopreserved BM-MNC from 3 non-CHIP controls, 3 CHIP individuals, 14 LR-MDS and 5 HR-MDS patients were obtained from the MDS registry and the BoHemE Study (NCT02867085) at the University Hospitals in Dresden and Leipzig. Hematopoietic stem and progenitor cells (HSPC), monocytes, monocytic myeloid-derived suppressor cells (M-MDSC), polymorphonuclear MDSC (PMN-MDSC), B lymphocytes, T lymphocytes and CD45- cells (control) were sorted from thawed BM-MNC on a BD FACS Jazz. RNA was isolated and the gene expression of IL1B, IL18, S100A9, IRAK4, NLRP3, PYCARD, CASP1 and NLRC4 was assessed by RT-qPCR. Results: The majority of the inflammasome-related genes, including IL1B, NLRP3, NLRC4 and S100A9 were expressed in all disease states predominantly by monocytes and M-MDSC (p<0.001). However, IL18 was expressed at the highest level in HSPC. Consistent to our previous analysis of whole BM-MNC, we found an association between cell-specific gene expression and LR-MDS genetics, with HSPC-derived IL18 mRNA being highest in SF3B1-mutated LR-MDS, while monocytic IL1B mRNA was highest in del(5q) LR-MDS. Furthermore, an apparent progression in expression from non-CHIP through to LR-MDS was detected, with mRNA levels of IL1B and NLRP3 in monocytic cells and PYCARD and CASP1 in HSPC increasing from non-CHIP to CHIP between 1.5- and 7.9-fold. From CHIP to LR-MDS, mRNA levels of CASP1 and NLRC4 in monocytic cells and PYCARD both in HPSC and in monocytic cells increased by 1.8- to 2.1-fold. Summary/Conclusion: We identify features of inflammasome-related gene expression in individual cell populations and disease states reflecting the progression from non-CHIP through CHIP to MDS. Our analysis suggests strongly that high resolution studies of gene expression in specific populations or single cells will resolve a spectrum of MDS-related inflammation states relevant to prognosis and personalized therapy. Therefore, we are currently performing RNA-Seq from sorted cell populations in order to extend our analysis beyond the core inflammasome reported here.

Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria

BackgroundAzacitidine (AZA) is approved for the treatment of high-risk chronic myelomonocytic leukemia (CMML) of myelodysplastic (MD) subtype. Data of response rates using the specific response criteria for this disease are scarce. The aim of this study was to evaluate the response to AZA in patients diagnosed with CMML from the Spanish Registry of Myelodysplastic Syndromes (MDS) applying the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) response criteria. MethodsWe retrospectively studied 91 patients with CMML treated with at least one cycle of AZA from the Spanish Registry of MDS. As it was a real-world study, the response rate was evaluated between cycle 4 and 6, applying the MDS/MPN response criteria FindingsThe overall response rate at cycle 4–6 was 58%. Almost half of the patients achieved transfusion independence and one quarter showed clinical benefit, regardless of the CMML French-American-British (FAB) and World Health Organization (WHO) subtypes and CMML Specific Prognosis Scoring (CPSS) risk groups. Toxicity was higher in the MD-CMML subtype. InterpretationIn our series, most CMML patients achieved an overall response rate with AZA according to the overlap-MDS/MPN response criteria regardless of the CMML FAB and WHO subtypes and CPSS risk groups. Thus, AZA may also be a treatment option for patients with the myeloproliferative CMML subtype and those with a lower-risk CPSS, but symptomatic.

Therapy-related myeloid neoplasms following treatment for multiple myeloma\u2014a single center analysis

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) can be late complications following mutagenic treatment. Limited data is available on the outcome of patients developing therapy-related MDS and AML after treatment for multiple myeloma (MM). We identified 250 patients with therapy-associated MDS or AML in the Duesseldorf MDS registry. Of those, 50 patients were previously diagnosed with multiple myeloma (mm-MDS/AML). We compared them to patients with de novo MDS (n = 4862) and to patients with MDS following other underlying diseases (tMDS) (n = 200). mm-MDS patients and tMDS patients showed similar karyotypes and degrees of cytopenia. However, mm-MDS patients had significantly higher blast counts and more often belonged to the high-risk group according to the International Prognostic Scoring System (IPSS) (both p < 0.05). Although the rate of progression to AML was similar in mm-MDS and tMDS, both transformed significantly more often than de novo MDS (p < 0.05). Median overall survival of patients with mm-MDS (13 months; range: 1–99) and tMDS (13 months; range 0–160) was also similar yet significantly shorter than patients with de novo MDS (32 months; range 0–345 months; p < 0.05). Furthermore, survival of mm-MDS patients was not affected by myeloma activity. Despite significantly more high-risk disease and higher blast cell counts, myeloma-associated MDS-patients show features akin to other tMDS. Survival is similar to other tMDS and irrespective of myeloma remission status or transformation to AML. Thus, patient outcome is not determined by competing clones but rather by MDS governing the stem cell niche.

Management of MDS with Isolated Del(5q) Patients in the European MDS (EUMDS) Registry, a Unique Prospective Real-World Dataset

Management of MDS with Isolated Del(5q) Patients in the European MDS (EUMDS) Registry, a Unique Prospective Real-World Dataset

Validation of the Qualms Questionnaire to Assess Health-Related Quality of Life in European and Israeli Patients with Myelodysplastic Syndromes: Results from the MDS-Right Project

Validation of the Qualms Questionnaire to Assess Health-Related Quality of Life in European and Israeli Patients with Myelodysplastic Syndromes: Results from the MDS-Right Project

Severe Anemia Is Associated with a Risk of Infection in Patients with Myelodysplastic Syndromes

Introduction: Infections are a well-recognized complication in patients (pts) with myelodysplastic syndromes (MDS) that contribute substantially to the morbidity and mortality particularly in pts suffering from neutropenia. Neutropenia and other immune defects including impaired neutrophil function have been reported to be predisposing factors for severe infections. Furthermore, some of the therapies may worsen neutropenia and lead to an additional risk factor to develop infectious episodes. Since infectious complications are no primary endpoint in clinical trials epidemiological data on infections in large cohorts of MDS pts is sparse.Methods: We performed a retrospective analysis of 3.787 MDS-patients from the Duesseldorf MDS Registry who were diagnosed between 1980 and 2018. Infectious complications were defined as clinical symptoms of infection associated with the need for antibiotic and/or antifungal therapy, and/or the isolation of a pathogen and/or an identifiable site of infection by physical examination. Infectious episodes were categorized as fever of unknown origin, microbiologically or clinically documented infection.Results: Amongst our study cohort, 42% of the pts suffered from at least one infectious complication of any type during the course of their disease. Most infectious diseases were of bacterial origin (34.7%) and in 17% a pathogen was isolated. Pneumonia was the most common site of infection (64%). Pts who experienced at least one infectious episode had a significant poorer overall survival (OS) than pts without such events (21 vs 37 months, p<0.001). Pts with a higher risk disease according to the IPSS-R had fewer infections during the course of the disease than pts with a lower-risk MDS (487 total infections vs 1481, p<0.001). Nevertheless, the presence of any infectious episode lead to an inferior OS in lower-risk (40 vs 29 months, p<0.001) as well as in higher-risk disease (38 vs 24 months, p=0.006).In univariate analyses comparing pts who had no infections versus those who had one or more, pts with older age (>65 years) tended to have a higher incidence of infectious episodes (p<0.001). In addition, patients older than 65 suffering from infections had a shorter OS than patients who did not experience an infectious complication. The difference in OS was highly significant with 16 months for pts suffering from infectious complications compared to 24 months (p<0.001). Likewise, an excruciating higher incidence of infections was noted in MDS pts compared to infections incidence in a non-MDS population in Germany. The risk of a 65-year-old or older MDS pt to suffer from pneumonia was 6.9 times higher compared to a non-MDS pt of the same age.We found a highly significant negative correlation between the depth of cytopenia in all three myeloid lineages and the presence of infections (p<0.001), suggesting that patients with severe cytopenia suffer from infectious episodes more frequently. However, pts with an isolated neutropenia having an absolute neutrophil count below a threshold of 0.8 × 10 9/L and suffering from infectious episodes had no inferior OS than neutropenic pts without any infection (25 vs 32 months, p=0.583). Pts with isolated severe thrombocytopenia with a platelet count <50 × 10 9/L had a similar OS of 26 months for pts with infectious complications. The difference in OS between pts with and without infections was even more pronounced in this group (26 vs 48 months, p=0.002). Still, a low hemoglobin (Hb) level <9g/dl appeared to be the most significant risk factor for pts with infections, resulting in the poorest OAS of only 17 months in pts with isolated anemia suffering from infections. In multivariate analyses, we found that Hb <9g/dl, followed by ANC <0.8 × 10 9/L, were independently associated with the risk to suffer from an infection during the disease. In addition, a Hb <9g/dl was the most important blood count parameter with regard to OS when compared to platelets <50 × 10 9/L, and ANC <0.8 × 10 9/L.Conclusion: The incidence of infections significantly increases in pts with advanced age. MDS-pts in general are more vulnerable for infection-related morbidity and mortality than non-MDS-pts. Low hemoglobin and platelet counts were both found to be associated with a worse prognosis compared to low neutrophil counts. The appearance of at least one infectious episode leads to an inferior DisclosuresNachtkamp: Jazz: Speakers Bureau; bsh medical: Speakers Bureau; Celgene: Other: Travel Support. Kobbe: Celgene: Research Funding. Gattermann: Celgene: Honoraria; Takeda: Research Funding; Novartis: Honoraria. Germing: Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria.

Core set of patient-reported outcomes for myelodysplastic syndromes: an EUMDS Delphi study involving patients and hematologists

AbstractPatient-reported outcomes (PROs) are relevant and valuable end points in the care of patients with myelodysplastic syndromes (MDS). However, a consensus-based selection of PROs for MDS, derived by both patients and hematologists, is lacking. We aimed to develop a core set of PROs for patients with MDS as part of the prospective European LeukemiaNet MDS (EUMDS) Registry. According to international guidelines, candidate PROs were identified from a comprehensive literature search of MDS studies. Overall, 40 PROs were selected and evaluated in a two-round Delphi survey by 40 patients with MDS and 38 hematologists in the first round and 38 patients and 32 hematologists in the second round. Based on an agreement scale and predefined inclusion criteria, both patients and hematologists selected “general quality of life” as a core PRO. Hematologists also selected “transfusion-dependency burden” and “ability to work/activities of daily living” as core PROs. The second Delphi round increased PRO rating agreements. Statistically significant rating differences between patients and hematologists were observed for 28 PROs (Mann-Whitney U test; P < .05) in the first round and for 19 PROs in the second round, with “disease knowledge” and “confidence in health care services” rated notably higher by patients. The overall mean PRO ratings correlation between the 2 groups was moderate (Spearman's rank correlation coefficient = 0.5; P < .05). This first consensus on a core set of PROs jointly developed by patients and hematologists forms the basis for patient-centered care in daily practice and clinical research.

The anemia-independent impact of myelodysplastic syndromes on health-related quality of life

Myelodysplastic syndromes (MDS) are in the majority of cases characterized by anemia. Both anemia and MDS per se may directly contribute to impairments in health-related quality of life (HRQoL). In this study, we aimed to investigate the anemia-independent impact of MDS on HRQoL. We evaluated participants (≥ 50 years) from the large population-based Lifelines cohort (N = 44,694, mean age 59.0 ± 7.4 years, 43.6% male) and the European MDS Registry (EUMDS) (N = 1538, mean age 73.4 ± 9.0 years, 63.0% male), which comprises a cohort of lower-risk MDS patients. To enable comparison concerning HRQoL, SF-36 scores measured in Lifelines were converted to EQ-5D-3L index (range 0–1) and dimension scores. Lower-risk MDS patients had significantly lower HRQoL than those from the Lifelines cohort, as illustrated in both the index score and in the five different dimensions. Multivariable linear regression analysis demonstrated that MDS had an adjusted total impact on the EQ-5D index score (B = − 0.12, p < 0.001) and an anemia-independent “direct” impact (B = − 0.10, p < 0.001). Multivariable logistic regression analysis revealed an anemia-independent impact of MDS in the dimension mobility, self-care, usual activities, and anxiety/depression (all except pain/discomfort). This study demonstrates that the major part of the negative impact of lower-risk MDS on HRQoL is not mediated via anemia. Thus, the therapeutic focus should include treatment strategies directed at underlying pathogenic mechanisms to improve HRQoL, rather than aiming predominantly at increasing hemoglobin levels.