Treatment strategies for high-risk MDS patients from an international perspective

Myelodysplastic syndrome (MDS) is a myeloid tumor characterized by pathological hematopoiesis, which can lead to ineffective clonal hematopoiesis, life-threatening infection or bleeding, and the risk of progression to acute myeloid leukemia (AML)
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Disease risk comes from many factors, including the degree and type of blood cell reduction, the proportion of bone marrow blasts, cytogenetic and molecular changes
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Patients with high-risk MDS have a shorter survival period.
Treatment aims to reduce MDS complications, improve quality of life and prolong survival.
Treatment options include allogeneic hematopoietic stem cell transplantation (allo-HSCT), use of demethylation drugs, innovative treatments, and clinical trials
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Professor Andrew Brunner of Harvard Medical School explained and shared the treatment strategies for high-risk MDS patients.
The editor summarizes the main content as follows
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Allo-HSCT will initially consider the potential of HSCT for high-risk MDS patients
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With the increase in the selection of alternative donors (including haploid donors) and the improvement of pretreatment programs, HSCT is currently the only possible cure for MDS, and more and more MDS patients are considering HSCT
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Choosing HSCT needs to balance the benefits and risks, especially the risk of death related to transplantation (although there is also a higher risk of death in non-transplant treatment)
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The results of several retrospective studies have shown that HSCT can improve the survival benefit of patients with high-risk MDS, and this benefit has been recognized
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Recently, the benefit of early HSCT was confirmed in a prospective study of BMT CTN 1102.
Compared with non-transplant treatment, HSCT significantly improved the survival benefit of patients (3-year overall survival [OS] rate 48% vs 27%, p=0.
0001)
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In the non-transplantation treatment group, avoiding transplantation does not seem to have any early advantages, and it can be observed that the survival curve of the HSCT group is better than that of the non-transplantation group at an early stage
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Although HSCT treatment still has some problems that can be improved, such as how to improve the patient's pre-transplant state? How to choose the best candidate patients? However, early transplantation is still the standard treatment for patients with high-risk MDS
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Treatment with demethylation drugs Regardless of whether transplantation is performed, most high-risk MDS patients are suitable for treatment with demethylation drugs (HMA) azacitidine or decitabine
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HMA has been the cornerstone and standard treatment for high-risk MDS patients in the past two decades.
Based on the AZA001 study, patients were randomly assigned to the azacitidine group or the "doctor's choice" group.
The results suggest that azacitidine can prolong the survival of patients.
Period
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A head-to-head prospective controlled study of azacitidine and decitabine has not been conducted, but a larger population study shows that the difference in survival benefits between the two drugs is very small
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The oral dosage form of Decitabine can obtain equivalent pharmacokinetics (PK) by adding the cytidine deaminase inhibitor cedazuridine, and is approved for high-risk MDS and chronic myelomonocytic leukemia (CMML) patients
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Although compared with alternative or supportive treatment, HMA can improve treatment response and prolong survival, but the prognosis of patients is still not optimal
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Only a few patients achieved remission after HMA treatment, and the 5-year survival rate was less than 10%
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Through continuous optimization of HMA monotherapy, combined with lenalidomide, vorinostat or idarubicin, but the combination did not prolong survival compared with HMA monotherapy
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Of course, the treatment goals of MDS patients may vary throughout the treatment process
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For patients who are about to undergo transplantation, it is very important to reduce the burden of disease and obtain deeper relief.
Choosing a treatment plan that achieves these goals becomes the best choice
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However, for patients who postpone transplantation or who are not suitable for transplantation, the improvement of blood cell reduction may be more important, reducing blood transfusion dependence or reducing the risk of infection and bleeding
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Considering the palliative nature of HMA treatment, prolonging survival is still the main goal, but other curative effects are also important and worthy of further study
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There are significant unmet need for treatment in these patients who are ineffective to HMA treatment or have disease progression.
Patients in this group have a short survival period, usually less than 6 months, and there is no standard treatment option
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Targeted therapy and future directions In addition to HSCT and HMA therapy, the treatment management of high-risk MDS is heterogeneous and needs to be adjusted according to the clinical and individual needs of patients
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Although the progress of supportive treatment means that many high-risk MDS patients have the opportunity to receive HMA treatment, some patients who refuse HMA or have other serious comorbidities make the application of HMA challenging
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It may be reasonable to use experimental therapies for low-risk MDS in IPSS-R, such as erythropoiesis stimulant (ESA) therapy or Luspatercept for patients with red blood cell transfusion dependent
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However, patients at the junction of MDS and AML diseases can use AML treatment strategies.
For example, MDS patients with NPM1 mutations have a higher response rate to 7+3 regimen induction chemotherapy or HMA+Veneclax
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A small number of MDS patients (<10%) carry IDH1 or IDH2 mutations.
Such mutations are more common in AML patients.
For such patients with mutations, the targeted inhibitors Ivosidenib or Enasidenib can be used to obtain meaningful therapeutic response
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Recent research results show that more and more drugs for the treatment of high-risk MDS are appearing in the public eye
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There are currently a number of phase III studies evaluating new combination therapies for high-risk MDS, including HMA combined with Pevonedistat (NCT03268954), combined with APR-246 for TP53 mutant MDS patients (NCT03745716), combined with anti-TIM3 antibody MBG453 (NCT04266301), combined with anti-CD47 antibody Magrolimab (NCT04313881), as well as the joint vinacola (NCT04401748)
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Adding new active drugs to treatment will be worth exploring, and it is possible to discover new strategies for treating diseases, including different diagnostic methods, improving treatment response and consolidating maintenance treatment options
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Reference source: Andrew Brunner, 2021 SOHO.
EXABS-149-MDS.
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