Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual ...patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.
•Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival.•Mutant TP53 AML/MDS-EB should be considered a single molecular disease entity.
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Slan+ non‐classical monocytes are equipped with a distinctive immunological gene set compared to DCs, and harbor monocyte‐like functional features.
Human 6‐sulfo LacNac‐positive (slan+) cells have ...been subject to a paradigm debate. They have previously been classified as a distinct dendritic cell (DC) subset. However, evidence has emerged that they may be more related to monocytes than to DCs. To gain deeper insight into the functional specialization of slan+ cells, we have compared them with both conventional myeloid DC subsets (CD1c+ and CD141+) in human peripheral blood (PB). With the use of genome‐wide transcriptional profiling, as well as functional tests, we clearly show that slan+ cells form a distinct, non‐DC‐like population. They cluster away from both DC subsets, and their gene‐expression profile evidently suggests involvement in distinct inflammatory processes. An extensive transcriptional meta‐analysis confirmed the relationship of slan+ cells with the monocytic compartment rather than with DCs. From a functional perspective, their ability to prime CD4+ and CD8+ T cells is relatively low. Combined with the finding that “antigen presentation by MHC class II” is at the top of under‐represented pathways in slan+ cells, this points to a minimal role in directing adaptive T cell immunity. Rather, the higher expression levels of complement receptors on their cell surface, together with their high secretion of IL‐1β and IL‐6, imply a specific role in innate inflammatory processes, which is consistent with their recent identification as non‐classical monocytes. This study extends our knowledge on DC/monocyte subset biology under steady‐state conditions and contributes to our understanding of their role in immune‐mediated diseases and their potential use in immunotherapeutic strategies.
Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus ...Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.
Summary
Most patients with myelodysplastic syndromes (MDS) require therapeutic intervention. However, there are few approved treatments for MDS. To explore reasons, we searched clinicaltrials.gov and ...clinicaltrialsregister.eu for MDS trials from 2000 to 2020. We assessed which agents were under investigation and analysed clinical trial characteristics and continuation rates from phase I to II to III to approval. As such, we identified 384 unique agents in 426 phase I, 430 phase II and 48 phase III trials. Success rates for phase III trials and agents were low, and MDS trials took markedly longer to complete than the average clinical trial. Although success rates were higher when MDS‐specific phase I trials were conducted, 52% of the agents had not been evaluated in a phase I trial for MDS. MDS trials often failed to include quality of life, an especially important outcome for older MDS patients. Our work identifies factors potentially contributing to the paucity of available agents for MDS. We suggest a framework to improve clinical research in MDS that might ultimately augment the number of available agents.
The diagnostic work‐up of patients suspected for myelodysplastic syndromes is challenging and mainly relies on bone marrow morphology and cytogenetics. In this study, we developed and prospectively ...validated a fully computational tool for flow cytometry diagnostics in suspected‐MDS. The computational diagnostic workflow consists of methods for pre‐processing flow cytometry data, followed by a cell population detection method (FlowSOM) and a machine learning classifier (Random Forest). Based on a six tubes FC panel, the workflow obtained a 90% sensitivity and 93% specificity in an independent validation cohort. For practical advantages (e.g., reduced processing time and costs), a second computational diagnostic workflow was trained, solely based on the best performing single tube of the training cohort. This workflow obtained 97% sensitivity and 95% specificity in the prospective validation cohort. Both workflows outperformed the conventional, expert analyzed flow cytometry scores for diagnosis with respect to accuracy, objectivity and time investment (less than 2 min per patient).
An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International ...Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with ≥10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT.
Current risk algorithms are primarily based on pre-treatment factors and imperfectly predict outcome in acute myeloid leukemia (AML). We introduce and validate a post-treatment approach of leukemic ...stem cell (LSC) assessment for prediction of outcome. LSC containing CD34+CD38- fractions were measured using flow cytometry in an add-on study of the HOVON102/SAKK trial. Predefined cut-off levels were prospectively evaluated to assess CD34+CD38-LSC levels at diagnosis (n = 594), and, to identify LSC
/LSC
(n = 302) and MRD
/MRD
patients (n = 305) in bone marrow in morphological complete remission (CR). In 242 CR patients combined MRD and LSC results were available. At diagnosis the CD34
CD38
LSC frequency independently predicts overall survival (OS). After achieving CR, combining LSC and MRD showed reduced survival in MRD
/LSC
patients (hazard ratio HR 3.62 for OS and 5.89 for cumulative incidence of relapse CIR) compared to MRD
/LSC
, MRD
/LSC
, and especially MRD
/LSC
patients. Moreover, in the NPM1mutant positive sub-group, prognostic value of golden standard NPM1-MRD by qPCR can be improved by addition of flow cytometric approaches. This is the first prospective study demonstrating that LSC strongly improves prognostic impact of MRD detection, identifying a patient subgroup with an almost 100% treatment failure probability, warranting consideration of LSC measurement incorporation in future AML risk schemes.
Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly ...defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia.
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•Mesenchymal deletion of Sbds in mice recapitulates bone defects in SDS•Mesenchymal niche cells induce genotoxic stress in HSPCs in this model•p53-S100A8/9-TLR4 signaling, activated in SDS and MDS, drives these phenotypes•Mesenchymal S100A8/9 predicts leukemic evolution and disease outcome in human MDS
Cell-extrinsic factors driving malignant transformation remain understudied. In a mouse model of pre-leukemia, Zambetti and colleagues establish a concept of mesenchymal niche-induced genotoxic stress in hematopoietic stem cells through p53-S100A8/9-TLR4 signaling, with relevance to human leukemia. The findings provide conceptual and mechanistic insights into the link between inflammation and cancer.
The current World Health Organization classification of myelodysplastic syndromes is based morphological evaluation of bone marrow dysplasia. In clinical practice, the reproducibility of the ...recognition of dysplasia is usually poor especially in cases that lack specific markers such as ring sideroblasts and clonal cytogenetic abnormalities.
We aimed to develop and validate a flow cytometric score for the diagnosis of myelodysplastic syndrome. Four reproducible parameters were analyzed: CD34(+) myeloblast-related and B-progenitor-related cluster size (defined by CD45 expression and side scatter characteristics CD34(+) marrow cells), myeloblast CD45 expression and granulocyte side scatter value. The study comprised a "learning cohort" (n=538) to define the score and a "validation cohort" (n=259) to confirm its diagnostic value.
With respect to non-clonal cytopenias, patients with myelodysplastic syndrome had increased myeloblast-related cluster size, decreased B-progenitor-related cluster size, aberrant CD45 expression and reduced granulocyte side scatter (P<0.001). To define the flow cytometric score, these four parameters were combined in a regression model and the weight for each variable was estimated based on coefficients from that model. In the learning cohort a correct diagnosis of myelodysplastic syndrome was formulated in 198/281 cases (sensitivity 70%), while 18 false-positive results were noted among 257 controls (specificity 93%). Sixty-five percent of patients without specific markers of dysplasia (ring sideroblasts and clonal cytogenetic abnormalities) were correctly classified. A high value of the flow cytometric score was associated with multilineage dysplasia (P=0.001), transfusion dependency (P=0.02), and poor-risk cytogenetics (P=0.04). The sensitivity and specificity in the validation cohort (69% and 92%, respectively) were comparable to those in the learning cohort. The likelihood ratio of the flow cytometric score was 10.
A flow cytometric score may help to establish the diagnosis of myelodysplastic syndrome, especially when morphology and cytogenetics are indeterminate.
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