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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Introduction (ID 242)
Mechanisms and predictors of drug resistance, intolerance to HMAs and clinical management strategies in high risk MDS (ID 50)
Oral Presentation: Is Race Important in Genomic Classification of Hematological Neoplasms? (ID 218)
Abstract
Background And Aims
In recent years, genome-based classifications for hematological neoplasms have been proposed successively and proved to be more accurate than histologic classifications. However, some previous studies have reported the racial differences of genetic landscape in persons with hematological neoplasms including myelodysplastic syndromes (MDS), which may cause a genomic classification based on a particular ethnic group does not operate in others.
Methods
To determine whether race plays an important role in the genomic-based classification, we validated a newly proposed genomic classification of MDS (J Clin Oncol.2021;JCO2001659), which was based on an European database, in Chinese patients from our center.
Results
The genetic profiles of Chinese patients are different from that of Western patients from European cohort, which is consistent with prior studies. These racial heterogeneities consequently led to significant differences between the two populations regarding the proportion of each subgroup to overall cohort when applying this novel genomic classification, for only 16% of our subjects were into cohorts 1, 3-6 defined by most commonly mutated class of genes in MDS that encode splicing factors compared with 67% in Europeans whereas more than ½ of our subjects were in cohort 0 without specific genomic features compared with 16% of Europeans (P <0.001).
Conclusions
Our results indicate that a genome-based classification of MDS operating in populations of European descent may not operate in other populations such as Chinese. Given the prevalent racial differences of genetic profiles in hematological malignancies, we believe that it is important to consider race when applying a genomic classification of hematological neoplasms.
Strategies to reduce relapse and improve survival post allogeneic stem cell transplant (ID 52)
Live Q&A (ID 243)
Poster Pitch: IGF-1R Activation Secondary to Haploinsufficiency of MIR-143 and MIR-145 is a Targetable Dependency of DEL(5Q) MDS (ID 127)
Abstract
Background And Aims
Chromosomal alterations frequently occur in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. First-line therapy, lenalidomide, is effective in 60 to 80% of patients and eventual resistance is common. The commonly deleted region (CDR) of chromosome 5q harbors several genes, including noncoding miRNAs, the loss of which contribute to disease phenotypes. miR-143 and miR-145 are located in the del(5q) CDR, but precise understanding of their role in human hematopoiesis and in the pathogenesis of del(5q) MDS is still lacking. The objective of this study was to 1. Examine the effect of miR-143/145 haploinsufficiency on hematopoietic stem and progenitor cells (HSPCs) 2. Identify other vulnerabilities due to miR-143/145 haploinsufficiency to target in lenalidomide-resistant del(5q) MDS.
Methods
We modeled haploinsufficiency of miR-143/145 using miR decoys in human CD34+ cord blood cells in vitro and in vivo to examine the impact on HSPC function. Bioinformatic analyses were used to identify potential targets of miR143/145 which were validated by RNA pull-down assays.
Results
We showed that IGF-1R is a target of miR-143/145 and increased IGF-1R expression (due to miR-143/145 depletion) in human HSPCs, provides both a growth advantage and increased survival. We showed that genetic or pharmacologic inhibition of IGF-1R blocks the growth advantage, and decreases viability of cells.
Conclusions
Our findings suggest a novel role of miR-143 and miR-145 as regulators of the proliferation and survival of HSPCs, through targeting of the IGF-1R pathway. This work thus provides a potential new therapeutic avenue for primary and lenalidomide-resistant del(5q) MDS.
Poster Pitch: Role of Allogeneic Stem Cell Transplant in Myelodysplastic Syndrome: A Study from the Italian FISIM Registry (ID 131)
Abstract
Background And Aims
Only few MDS patients(pts) are transplant-eligible and only some of them proceed to HSCT, the sole curative option in MDS. We aimed to assess the actual proportion of MDS undergoing HSCT, the impact of pre-HSCT therapies on outcome and the reasons preventing eligible pts from HSCT.
Methods
We included 1293MDS pts prospectively enrolled in the FISiM registry between 1994 and 2019. HSCT eligible pts(n=211) were selected with the consensus criteria by De Witte et al(Blood 2017).
Results
Median age of HSCT-eligible pts was 64, 46% were at higher IPSS-R risk and 39% at intermediate risk. Sixty-seven pts underwent HSCT (5% of the study population and 32% of HSCT-eligible pts), 42% after intensive chemotherapy (IC), 41% after azacitidine and 17% upfront. Median survival after HSCT was 45 months and was not affected by pre-HSCT treatment. HSCT improved survival only in pts at higher IPSS-R risk (median 33 vs 14 months,p <0.001).
The main reasons preventing eligible pts from HSCT were procrastination of HSCT and failure of cytoreductive treatment. Some lower risk pts (n=21) were considered for HSCT at progression when they were no longer transplant-eligible or progressed to AML(n=16) failing induction treatment. MDS-EB (n=134) received a cytoreductive treatment as bridge to HSCT that failed in 60% of cases, and only 16% was rescued by II line therapy undergoing HSCT.
Conclusions
HSCTeligibile pts should be promptly referred to HSCT-Centers to find the best window for transplant in lower risk pts and optimize the bridge therapy to HSCT in higher risk ones, also considering HSCT upfront.
Poster Pitch: APR 246 plus Azacitidine (AZA) in TP53 mutated (M) MDS and AML. Long term follow up of phase 2 study by the GFM (ID 151)
Abstract
Background And Aims
Our team and Sallman et al recently published results of 2 phase 2 studies combining AZA and APR246, a TP53 “reconforming agent” in TP53 m MDS/AML (Cluzeau et al; JCO 2021). We report here long term follow up of our study.
Methods
Int, high or very high IPSS-R TP53m MDS and AML untreated adult patients were eligible. Patients received APR-246 4500 mg IV /d (6 hour infusions) (days 1-4) followed by AZA 75 mg/m²/d (days 4-10) in 28 day cycles.
Results
52 patients were enrolled between Sept 2018 and July 2019 in 7 GFM centers: median age was 73 years (range 44-87), M/F: 28/25; 34 MDS (including 74% very high IPSS-R) and 19 had AML; 87% complex monosomal karyotypes. Only two patients are still on treatment after 19 and 26 cycles.
As of 1 May 2021, with a median follow up of 12.5 months, median OS was 12.1 months, and 12.1, 14.8 and 3.0 months in MDS, AML (20-30% blasts) and AML (>30% blasts), respectively. Median response duration was 16.6 months (5.1-30.3+) OS was higher in patients reaching MRD negativity (5% sensitivity): median 16.6 vs 4.1 months, p<0.0001. 4 were allo-transplanted (all were still alive after 21.8 to 30.3 months). 11 patients were still alive after 21.8 to 30.3 months.
Conclusions
Our results suggest an OS improvement in TP53 mutated MDS/AML patients treated by AZA + APR 246 , mainly in patients obtaining deeper response and allografted.
Poster Pitch: Bone Marrow Microenvironment in Therapy-Related Myeloid Neoplasms is distinct from other Myeloid Neoplasms, probably driven by prior Cytotoxic Therapy (ID 175)
Abstract
Background And Aims
Background: Therapy-related myeloid neoplasms (t-MN) are associated with dismal outcomes in otherwise long-term cancer survivors and are considered to be a direct consequence of DNA damage induced in haematopoietic stem cells (HSC) by cytotoxic therapy (CT). However, it largely ignores CT-induced changes to bone marrow (BM)-microenvironment.
Aims: (i) to compare BM-microenvironment in t-MN with other-MN and age-matched healthy controls, (ii) to decipher CT-induced changes from MN induced changes in BM-microenvironment.
Methods
BM-mesenchymal stromal cells (MSC) phenotype, function, and whole transcriptome was compared in four well-selected cohorts: (1) t-MN, whereby MN occurred in cancer survivors following CT exposure; (2) MN in cancer survivors without prior exposure to CT (multiple cancers-MN; MC-MN); (3) primary-MN (p-MN) without preceding independent cancer and/or exposure to CT and (4) age-matched healthy controls (HC).
Results
t-MN-MSC exhibited altered morphology, proliferation, DNA damage repair, differentiation capacity and senescence compared to HC and other-MN (Fig.1A-B). t-MN-MSC also display Senescence Associated Secretory Phenotype and high expression of CDKN1A, a critical cyclin dependent kinase inhibitor orchestrating cell cycle arrest. Aberrant t-MN-MSC were unable to support haematopoiesis (Fig.1C). Transcriptome analysis showed reduced expression of genes involved in DNA damage repair, cell cycle regulation and HSC-support pathways (Fig.1D).
Analysis of sequential BM samples elucidated impaired BM-MSC proliferation and differentiation following CT, well before diagnosis of t-MN (Fig.1E).
Conclusions
This is the first comprehensive study demonstrating aberrant BM-microenvironment and providing molecular insight in t-MN. Moreover, our findings suggest that CT-induces long-term irreversible damage to BM-microenvironment which potentially contributes to t-MN pathogenesis.
Poster Pitch: Leukemogenesis in Gata2 Haploinsufficient Mice is a Secondary Event after Bone Marrow Failure (ID 182)
Abstract
Background And Aims
MDS in young individuals is often not a random event but occurs in association with genetic predisposition. GATA2, a transcription factor shaping the hematopoietic system, is mutated in 7% of cases with RCC and 15% of cases with MDS-EB. The penetrance of myeloid neoplasia is exceedingly high in affected individuals (80% risk at the age of 40 years). Despite this high risk of MDS and leukemia, the mechanisms underlying malignant transformation are only insufficiently studied.
Methods
Using mice with GATA2 haploinsufficient hematopoietic system, we developed two model systems that allow to study leukemogenesis.
Results
In the first model, ENU was applied to introduce random mutations. Gata2+/- leukemias developed significantly faster than their wildtype (WT) counterparts, but acquired driver mutations were similar in both genotypes. Interestingly, Gata2+/- but not WT leukemias were preceded by bone marrow hypocellularity In the second mouse model, leukemias developed spontaneously after stem/progenitor cell transplantation into lethally irradiated WT hosts. In sum, 15% of recipient mice succumbed to leukemia. Yet, leukemias emerged exclusively in mice that had developed BM failure first (40% of recipients). In contrast, 60% of recipients remained healthy. Leukemia development was always associated with somatic mutations and/or chromosomal alterations indicating clonal evolution. Profound transcriptomic changes in stem/progenitor cells indicate that epigenetic alterations might contribute to the different outcomes in our mouse model.
Conclusions
GATA2 haploinsufficiency predisposes to bone marrow failure in mice, which paves the way for secondary leukemia. Somatic events contribute to the different outcomes observed in our mouse model and can serve as prognostic markers.
Poster Pitch: Outcomes of Relapsed Juvenile Myelomonocytic Leukemia: the role of Second Hematopoietic Stem Cell Transplantation (ID 184)
Abstract
Background And Aims
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most patients with juvenile myelomonocytic leukemia (JMML). Disease recurrence remains the major cause of treatment failure.
Methods
Outcome analysis of relapsed patients with JMML in the European Working Group of Myelodysplastic Syndromes in Childhood.
Results
Relapse occurred in 137 of 434 JMML patients (32%) who received allogeneic HSCT. The 5-year overall survival (OS) of all relapsed patients was 30%. Therapy approach for relapse included donor leukocyte infusion (DLI), low-dose (e.g. azacitidine) or intensive chemotherapy, and/or second HSCT. DLI (n=28) led to remission in 4 relapsed patients, but 3 of them died of complications. Chemotherapy alone was not effective for relapsed JMML. Majority of patients who did not receive second HSCT died shortly after relapse (no HSCT n=61, 5 year-OS: 8%). Remaining 76 patients (55%) received second HSCT; transplant outcomes were analyzed in 68 patients with sufficient data. The 5-year-OS, disease free survival, cumulative incidence of relapse and non-relapse mortality after second HSCT were 40%, 36%, 41% and 23%, respectively (med. follow-up: 7.7 years). Patients of older age at second HSCT (> 3 years) and early relapse (< 180 days) after first HSCT tended to have worse outcomes, while mutational subtype, type of donor, change of donor for second HSCT and conditioning regimens did not affect outcomes.
Conclusions
Second HSCT can achieve durable remission in patients with relapsed JMML, if it is feasible. Further efforts to reduce relapses after first HSCT and development of novel therapies for relapse are necessary.
Poster Pitch: Appraisal of Vendor-Supplied NGS Filter for Clinical Variant Detection in MDS and MDS/MPN Patients (ID 188)
Abstract
Background And Aims
Our clinical NGS experience (accompanying abstract & submitted paper) highlights challenges of using vendor-supplied filters with conservative pipelines. We aimed to appraise the proprietary “Oncomine” filter (OF; ThermoFisher) for clinical use.
Methods
OncomineTM Myeloid (ThermoFisher) NGS panel for 74 patients with confirmed or suspected MDS or MDS/MPN, comparing variants detected with OF versus a manual workflow including assessment with population databases (gnomAD), COSMIC, and IGV.
Results
54/74 (73%) patients had at least one variant, with 169 total variants detected by manual variant calling (mean = 2.6 variants/patient). 63/169 (37%) did not match calls made by OF overall, while 49/169 (29%) did not match OF when excluding those that fell below the 5% variant allele frequency (VAF) cut-off applied for clinical reporting. Genes with most variants missed by OF include TP53 (11%), TET2 (8%), RUNX1 (6%), DNMT3A (6%), and EZH2 (6%). Furthermore, we had serial samples for 8/74 patients, including one MDS patient with four serial sequencing results. Findings for this patient were especially informative. Three clinically-relevant variants were not captured by OF, including in PRPF8 (VAFs of 55% and later 26%), and two ETV6 variants (14% and 21%; and 43% and 29%); especially important given the prognostic significance of ETV6 variants in MDS patients. Varying VAFs between these samples are attributed to selective pressures of azacitidine treatment undergone by this patient (10 cycles completed).
Conclusions
While the conservative OF is meant to prevent over-calling of non-clinically relevant variants, our results suggest that laboratories may wish to consider complementary software for clinical variant calling.
Poster Pitch: Comparison of Cytogenetic Aberrations in 1590 Patients with Therapy-Related MDS (T-MDS) and 4738 Patients from the Revised International Prognostic Scoring System Database with Primary-MDS (P-MDS) (ID 201)
Abstract
Background And Aims
We performed an analysis on the distribution of karyotypes in therapy-related versus primary-MDS.
Methods
1590 patients with t-MDS and 4738 with p-MDS were included.
Results
Some, like -7, abnormalities(7q), +1,der(1;7), and t(11q23) appeared more frequently in t-MDS. The largest differences were found in highly complex karyotypes. Del(5q), –Y, and +8 as single aberrations were more frequent in p-MDS, as highly complex in t-MDS. Del(11q) and del(20q) did not differ between p- and t-MDS. Some abnormalities occurring regularly in p-MDS, like del(12p), i(17q), and +21 are rare in t-MDS. Regarding p-MDS, del(5q), +8, -Y, del(20q), and del(11q) are more frequent as single abnormalities. In t-MDS most aberrations, especially del(5q), are more frequent in complex karyotypes.
Isolated -7 occurred frequently after AML or lymphoma, while -Y often occurred after prostate, and del(5q) after breast cancer. –Y and del(5q) were found preferentially after radio-, -7/abn(7q) after chemotherapy. +8, del(11q), and del(20q) showed no preferences regarding pretreatment.
As many t-MDS patients were treated in MDS phase, while more p-MDS patients were not, we tried to evaluate the potential bias on the karyotypes observed. Regarding cytogenetic risk categories (IPSS-R), treated patients had a higher-risk score, but still t-MDS patients had higher-risk karyotypes than p-MDS (very poor-risk: 6% in untreated, 12% in treated p-MDS, 24% in untreated, 38% in treated t-MDS). Good or intermediate-risk karyotypes, like +8, del(20q), and -Y showed, if isolated, no differences between treated and untreated patients.
Conclusions
Our results show substantial differences between therapy-related and primary-MDS regarding cytogenetic risk-groups and the occurrence of specific aberration patterns.
Poster Pitch: PIGN Suppresses CIN and Leukemia Progression Via Regulation of the Spindle Assembly Checkpoint (ID 219)
Abstract
Background And Aims
The spindle assembly checkpoint complex (SAC) is responsible for proper chromosomal segregation during mitosis and chromosomal stability. Our published data showed that PIGN expression aberrations were linked with chromosomal instability(CIN). Thus, we investigated the mechanistic link between PIGN, CIN and the SAC.
Methods
CRISPR/Cas9 gene knockout and siRNA gene suppression, and overexpression constructs were used to study the impacts of PIGN gene expression. Cell cycle suppreson and release experiments were conducted. Co-immunoprecipitaton experiments and confocal analysis were conducted to study the interaction among PIGN and SAC protiens.
Results
CRISPR/Cas9 mediated knockout of PIGN in CD34+ mononuclear cells derived from a healthy individual resulted in the suppression of MAD1 and MAD2. A similar observation was made in HEK293 PIGN knockout cells. PIGN loss in the HEK293 cells resulted in MAD1, MAD2, and MPS1 suppression but led to BUBR1upregulation. PIGN downregulation resulted in impaired mitotic checkpoint activation and consequently impacted mitotic exit. PIGN downregulation results in defective mitotic checkpoint signaling and mitotic exit with an accumulation of missegregation errors. Interestingly, ectopic overexpression of PIGN restored the MAD1 and MAD2 expression. PIGN physically interacts with and regulates the SAC via MAD1, MAD2, MPS1 and BUBR1 during mitotic cell cycle progression. The co-purification of PIGN with some of these mitotic checkpoint proteins showed the direct role that PIGN may play in the regulation of mitotic checkpoint signaling.
Conclusions
PIGN as a CIN suppressor may be crucial in the regulation of mitotic integrity via the SAC as part of maintaining genome stability.
Poster Pitch: Cytogenetic Risk Stratification according to IPSS-R in Pediatric Myelodysplastic Syndrome (ID 226)
Abstract
Background And Aims
Pediatric myelodysplastic syndrome (MDS) is a rare disease with a risk of progression to acute myeloid leukemia. Its incidence may be underestimated due to diagnosis difficulties. In this sense, cytogenetic analysis remains one of the essential pillars for diagnosis and prognosis. Nowadays, the standard tool to predict prognosis is the Revised International Prognostic Scoring System (IPSS-R) which included a new cytogenetic score, but it was based on adult patients' studies. The aim of this study was to analyze the frequency of cytogenetic abnormalities in pediatric MDS and their risk stratification according to IPSS-R, focusing on leukemic evolution.
Methods
We studied 181 patients (1-18 years) between 2000-2020 with MDS. Chromosomal analysis was performed using G-banding and FISH. The IPSS-R was applied based on cytogenetic risk stratification.
Results
Cytogenetic abnormalities were observed in 54.6% of all cases. The most frequent abnormalities were: -7 (23.8%), del(11)(q23) (11.3%) and complex karyotypes (8%). The AML evolution was present in 26.5% (48/181). According to IPSS-R, 6.6% of patients were classified as very good prognosis, 54.6% as good prognosis, 21.5% as intermediate, 13.2% as poor, and 4% as very poor prognosis. In these groups, leukemic evolution was observed in 50% (6/12), 9% (9/99), 28% (11/39), 54% (13/24), and 85% (6/7), respectively.
Conclusions
The predictive value of the cytogenetic risk of the IPSS-R was not consistent in patients with del(11)(q23) and +8, as these patients had MDS evolution. Thus, our results indicate the need for further studies to better classify the cytogenetic risk prognosis in pediatric MDS.