Active Treatments

Overview

Many patients with MDS become transfusion-dependent, resulting in complications. Active treatments can be used to help manage anemia associated with MDS.Lewis R, et al. Cancer Manag Res. 2021;13:645-657. Kubasch AS, et al. Blood Adv. 2021;5(5):1565-1575.

Official recommendations describing the use of active treatments for MDS continue to evolve. Please review the latest NCCN Guidelines® for more information

For lower-risk MDS (LR-MDS), the primary goals of active treatment are to increase patient quality of life by improving cytopenias and decreasing transfusion burden.Platzbecker U. Blood. 2019;133(10):1096-1107.

Erythroid Maturation Agents (EMAs)

In MDS, aberrant TGF-β signaling impairs late-stage erythropoiesis, preventing the maturation of erythroid progenitor cells.Kubasch AS, et al. Blood Adv. 2021;5(5):1565-1575.

Agents in this class: Luspatercept

Baso, basophilic erythroblast; BFU-E, burst-forming unit erythroid cells; CFU-E, colony-forming unit erythroid cells; Erythro, erythrocyte; HSC, hematopoietic stem cell; OrthoC, orthochromatic erythroblast; PolyC, polychromatic erythroblast; ProEbl, proerythroblast; Reti, reticulocyte; TGF, transforming growth factor.

Luspatercept is a recombinant fusion protein that binds to TGF-β superfamily ligands leading to reduction in SMAD signaling allowing for erythroid maturation through differentiation and increased erythroid precursors, thereby increasing red blood cell (RBC) production and improvement of anemia.Kubasch AS, et al. Blood Adv. 2021;5(5):1565-1575. Vinchi F, Platzbecker U. Hemasphere. 2024;8(3):e41.

Role in MDS

EMAs can be used for the treatment of anemia associated with MDS in patients with transfusion-dependent, LR-MDS regardless of previous exposure to ESAs.Vinchi F, Platzbecker U. Hemasphere. 2024;8(3):e41. DailyMed – Reblozyl. Accessed May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82f4d266-3f52-41eb-86ba-0abf3cf468e8

Potential characteristics and limitations to EMA use in LR-MDS include:Lewis R, et al. Cancer Manag Res. 2021;13:645-657. DailyMed – Reblozyl. Accessed May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82f4d266-3f52-41eb-86ba-0abf3cf468e8 Merz AMA, Platzbecker U. Haematologica. 2025;110(2):330-338.

  • May improve anemia associated with MDS
  • May facilitate transfusion independence and increased hemoglobin
  • Can be used regardless of prior ESA use
  • Risk of AEs including:
    • Hypertension
    • Fatigue
    • Diarrhea
    • Nausea
    • Dizziness

Review the full US Prescribing Information for more information about prescribing luspatercept, including important warnings and adverse events.

Additional Studies and Considerations

Clinical studies are ongoing to determine the safety and effectiveness of luspatercept vs epoetin alfa in preventing the progression to transfusion dependence in ESA-naïve adult patients with LR-MDS.Merz AMA, Platzbecker U. Haematologica. 2025;110(2):330-338.

Further studies are needed to investigate luspatercept:Merz AMA, Platzbecker U. Haematologica. 2025;110(2):330-338. Komrokji RS, et al. Blood Adv. 2023;7(14):3677-3679. McMahon C, et al. Am Soc Clin Oncol Educ Book. 2025;45(3):e473654.

  • Combination with active treatments
  • Sequencing of therapies
  • Alternate dosing strategies

Erythropoiesis-Stimulating Agents (ESAs)

Ineffective erythropoiesis in MDS is the result of disrupted signaling pathways preventing proper production of mature RBCs, such as erythropoietin (EPO) and its receptor (EpoR).Kubasch AS, et al. Blood Adv. 2021;5(5):1565-1575. Vinchi F, Platzbecker U. Hemasphere. 2024;8(3):e41.

Agents in this class: Epoetin alfa and darbepoetin alfa

Baso, basophilic erythroblast; BFU-E, burst-forming unit erythroid cells; CFU-E, colony-forming unit erythroid cells; Erythro, erythrocyte; HSC, hematopoietic stem cell; OrthoC, orthochromatic erythroblast; PolyC, polychromatic erythroblast; ProEbl, proerythroblast; Reti, reticulocyte; TGF, transforming growth factor.

ESAs act during early-stage erythropoiesis by binding EpoR on erythroid progenitor cells to drive production of mature RBCs by activating pathways responsible for differentiation, proliferation, and survival.Vinchi F, Platzbecker U. Hemasphere. 2024;8(3):e41. Trivedi G, et al. Trends Mol Med. 2021;27(10):990-999. Elliot S, et al. Ann Hematol. 2014 ;93 :181-192.

Role in MDS

ESAs are not indicated for treatment of anemia associated with MDS within the US, however there are clinical data to support their use in this setting.DailyMed – Epogen. Accessed May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1f2d0b28-9cc5-4523-80b8-637fdaf3f7a5 Dailymed – Aranesp. Accessed May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0fd36cb9-c4f6-4167-93c9-8530865db3f9

Potential characteristics and limitations to ESA use in LR-MDS include:Lewis R, et al. Cancer Manag Res. 2021;13:645-657. Di Veroli A, et al. J Rare Dis Res Treat. 2017;2(6):41-44. Hendrick F, et al. Medicare Medicaid Res Rev. 2014;4(4):mmrr2014-004-04-a02. Fenaux P, et al. Leukemia. 2018;32:2648-2658. Platzbecker U, et al. Leukemia. 2017;31:1994-1950.

  • May improve anemia associated with MDS
  • Can reduce the need for RBC transfusions
  • Not FDA-approved for MDS
  • Some patients are or may become treatment refractory
  • Risk of AEs including:
    • Asthenia
    • Fatigue
    • Dyspnea

Review the full US Prescribing Information for more information about prescribing epoetin alfa and darbepoetin alfa, including important warnings and adverse events.

Additional Studies and Considerations

ESAs may not be as effective in certain patient populations, such as those with:Lewis R, et al. Cancer Manag Res. 2021;13:645-657.

  • High RBC transfusion requirements
  • High serum EPO level (200-500 mU/mL)

Hypomethylating Agents (HMAs)

Aberrant DNA methylation plays a pivotal role in cancer-related pathways, such as invasion, DNA repair, and cell cycle regulation.Stomper J, et al. Leukemia. 2021;35:1873-1859.

Agents in this class: Azacitidine, decitabine, and cedazuridine

DNMT, DNA methyltransferase; hCNT, human concentrative nucleoside transporter; hENT, human equilibrative nucleoside transporter.

HMAs are taken into the cell, activated, and incorporated into nucleic acids where they inhibit DNA methylation proteins and induce DNA hypomethylation. While decitabine is exclusively incorporated into DNA, only 10-20% of azacitidine follows the same process, as the majority is incorporated into RNA.Stomper J, et al. Leukemia. 2021;35:1873-1859.

Role in MDS

  • HMA use for treatment of LR-MDS is limited to late stages of treatment after failure of 1L ESAsPlatzbecker U. Blood. 2019;133(10):1096-1107.
  • HMAs are the only approved therapeutics for patients with HR-MDS who are not suitable for intensive treatment optionsPlatzbecker U. Blood. 2019;133(10):1096-1107.

Potential characteristics and limitations to HMA use in LR-MDS include:Stomper J, et al. Leukemia. 2021;35:1873-1859. DailyMed – Azacitidine. Accessed May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cd9db533-8a49-4d01-99e2-b2db8db1ed38 Dailymed – Decitabine. Accessed May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5662c353-05d0-4bd8-87e4-c92ec9ca861e DailyMed. Cedazurdiine and decitabine. Accessed August 2025. https://dailymed. nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fa97bf5-28a2-48f1-8955-f56012d296be

  • May lead to achievement of transfusion independence
  • Can be used as a low dose, 3-day regimen based on prospective studies
  • Patients may be at risk for developing resistance and relapse
  • Risk of AEs including:
    • Cytopenias
    • Embryo-fetal toxicity
    • Hepatotoxicity
    • Renal toxicity
    • Tumor lysis syndrome
    • Myelosuppression

Review the full US Prescribing Information for more information about prescribing azacitidine, decitabine, and cedazuridine, including important warnings and adverse events.

Additional Studies and Considerations

Next generation HMAs are currently being investigated for improvements in:Stomper J, et al. Leukemia. 2021;35:1873-1859.

  • Drug half-life
  • Oral bioavailability

Immunomodulatory Agents (IMiDs)

In a subset of patients with MDS, specific deletions in chromosome 5 [del(5q)] lead to abnormal gene expression, resulting in macrocytic anemia and thrombocytosis.Fink EC, Ebert BL. Blood. 2015;126(21):2366-2369.

Agents in this class: Lenalidomide

CUL4A, Cullin 4A; CRBN, cereblon; DDB1, damage-specific DNA binding protein 1; LEN, lenalidomide; ROC1, ring-box 1.

Lenalidomide binds CRBN and recruits the substrate casein kinase 1α (CK1α), which is then ubiquitinated by E3 ubiquitin ligase. Ubiquitination of CK1α leads to increased apoptosis in del(5q) MDS cells. Lenalidomide also acts on MDS cells directly by inhibiting proliferation, as well as having a modulatory effect on the immune cells in the bone marrow microenvironmentTrivedi G, et al. Trends Mol Med. 2021;27(10):990-999. Fink EC, Ebert BL. Blood. 2015;126(21):2366-2369. Stahl M, Zeidan AM. Cancer. 2017;123(10):1703-1713.

Role in MDS

IMiDs are used for the treatment of low- or intermediate-1 risk transfusion-dependent MDS with del(5q) with or without additional cytogenetic abnormalities.Lewis R, et al. Cancer Manag Res. 2021;13:645-657. DailyMed Revlimid. Accessed May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fa97bf5-28a2-48f1-8955-f56012d296be

Potential characteristics and limitations to IMiD use in LR-MDS include:DailyMed Revlimid. Accessed May 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fa97bf5-28a2-48f1-8955-f56012d296be Roncador M et al. Blood. Published online August 4, 2025. doi:10.1182/blood.2025028619

  • May lead to achievement of transfusion independence
  • Clinical data demonstrated complete cytogenetic response
  • Limited efficacy in patients without del(5q)
  • Black box warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism

Review the full US Prescribing Information for more information about prescribing lenalidomide, including important warnings and adverse events.

Additional Studies and Considerations

Additional studies are investigating the use of lenalidomide in:Brunner AM, et al. Blood Cancer J. 2022;12(12):166.

  • Non-transfusion-dependent del(5q) LR-MDS patients
  • Non-transfusion-dependent, non-del(5q) LR-MDS, in combination with EPO

Telomerase Inhibitors

Telomerase is a protein that maintains the protective ends of chromosomes (telomeres). It allows cells to divide as needed without the shortening of chromosomes. In MDS, telomerase is overactive, which promotes malignant cell growth.DailyMed. Imetelstat. Accessed May 7, 2025. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b0fab7ca-e578-43c5-9df6-bdaff4182257&type=display National Cancer Institute Dictionary of Cancer Terms. Telomerase. Accessed May 5, 2025. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/telomerase National Human Genome Research Institute. Telomere. Accessed May 7, 2025. https://www.genome.gov/genetics-glossary/Telomere Lennox AL et al. Clin Transl Sci. 2024;17(11):e70076.

Agents in this class: Imetelstat

In normal cells, telomerase is active only at certain times to support required cell division. In LR-MDS, malignant cells have higher telomerase activity, interfering with cell death; at the same time, they often have shortened telomeres. Increased telomerase activity in malignant progenitor cells leads to abnormal growth and disrupts production of mature healthy cells in MDS.Lennox AL et al. Clin Transl Sci. 2024;17(11):e70076. Platzbecker U et al. Lancet. 2024;403(10423):249-260.

Telomerase inhibitors block malignant cell growth and promote their death. They do this by preventing malignant cells from maintaining telomere length resulting in the loss of their ability to continually grow and divide. This results in cell death.Lennox AL et al. Clin Transl Sci. 2024;17(11):e70076.

Role in MDS

Telomerase inhibitors can be used to treat adult patients with transfusion-dependent, LR-MDS who are unresponsive to or ineligible for ESA use. DailyMed. Imetelstat. Accessed May 7, 2025. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b0fab7ca-e578-43c5-9df6-bdaff4182257&type=display Lennox AL et al. Clin Transl Sci. 2024;17(11):e70076. Platzbecker U et al. Lancet. 2024;403(10423):249-260.

 

Potential characteristics and limitations to telomerase inhibitors use in LR-MDS include:Merz AMA, Platzbecker U. Haematologica. 2025;110(2):330-338. DailyMed. Imetelstat. Accessed May 7, 2025. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b0fab7ca-e578-43c5-9df6-bdaff4182257&type=display Platzbecker U et al. Lancet. 2024;403(10423):249-260.

  • May lead to achievement of transfusion independence
  • May reduce underlying population of malignant clones
  • Risk of AEs including:
    • Severe thrombocytopenia or neutropenia
    • Infusion-related reactions
    • Infections 
    • Sepsis 
    • Fracture
    • Cardiac failure
    • Hemorrhage
    • Elevated liver enzymes
    • Fatigue

Review the full US Prescribing Information for more information about prescribing ivosidenib, olutasidenib, or enasidenib, including important warnings and adverse events.

Targeted therapies are useful for specific patients

Targeted therapies block pathways that drive dysfunctional growth or survival in cancer cells. These therapies are designed to minimize harm to normal, healthy cells.National Cancer Institute Dictionary of Cancer Terms. Targeted Therapy. Accessed May 6, 2025. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/targeted-therapy Zhong L et al. Signal Transduct Target Ther. 2021;6(1):201.

Targeted therapies can help certain patients with MDS achieve transfusion independence by addressing defects in hematopoiesis.Merz AMA, Platzbecker U. Haematologica. 2025;110(2):330-338. Molenaar RJ, Wilmink JW. J Histochem Cytochem. 2022;70(1):83-97. DailyMed. Ivosidenib. Accessed May 6, 2025. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=65d254c0-67ad-42c4-b972-ad463b755b2d&type=display 

An example of targeted therapies that may be used for the treatment of MDS include IDH1/IDH2 inhibitors.DailyMed. Ivosidenib. Accessed May 6, 2025. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=65d254c0-67ad-42c4-b972-ad463b755b2d&type=display  Sebert M et al. Blood. 2024;144(Supplement 1): 1839-1840. DiNardo CD et al. Blood Adv. 2023;7(11):2378-2387.

IDH1/IDH2 Inhibitors

Isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) are key enzymes in cellular metabolism. In MDS, mutations in the IDH1 or IDH2 genes disrupt normal differentiation of precursor cells.Molenaar RJ, Wilmink JW. J Histochem Cytochem. 2022;70(1):83-97. DiNardo CD et al. Blood Adv. 2023;7(11):2378-2387. Medeiros BC et al. Leukemia. 2017;31(2):272-281.

Agents in this class: Ivosidenib (IDH1), olutasidenib (IDH1), and enasidenib (IDH2)

Mutant IDH1 or IDH2 makes the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates cellular metabolism and gene expression. This prevents differentiation of precursor cells into mature healthy cells and promotes accumulation of blast cells.Molenaar RJ, Wilmink JW. J Histochem Cytochem. 2022;70(1):83-97. DiNardo CD et al. Blood Adv. 2023;7(11):2378-2387. Medeiros BC et al. Leukemia. 2017;31(2):272-281.

Small molecule IDH1 inhibitors (ivosidenib and olutasidenib) or IDH2 inhibitors (enasidenib) block the activity of mutant IDH1 or IDH2, reducing 2-HG levels. This process induces myeloid differentiation and hematopoietic recovery.Molenaar RJ, Wilmink JW. J Histochem Cytochem. 2022;70(1):83-97. DailyMed. Ivosidenib. Accessed May 6, 2025. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=65d254c0-67ad-42c4-b972-ad463b755b2d&type=display DailyMed. Olutasidenib. Accessed May 6, 2025. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4a0c7c8b-b95f-455d-9600-b7351e4397fe&type=display DailyMed. Enasidenib. Accessed May 20, 2025. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a5b4cdf0-3fa8-4c6c-80f6-8d8a00e3a5b6&type=display Abou Dalle I, DiNardo CD. Ther Adv Hematol. 2018;9(7):163-173.

Role in MDS

Currently, IDH1 inhibitors may be considered for the treatment of:DailyMed. Ivosidenib. Accessed May 6, 2025. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=65d254c0-67ad-42c4-b972-ad463b755b2d&type=display Cortes JE et al. Blood. 2024;144(Supplement 1):4600-4601.

  • Adult patients with relapsed/refractory MDS and
  • A susceptible IDH1 mutation confirmed by molecular testing

Potential characteristics and limitations to IDH1 inhibitors use in LR-MDS include:DailyMed. Ivosidenib. Accessed May 6, 2025. https://www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=65d254c0-67ad-42c4-b972-ad463b755b2d&type=display Cortes JE et al. Blood. 2024;144(Supplement 1):4600-4601. Zeidan AM et al. Blood. 2023;141(17):2047-2061.

  • May reduce blast cell counts and increase mature myeloid cells
  • May lead to achievement of transfusion independence
  • Potential achievement of complete remission within ~6 months
  • Risk of AEs including:
    • Irregular heart rhythm
    • Guillain-Barré syndrome
    • Fatigue
    • Rash
    • Leukocytosis
    • Laboratory abnormalities
  • Black box warning for differentiation syndrome

Review the full US Prescribing Information for more information about prescribing ivosidenib, olutasidenib, or enasidenib, including important warnings and adverse events.

Additional Studies and Considerations

Enasidenib is an emerging agent in this class that is being investigated as a potential treatment option for patients with MDS with a susceptible IDH2 mutation.Sebert M et al. Blood. 2024;144(Supplement 1): 1839-1840. DiNardo CD et al. Blood Adv. 2023;7(11):2378-2387.

Clinical studies are ongoing to evaluate the safety and efficacy of enasidenib in various MDS patient subpopulations. Data supporting the use of enasidenib in MDS as a single agent, or in combination with other active treatments, is evolving.Sebert M et al. Blood. 2024;144(Supplement 1): 1839-1840. DiNardo CD et al. Blood Adv. 2023;7(11):2378-2387.

Patients may require subsequent therapy and there are ongoing clinical trials investigating new therapies and existing therapies in new settings.

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