Welcome to the MDS 2021 Interactive Programme

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Please note that all sessions will run at their scheduled time and be followed by a LIVE Q&A at the end

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Displaying One Session

Room
Plenary Sessions
Session Time
12:30 PM - 02:00 PM
Session Type
Plenary Session

Introduction (ID 234)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
12:30 PM - 12:32 PM

TGFbeta pathway targeting (ID 39)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
12:32 PM - 12:52 PM

Management of Low risk disease- now and future (ID 40)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
12:52 PM - 01:12 PM

Live Q&A (ID 42)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
01:12 PM - 01:30 PM

Poster Pitch: TET2 Dysfunctions Unveil Clinical and Prognostic Phenotypes in Patients with MDS (ID 98)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
01:30 PM - 01:32 PM

Abstract

Background And Aims

TET2 gene is involved in regulation of hematopoietic stem cell fate and monocytic commitment via modulation of methylation in promoters of lineage-specific transcription factors. The general down-regulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which, albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors, which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients.

Methods

DNA/RNA-sequencing and 5-hmC data were collected from 1665 MDS patients and 91 healthy controls (HC).

Results

fig.1 ok.pngIrrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, while 5-hmC levels were not uniformly decreased (Fig.1A-B). In searching for factors explaining compensatory mechanisms, we discovered that TET3 was up-regulated in MDS and inversely correlated with TET2 expression in wild-type cases (Fig.1C). While TET2 was reduced across all age-groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. The inverse relationship of TET2 and TET3 expression also paralleled the level of expression of L-2-hydroxyglutarate dehydrogenase, an enzyme involved in agonist/antagonist substrate metabolism (Fig.1D-E). Importantly, elevated TET3 levels influenced the clinical phenotypes of TET2-deficiency in both univariate and multivariate settings whereby the lack of compensation by TET3 was associated with higher risk features (Fig.1F-G).

Conclusions

While TET2 mutations lack prognostic impact, TET2/TET3 expression profiles unveil clinico-prognostic significance in MDS. Application of new therapeutic approaches (e.g., vitamin C) should be informed by analyses of these factors.

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Poster Pitch: Bone Marrow Derived Stromal Cells from Myelodysplastic Syndromes are Altered but not Clonally Mutated in Vivo (ID 113)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Presenter
Lecture Time
01:32 PM - 01:34 PM

Abstract

Background And Aims

Increasing evidence suggests that the pathogenesis of Myelodysplastic Syndromes (MDS) is not only driven by the hematopoietic compartment but also the bone marrow (BM) microenvironment. Seminal studies in murine models have demonstrated that isolated mutations in the BM niche can disrupt the non-mutated hematopoietic compartment and induce MDS-like diseases. An unanswered question has therefore been whether primary MDS in humans is possibly also associated with acquired mutations in the BM stroma.

Methods

In order to address this hypothesis, we performed a comprehensive whole exome sequencing study on BM derived in vitro expanded mesenchymal stromal cells (MSCs) of n=98 MDS and myeloid neoplasia patients and a control group of n=20 healthy individuals. In addition, MSCs in serial culture passages and different BM aspirations from the same patients were sequenced in order to investigate whether acquired mutations in MSCs were artefacts of the ex vivo expansion. Putatively high confidence mutations were further backtracked by deep re-sequencing in primary sorted CD45-CD235a-CD31-CD271+ BM cells in n=9 cases.

Results

We discovered multiple recurrently acquired mutations in expanded MSCs of MDS patients in genes such as ZFX (n=8/98), RANK (n=5/98), and others. Expanded MSCs from MDS patients displayed a higher mutational burden and distinct mutational signatures. However, all validation experiments in serial cultures and primary sorted MSCs indicated that the discovered mutations were expanded by in vitro culture but not present in relevant cell populations in the primary BM.

Conclusions

Thus, we conclude that there is no evidence for clonal mutations in the BM stroma of MDS patients.

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Poster Pitch: Using Next-Generation Sequencing to Assess the need for Bone Marrow Biopsies in Patients with Cytopenia (ID 137)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
01:34 PM - 01:36 PM

Abstract

Background And Aims

Bone marrow biopsies are currently the core of the diagnostic work-up of persistent cytopenias. Aiming to explore whether next-generation sequencing (NGS) could obviate the need for a bone marrow biopsy, we incorporated NGS in a model to predict presence of disease in the bone marrow of patients with cytopenia.

Methods

We analyzed the occurrence of mutations in 508 patients with cytopenias from 2015-2020, referred for primary work-up for a suspected hematological malignancy. We divided patients into a discovery (n = 340) and validation (n = 168) cohort, and NGS of genes associated with myeloid malignancies, bone marrow biopsy and complete blood count (CBC) were performed in all patients.

Results

Mutations were identified in 270 (53%) patients. Abnormal bone marrow morphology was found in 188 (37%) patients. Using logistic regression, we constructed a model to predict the presence of abnormal bone marrow morphology based on age, sex, CBC and mutational status. Mutations in TET2, SF3B1, U2AF1, TP53 and RUNX1 were significantly associated with abnormal bone marrow morphology. In the validation cohort, 28 (17%) patients had less than 10% predicted risk of abnormal bone marrow morphology. None of these patients had abnormal bone marrow morphology, corresponding to a sensitivity of 100% (95%-CI: 0.93-1.00). The negative predictive value of having less than 10% risk of abnormal bone marrow morphology was 100% (95%-CI: 0.88-1.00).

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Conclusions

This is the first study to show that NGS can be used to assess the necessity of bone marrow biopsies, which can potentially spare patients a painful and unnecessary procedure.

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Poster Pitch: Low-risk myelodysplastic syndromes (MDS) without mutations are as good as idiopathic cytopenia of undetermined significance (ICUS) (ID 150)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
01:36 PM - 01:38 PM

Abstract

Background And Aims

Idiopathic cytopenia of undetermined significance (ICUS) and low-risk myelodysplastic syndromes (MDS) are distinguished mainly by morphologic dysplasia, which sometimes shows discrepancy among examiners. We hypothesized that gene mutations are an independent prognostic factor for ICUS and low-risk MDS.

Methods

From four medical centers, we enrolled patients with cytopenia≥1 lineage (ANC<1,800/mm3, hemoglobin<13 g/dL (male) or<12 g/dL (female), platelet<150x109/mL). Bone marrow examinations were evaluated by hematologists. Diagnosis of low-risk MDS was made according to WHO classification 2016 and revised-international prognostic scoring system (R-IPSS)≤3.5. DNA was extracted from bone marrow/blood and sequenced by targeted next generation sequencing (NGS).

Results

One hundred twenty-three patients were recruited; 25.2% ICUS and 74.8% low-risk MDS. Patients with ICUS were younger than low-risk MDS (68 y.o. vs. 72 y.o.; p=0.04). Complete blood counts were not different between the 2 groups. Low-risk MDS harbored significantly more abnormal karyotypes (27.8% vs. 4.2%; p=0.01) and higher numbers of mutations (1 vs. 0; p=0.04) compared to ICUS. Overall, most frequent mutations were TET2 (14.6%), SF3B1 (12.2%) and ASXL1 (9.7%). Without mutation, the outcomes of low-risk MDS vs. ICUS were not different (p=0.53). Notably, low-risk MDS with any gene mutations showed inferior progression free survival at 5-year compared to the others (75.0% vs 96.4%; p=0.01). In multivariate analysis, IDH2 and DNMT3A mutations in low-risk MDS were associated with a higher risk of leukemic transformation [HR=47.95 (4.5-510.5; 95%CI); p=0.001, HR=6.06 (1.3-29.4; 95%CI); p=0.03].

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Conclusions

Mutation detection by NGS is important for proper risk stratification of patients with cytopenia.

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Poster Pitch: Predictive Factors of Oligomonocytic Chronic Myelomonocytic Leukemia (OM-CMML) Evolution to Overt Chronic Myelomonocytic Leukemia (CMML) (ID 159)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Presenter
Lecture Time
01:38 PM - 01:40 PM

Abstract

Background And Aims

INTRODUCTION

Recent studies have shown that OM-CMML and CMML have a similar clinical and biological profile. Although a high percentage of OM-CMML evolve to CMML, some of them die before evolving. Identifying predictive factors of evolution to CMML may be valuable since, as previously reported, OM-CMML that evolve to CMML show shorter overall survival (OS).

AIM

To identify factors for predicting OM-CMML evolution into CMML.

Methods

METHODS

We analyzed clinical, genetic, and immunophenotypic data of a series of 94 patients diagnosed with OM-CMML (N=41) and CMML (N=53).

Results

RESULTS

At a median follow-up of 42 months, 30% OM-CMML evolved to CMML. Patients with >3 mutated genes (HR:4.24, 95%CI 1.08-16.71, P=0.039) and monocytosis >20% (HR:3.48, 95%CI 1.05-11.47, P=0.041) showed a significant shorter time to CMML. These two variables were faced in a multivariate analysis and maintained their significance for predicting time to CMML (HR:4.33, 95%CI 1.23-15.20, P=0.022; and HR:5.82, 95%CI 1.32-25.7 , P=0.02). Moreover, these variables were also independent adverse prognostic factors for OS in our series of 94 patients (HR:4.39, 95%CI 1.99-9.68 , P<0.001; HR:3.05 , 95%CI 1.27-7.34 , P=0.013). Figure 1 depicts univariate survival analysis. Given the similar HR for predicting time to CMML of both variables, we implemented a model for predicting time to CMML: 0 points (none of them), 1 (one of them) or 2 points (both). This model offered an excellent predictive power (C-index: 0.82).prediction cmml.jpg

Conclusions

CONCLUSION

OM-CMML with higher molecular complexity and higher relative monocytosis are at greater risk of CMML evolution.

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Poster Pitch: A Multi-Center Experience of Hypocellular Myelodysplastic Syndromes (H-MDS): From Clinical Description to Immunological Characterization (ID 174)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
01:40 PM - 01:42 PM

Abstract

Background And Aims

Hypocellular Myelodysplastic Syndromes (hMDS) are a rare subset of MDS, defined by a reduced bone marrow (BM) cellularity, irrespective of WHO classification. We aimed to characterize the clinical features and outcome of hMDS patients and to identify common potential immune deregulations, which might account for hMDS-related BM failure and pathogenesis.

Methods

We compared overall survival (OS) of 336 hMDS and 1609 normo/hypercellular MDS (nMDS) enrolled in the national registry of the Italian Foundation of MDS (FISiM). BM and peripheral blood (PB) of twelve hMDS patients, recruited within FISiM NK-hMDS protocol, were also characterized by immunophenotypic and molecular analyses.

Results

According to R-IPSS groups, lower-risk hMDS had a median OS of 125months (m) versus 74m of nMDS (p<0.001). Conversely, higher-risk hMDS showed a median OS of 19m, similar to 20m of n-MDS.

A clonal CD3+/CD8+/CD57+ T cell expansion was observed in 6/12 (50%) h-MDS patients, with 5/6 (83%) belonging to the Higher Risk group. Two of them also harbored a STAT3 activating mutation. On the contrary, a clonal CD3-/CD16bright/CD56dim/neg/CD57+/NKG2C+ NK cell expansion was found in 4/12 (33%) cases, with 3/4 (75%) included in the Lower Risk group.

Conclusions

Our data show an advantage in OS in Lower Risk h-MDS, compared to n-MDS. We also reveal peculiar immune alterations, which might represent novel prognostic biomarkers and relevant predictors of response to therapy. Further studies in a large series of patients are warranted to elucidate the actual meaning of these alterations and their clinical implications.

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Poster Pitch: Incorporation of Cohesin Mutational Data into Current IPSS-R Classification Refines the Prognostic Stratification of very Low/Low-Risk Myelodysplastic Syndromes (ID 178)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
01:42 PM - 01:44 PM

Abstract

Background And Aims

Background&Aims:The clinical impact of cohesin mutations in the myelodysplastic syndromes(MDS) is still undetermined. Thus, the aim of the study was the molecular and clinical characterization of MDSpatients harboring cohesin mutations.

Methods

Patients&Methods:418 MDSpatients were analyzed by targeted deep sequencing using a custom panel of 117myeloid-related genes, including cohesin genes: STAG1;STAG2;SMC1A;SMC3;RAD21;CTCF.

Results

Results:The sequencing study identified 52mutations in cohesin genes in 48patients (11.5%). Regarding the molecular landscape of patients with cohesin mutations: mutated patients presented a significantly higher number of mutations (p<0.0001) and displayed a specific mutational profile with a strong co-occurrence between cohesin and splicing mutations (p<0.0001) and trisomy8 (p<0.0001).

Regarding the clinical characterization, patients with cohesin mutations displayed a poor prognosis disease phenotype, characterized by several cytopenia in blood, a higher number of blasts in bone marrow (p=0.0014) and a higher rate of progression to sAML (p<0.0001).

Regarding the influence on clinical outcome, cohesin-mutated patients showed a shorter time to sAML progression (LFS:1.4 vs. 8.3 years, p<0.0001) and a shorter overall survival (OS:3.1 vs. 5.2 years, p=0.069). Noteworthy, the adverse impact on LFS was observed mainly in very low/low/intermediate-risk IPSS-R patients (multivariate analysis: HR 2.4, 95%CI 1.2-5.0; p=0.015).

Furthermore, we assessed the prognostic value of cohesin mutations on the IPSS-R stratification. Of note, the OS and LFS of very low/low-risk patients who harbored cohesin mutations were statistically significant shorter than those without these mutations, but nearly identical to intermediate-risk patients.figure mds international 2021.jpg

Conclusions

Conclusions:The incorporation of cohesin mutational data into current IPSS-R classification improved the prognostic stratification of very low and low-risk MDS patients.

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Poster Pitch: Conditional Relative Survival in Myelodysplastic Syndromes Reveals a Permanent Excess Mortality Risk for Long-Term Survivors: A Population-Based Study in The Netherlands (ID 197)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
01:44 PM - 01:46 PM

Abstract

Background And Aims

Most patients with myelodysplastic syndromes (MDS) experience excess mortality compared to an age- and sex-matched group from the general population, especially within the first few years post-diagnosis. Up-to-date statistics on the survival expectations of MDS patients who survived several years post-diagnosis are lacking. Therefore, we assessed the conditional 5-year relative survival (CRS) among MDS patients with long-term follow-up.

Methods

We selected all adult (≥18 years) MDS patients diagnosed in the Netherlands between 2001-2018—with survival follow-up through 2020—from the nationwide Netherlands Cancer Registry. Five-year CRS for each additional year survived up to 10 years post-diagnosis was calculated for three age groups (18-64, 65-74, and ≥75 years). Up-to-date statistics of 5-year CRS were estimated with the hybrid approach for the follow-up interval 2014-2020 (Figure). Excess mortality is considered minimal when the 5-year CRS is ≥95%.

Results

A total of 12,590 adult MDS patients (median age, 75 years) were included, of whom 5,956 (47%) were alive at some point during the follow-up interval and contributed to the survival estimates. There was a prognostic effect of age on 5-year RS at diagnosis (Figure). This effect essentially persisted up to ten years post-diagnosis (Figure). Excess mortality decreased with each additional year survived across all age groups (Figure). Nevertheless, excess mortality remains substantial across all age groups studied (Figure).

figures.jpg

Conclusions

Significant excess mortality persists in MDS patients, even for those who survived up to ten years post-diagnosis. The excess mortality might be inherently tied to the incurable nature of most MDS subtypes, comorbidities, or late treatment-related mortality.

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Live Q&A (ID 339)

Session Type
Plenary Session
Date
09/24/2021
Session Time
12:30 PM - 02:00 PM
Room
Plenary Sessions
Lecture Time
01:46 PM - 01:59 PM