Welcome to the MDS 2021 Interactive Programme
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Introduction to the Tito Bastianello Awards (ID 328)
Trajectories of MDS Evolution in the Context of Aplastic Anemia (ID 97)
Abstract
Background And Aims
Clonal evolution occurring in about 20% of aplastic anemia (AA) patients provides instructive clues for the general understanding of MDS.
Methods
An integrative analysis of germline (GL) and somatic leukemogenic and immune-escape mutations (HLA,PIGA) was performed during AA to MDS progression.
Results
Among 350 AA patients, 11% developed MDS at a median time of 6yrs. MDS evolution was less common in moderate AA and reciprocal to PNH clone expansion (p=.0003) with abnormal karyotype present in 83% of patients, involving chr.7 in 47% of cases (vs. 7.5% in primary MDS-pMDS, Fig.1A-B). GL pathogenic (e.g.,SAMD9L, SBDS) alterations (n=9) and likely-pathogenic (n=11), were enriched in progressors and del(7q) patients (p=.0001) but no immunogenetic associations (HLA risk-alleles nor evolutionary divergence) were found. Progression was associated with acquisition of new somatic hits, including e.g., ASXL1, SETBP1 and ETV6 in del(7q)/-7 carriers (Fig.1C-F). In 9 patients antecedent TET2, DNMT3A and ASXL1 mutant clones were present and further expanded upon MDS evolution (p=.0001; Fig.1G-H). Clonal hierarchy by allelic imbalance identified del(7q)/-7 as a founder lesion in 60% of patients (vs. 50% in pMDS). Concomitant with leukemogenic mutations, 21% of progressors (vs. 13% of non-progressing AA; Fig.1I) harbored somatic HLA class-I/II lesions, while PIGA clones were found in 9% of cases.
Conclusions
In the context of immune-mediated attack and common immunogenetic predisposition, clonal evolution is a maladaptive phenomenon characterized by acquisition of immune-escape phenotype (HLA,PIGA mutations) and somatic leukemogenic events. In addition to complete polyclonal hematopoietic recovery, evolution of HLA-mutant or PIGA/PNH hematopoiesis corresponds to adaptive and semi-adaptive clonal recovery, respectively.
A Pre-Clinical Patient-Derived Xenograft Model of Myelodysplastic Syndromes Demonstrates Efficacy and Safety Of Eltrombopag (ID 168)
Abstract
Background And Aims
Pre-clinical research of MDS is impeded by the lack of feasible in-vitro and in-vivo models. Previously, we have established a robust niche-based PDX model of MDS. In this study, we demonstrate for the first time that this model is applicable as a pre-clinical platform to address pending clinical questions by investigating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag (EPAG).
Methods
BM derived CD34+ cells and MSCs of MDS patients were intrafemorally transplanted (IF TX) into NSG mice. Engrafted mice were treated with EPAG or vehicle for 18-24 weeks. In PB, huCD41+ platelets were absolutely quantified using a bead-based flow cytometric assay. Sorted huCD45+ BM cells of PDX samples at different time points were analyzed by whole exome sequencing to determine clonal evolution throughout treatment.
Results
In total, we included n=49 PDX of n=9 MDS primary patient samples. In EPAG-treated PDX, overall response rate in human platelets was 56%. Increase in human megakaryocytes was confirmed by IHC and FACS. Human engraftment and percentage of huCD34+ cells were not affected by EPAG treatment. The clonal BM composition remained stable in the majority of cases. Novel molecular lesions were observed in n=4 (17%) vehicle- and n=2 (8%) EPAG-treated PDX.
Conclusions
In conclusion, this experimental setup allowed for vehicle- and replicate-controlled analyses on a patient-individual level deciphering substance-specific effects from natural disease progression thereby supporting efficacy and safety data of EPAG in MDS, and validating our MDS PDX model to be a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.
Immune Escape via Class I And II HLA Somatic Mutations in Myelodysplastic Syndromes and Acute Myeloid Leukemia Relapsing after Hematopoietic Stem Cell Transplantation (ID 200)
Abstract
Background And Aims
Curative potential of allogeneic hematopoietic stem cell transplantation (HSCT) in myeloid malignancies depends on effective graft versus leukemia effect (GvL). Decreased expression or genomic aberrations involving human leukocyte antigen (HLA) region (somatic 6p deletion/loss of heterozygosity [LOH]) have been described in haploidentical/mismatched and matched contexts as mechanisms facilitating leukemic relapse. We hypothesized that somatic mutations in class I-II HLA alleles may also contribute to immune escape from GvL.
Methods
We performed a genetic characterization of sequential specimens from 48 patients with MDS and AML relapsing after HSCT, assessing HLA region along with 173 leukemia-associated genes.
Results
Ninety-six serial samples (39 at MDS/AML diagnosis, 48 at post-HSCT and 9 at post-chemotherapy relapse) were analyzed. Disruptive HLA mutations were found in 29% of the patients (4% at diagnosis and 25% at post-transplant relapse), in both class I and II loci. In post-transplant group, 75% of those events were found in patients receiving graft from a matched donor, while 25% received a haploidentical transplant. Patients with HLA mutations had more likely a later relapse (median time: 554 vs 150 days after transplant, p=.00042). Also, among those who received donor lymphocyte infusion-based regimens, none of the HLA-mutated (0/6) vs 12/19 HLA wild-type patients had transient or stable responses. Interestingly, when examining the somatic myeloid landscape, HLA-mutated cases were enriched in genetic aberrations in epigenetic regulators (such as TET2, EZH2, EP300 and DNMT3A) (Figure 1).
Conclusions
In conclusion, here we describe the existence of a new mechanism of HLA-loss and post-transplant immune escape facilitating leukemia relapse.
Single-Cell-Level Analysis of SF3B1-Mutant Myelodysplastic Syndrome with Ringed Sideroblasts (ID 229)
Abstract
Background And Aims
SF3B1 mutations (SF3B1MT) cause abnormal erythroid terminal differentiation, resulting in myelodysplastic syndromes with ringed sideroblasts (MDS-RS), which are characterized by peripheral blood (PB) anemia and the accumulation of ringed sideroblasts in the bone marrow (BM). Many studies have analyzed the transcriptional and splicing landscape of bulk hematopoietic stem and progenitor cells (HSPCs) with SF3B1MT. Here, we sought to understand how SF3B1MT affect the differentiation potential of HSPCs and more differentiated BM mononuclear cells (MNCs) at the single-cell level.
Methods
We used single cell technologies combined with functional studies to analyze the expression profile of single HSPCs and MNCs isolated from patients with MDS-RS at different stages of the disease.
Results
We found that SF3B1MT enhance an initial differentiation of MDS stem cells towards the erythroid lineage but then induce a more downstream differentiation arrest when erythroid cells are at the orthochromatic step of maturation before their release into the PB. Expression analysis of erythroid cells across the last stages of erythroid differentiation in the BM revealed a significant upregulation of genes involved in the response of eukaryotic translation initiation factor 2 alpha kinase 1 (EIF2AK1) to heme deficiency, including EIF2AK1, EIF2S1, ATF4, and DDIT3, culminating in the upregulation of the autophagy signature in orthochromatic cells. These aberrant pathways were completely rescued when patients achieved complete remission and became transfusion-independent after hypomethylating agent treatment.
Conclusions
Our findings suggest that the EIF2AK1 signaling pathway should be further investigated to help develop therapies that elicit stable responses in MDS-RS patients.