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Journal ArticleDOI

How we manage adults with myelodysplastic syndrome

01 Jun 2020-British Journal of Haematology (Br J Haematol)-Vol. 189, Iss: 6, pp 1016-1027
TL;DR: Treatment mainly aims at improving cytopenias, principally anaemia, while in HR‐MDS it aims at delaying disease progression and prolonging survival, and the role of new drugs, including venetoclax or, in case of specific mutations, IDH1 or IDH2 inhibitors, is investigated.
Abstract: The prognosis in Myelodysplastic syndromes (MDS), although recently refined by molecular studies, remains largely based on conventional prognostic scores [International Prognostic Scoring System (IPSS), revised IPSS], classifying patients into "lower risk" MDS (LR-MDS) and "higher risk" MDS (HR-MDS). In LR-MDS, treatment mainly aims at improving cytopenias, principally anaemia, while in HR-MDS it aims at delaying disease progression and prolonging survival. In LR-MDS without deletion 5q, anaemia is generally treated first by erythropoietic stimulating factors, while second line treatments are currently not approved [lenalidomide, hypomethylating agents (HMA), luspatercept] or rarely indicated (antithymocyte globulin). Lenalidomide has major efficacy in LR-MDS with deletion 5q. Allogeneic stem cell transplantation (allo-SCT) is sometimes considered in LR-MDS, and iron chelation can be considered when multiple red blood cell transfusions are required. Allo-SCT is the only potentially curative treatment for HR-MDS; however, it is rarely applicable. It is generally preceded by intensive chemotherapy (IC) or HMA in patients with excess of marrow blasts (especially if >10%). In other patients, HMA can improve survival. The role of new drugs, including venetoclax or, in case of specific mutations, IDH1 or IDH2 inhibitors, is investigated. IC is mainly indicated as a bridge to allo-SCT, in the absence of unfavourable karyotype.
Citations
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Journal ArticleDOI
TL;DR: Evidence that overactivation of SMAD2/3 signaling pathways in MDSs causes anemia due to impaired erythroid maturation is summarized and the basis for biological activity of activin receptor ligand traps and novel fusion proteins such as luspatercept are described.
Abstract: Signaling by the TGF-β superfamily is important in the regulation of hematopoiesis and is dysregulated in myelodysplastic syndromes (MDSs), contributing to ineffective hematopoiesis and clinical cytopenias. TGF-β, activins, and growth differentiation factors exert inhibitory effects on red cell formation by activating canonical SMAD2/3 pathway signaling. In this Review, we summarize evidence that overactivation of SMAD2/3 signaling pathways in MDSs causes anemia due to impaired erythroid maturation. We also describe the basis for biological activity of activin receptor ligand traps, novel fusion proteins such as luspatercept that are promising as erythroid maturation agents to alleviate anemia and related comorbidities in MDSs and other conditions characterized by impaired erythroid maturation.

32 citations

Journal ArticleDOI
TL;DR: Fit patients with NPM1-mutated MNs with <20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS-directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data.
Abstract: Nucleophosmin (NPM1) gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented NPM1 mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of blasts, and 3% of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) cases, prevalently classified as chronic myelomonocytic leukemia. These uncommon malignancies are associated with an aggressive clinical course, relatively rapid progression to overt acute myeloid leukemia (AML) and poor survival outcomes, raising controversies on their classification as distinct clinico-pathologic entities. Furthermore, fit patients with NPM1-mutated MNs with <20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS-directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data, obtained from small and mainly retrospective series. Caution is also suggested in definitely diagnosing NPM1-mutated MNs with blast count <20%, since NPM1-mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to NPM1-mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether NPM1 mutations may become sufficient to diagnose AML, irrespective of blast percentage.

28 citations


Cites background from "How we manage adults with myelodysp..."

  • ...Moreover, standard induction chemotherapy could usually be suggested as a bridge to transplant cytoreduction for patients with favorable or intermediate risk karyotype, whereas HMA may be preferred for cases showing unfavorable genetic lesions [89,100]....

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Journal ArticleDOI
28 May 2021-Leukemia
TL;DR: In this paper, the authors discuss some of the challenges related to the current myelodysplastic syndromes (MDS) treatment landscape, as well as new approaches currently in development.
Abstract: Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia. Most patients with MDS are affected by anemia and anemia-related symptoms, which negatively impact their quality of life. While many patients with MDS have lower-risk disease and are managed by existing treatments, there currently is no clear standard of care for many patients. For patients with higher-risk disease, the treatment priority is changing the natural history of the disease by delaying disease progression to acute myeloid leukemia and improving overall survival. However, existing treatments for MDS are generally not curative and many patients experience relapse or resistance to first-line treatment. Thus, there remains an unmet need for new, more effective but tolerable strategies to manage MDS. Recent advances in molecular diagnostics have improved our understanding of the pathogenesis of MDS, and it is becoming clear that the diverse nature of genetic abnormalities that drive MDS demands a complex and personalized treatment approach. This review will discuss some of the challenges related to the current MDS treatment landscape, as well as new approaches currently in development.

24 citations

Journal ArticleDOI
31 Mar 2021-Cancers
TL;DR: A review of the current management of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) can be found in this paper.
Abstract: Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are two distinct blood cancers with a variable clinical symptom burden and risk of progression to acute myeloid leukemia. Management decisions should be guided by individual patient and disease characteristics and based on validated risk stratification tools. While supportive care with red blood cell transfusions, erythropoiesis-stimulating agents, and iron chelation remains the mainstay of therapy for lower-risk (LR)-MDS patients, luspatercept has recently been approved for transfusion-dependent anemic LR-MDS patients ending a decade without any new drug approvals for MDS. For higher-risk patients, allogeneic hematopoietic cell transplant (allo-HCT) remains the only curative therapy for both MDS and CMML but most patients are not eligible for allo-HCT. For those patients, the hypomethylating agents (HMA) azacitidine and decitabine remain standard of care with azacitidine being the only agent that has shown an overall survival benefit in randomized trials. Although early results from novel molecularly driven agents such as IDH1/2 inhibitors, venetoclax, magrolimab, and APR-246 for MDS as well as tagraxofusp, tipifarnib, and lenzilumab for CMML appear encouraging, confirmatory randomized trials must be completed to fully assess their safety and efficacy prior to routine clinical use. Herein, we review the current management of MDS and CMML and conclude with a critical appraisal of novel therapies and general trends in this field.

11 citations

References
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Journal ArticleDOI
15 Mar 1997-Blood
TL;DR: The International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems as discussed by the authors.

4,133 citations

Journal ArticleDOI
20 Sep 2012-Blood
TL;DR: This revised IPSS-R comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS and should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.

2,310 citations

Journal ArticleDOI
TL;DR: Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
Abstract: Summary Background Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. Methods In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m 2 per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French–American–British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Findings Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21·1 months (IQR 15·1–26·9), median overall survival was 24·5 months (9·9–not reached) for the azacitidine group versus 15·0 months (5·6–24·1) for the conventional care group (hazard ratio 0·58; 95% CI 0·43–0·77; stratified log-rank p=0·0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50·8% (95% CI 42·1–58·8) of patients in the azacitidine group were alive compared with 26·2% (18·7–34·3) in the conventional care group (p Interpretation Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care. Funding Celgene Corporation.

2,282 citations


"How we manage adults with myelodysp..." refers background in this paper

  • ...In a randomised phase 3 clinical trial in higher-risk MDS patients, a survival benefit with azacitidine was demonstrated over conventional care regimens (Fenaux et al, 2009), with a median survival of 24 4 months compared to 15 months....

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  • ...Hypomethylating agents, including azacitidine (and decitabine, not approved in Europe)—are currently the first line treatment in most cases of higher-risk MDS (Fenaux et al, 2009; Kantarjian et al, 2012)....

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  • ...The survival advantage with azacitidine was seen irrespective of age, marrow blast percentage and karyotype (Fenaux et al, 2009)....

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  • ...The role of intensive chemotherapy (IC, mainly based on anthracycline-cytarabine combinations) in HR-MDS has been challenged by the advent of HMAs (Fenaux et al, 2009): IC can induce 40–60% complete response (CR) rates but these are usually of short duration (median less than 12 months) (Wattel et…...

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05 Dec 2005

1,624 citations

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How i treat myelodysplastic syndrome in an adult with Down syndrome?

The provided paper does not mention how to treat myelodysplastic syndrome specifically in adults with Down syndrome.