Evolving therapies for lower-risk myelodysplastic syndromes

Bewersdorf, Jan Philipp; Zeidan, Amer M.

doi:10.1007/s00277-020-03963-1

Cited by 15 publications

(20 citation statements)

References 130 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of the bone marrow haematopoietic stem cells, characterized by impaired haematopoiesis, peripheral blood cytopenias, increased blast populations in the peripheral blood and/or bone marrow and a higher risk of developing acute myeloid leukaemia (AML) [1,2]. While allogeneic hematopoietic stem cell transplant is the only potentially curative option for MDS (and other advanced haematological malignancies), many patients are not eligible for the procedure and the hypomethylating agents (HMAs) azacitidine and decitabine are the mainstay of therapy to alleviate cytopenia, control disease and prolong survival in these patients [1,[3][4][5]. HMAs are cytidine-nucleoside analogues that incorporate into DNA during the S-phase of the cell cycle and covalently bind DNA methyltransferase 1, which is then degraded and depleted within the cell, resulting in reduced methylation of CpG residues in genomic DNA, altered epigenetic pattern and modified gene expression [3,6].…”

Section: Introductionmentioning

confidence: 99%

Decitabine/Cedazuridine: First Approval

Dhillon

2020

Drugs

View full text Add to dashboard Cite

A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi ®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.

show abstract

Section: Introductionmentioning

confidence: 99%

Decitabine/Cedazuridine: First Approval

Dhillon

2020

Drugs

View full text Add to dashboard Cite

show abstract

“…While anemia is the most common symptom in MDS patients, neutropenia and thrombocytopenia occur in 15–20% and 50% of patients with MDS, respectively [ 62 , 63 ]. Supportive care with G-CSF can be considered for selected patients with neutropenia in the setting of recurrent infections.…”

Section: Treatment Algorithm For Mdsmentioning

confidence: 99%

Risk-Adapted, Individualized Treatment Strategies of Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Bewersdorf

Zeidan

2021

Cancers

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…28,29 It is also important to assess for symptoms, as asymptomatic low-risk patients without any significant cytopenias can undergo active surveillance alone with deferred treatment. 30…”

Section: Current Treatment Paradigm Anemia Evaluationmentioning

confidence: 99%

Clinical Management of Anemia in Patients with Myelodysplastic Syndromes: An Update on Emerging Therapeutic Options

Lewis¹,

Bewersdorf²,

Zeidan³

2021

CMAR

Self Cite

View full text Add to dashboard Cite

For the majority of patients with lower-risk myelodysplastic syndrome (LR-MDS), one of the primary clinical goals is to alleviate the symptoms associated with the resultant cytopenias and to minimize the transfusion burden. While supportive red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs) may lead to clinical improvement, frequent transfusions are often complicated by iron overload and decreased quality of life; furthermore, most patients either do not respond to ESAs or will eventually develop resistance. As such, there is a great need for further therapeutic options in the management of anemia related to MDS. Several additional therapeutics are now available in select patients with LR-MDS and symptomatic anemia including luspatercept, lenalidomide, and immunosuppressive therapy. Furthermore, several novel agents are currently in development to address this area of clinical need such as imetelstat and roxadustat. In this article, we review the currently available therapeutic options for symptomatic anemia in LR-MDS as well as review the therapeutic agents in development.

show abstract

Evolving therapies for lower-risk myelodysplastic syndromes

Cited by 15 publications

References 130 publications

Decitabine/Cedazuridine: First Approval

Decitabine/Cedazuridine: First Approval

Risk-Adapted, Individualized Treatment Strategies of Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Clinical Management of Anemia in Patients with Myelodysplastic Syndromes: An Update on Emerging Therapeutic Options

Contact Info

Product

Resources

About