Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Myelodysplastic syndromes (MDS) are a heterogeneous group of rare hematologic disorders characterized by ineffective hematopoiesis, dysplasia, and an increased risk of transformation to acute myeloid leukemia (AML).1 Patients may also be asymptomatic and not require immediate treatment. For these patients, blood or platelet transfusions can be used as supportive treatment.1
The therapeutic approach to MDS is typically individualized according to the potential morbidity and mortality associated with each therapy. Treatment may be considered for low-risk disease, and some type of therapy is often recommended for patients with intermediate- or high-risk disease.1 Over the years, several therapeutic options have emerged to manage MDS and improve patient outcomes.
Therapies for Patients With Lower-Risk Disease
Not all patients with low-risk disease require treatment at diagnosis. Regular follow-ups, including laboratory testing and bone marrow examination, can monitor the need for treatment, which at this stage, is designed to amend or moderate cytopenias and improve the patient’s quality of life.2
Patients may develop parenchymal iron overload that is linked to transfusion dependence. These patients may benefit from treatment with iron chelators such as deferasirox (sold as Exjade® and Jadenu®).2
Read more about MDS complications
Transfusion-dependent patients who are younger than 60 years old, present less than 5% marrow blasts, and normal cytogenetics may be candidates for immunosuppressive therapy with antithymocyte globulin combined with cyclosporine. This therapy is highly recommended in patients with hypoplastic bone marrow.3
Erythropoiesis-stimulating agents (ESAs), such as recombinant human erythropoietin and Aranesp® (darbepoetin alfa), may be administered to patients with low-risk MDS to increase the production of red blood cells. Levels of serum erythropoietin higher than 500 mU/mL may indicate that a patient will not benefit from this therapy, and therefore immunosuppressive treatment should be considered.1,2
Revlimid® (lenalidomide) is a thalidomide derivative that is orally administered to patients who present with symptomatic anemia and 5q deletion. Patients who have lower-risk disease treated with lenalidomide may become transfusion independent. However, it is not uncommon to observe re-emergence of the del(5q) clone and recurrence of anemia after 2 to 3 years of treatment.1,2
Read more about MDS prognosis
Reblozyl® (Luspatercept-aamt) is a first-in-class FDA-approved erythroid maturation agent manufactured by Celgene Corporation (a Bristol-Myers Squibb Company) and indicated for the treatment of anemia in patients who have MDS with ring sideroblasts (MDS-RS) or who have myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).4
Luspatercept-aamt, the active agent in Reblozyl, is a fusion protein that binds to the transforming growth factor beta (TGF-β) superfamily of ligands, helping to reduce transfusion dependence.5 The recommended starting dose is 1 mg/kg once every 3 weeks, given by subcutaneous injection.4
The efficacy of Reblozyl was evaluated in adult patients with beta thalassemia in the phase 3 clinical trial BELIEVE (NCT02604433). This was a randomized, double-blind study in which the primary endpoint was the percentage of patients with a transfusion burden reduction of at least 33% from baseline during weeks 13 through 24 of treatment plus a reduction of at least 2 red cell units over the same 12-week interval.6
In the BELIEVE trial, the percentage of patients with transfusion-dependent β-thalassemia whose transfusion burden was reduced was significantly greater in the luspatercept group than in the placebo group.6
Adverse events observed following luspatercept administration included fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, and hypersensitivity.4
Read more about MDS clinical trials
Therapies for Patients With Higher-Risk Disease
Hypomethylating agents (HMAs), such as Dacogen® (decitabine) and Vidaza® (azacitidine), are often the main initial therapies used to alleviate cytopenia, control disease, and prolong survival in patients with higher-risk MDS who are not candidates for allogeneic hematopoietic stem cell transplant.2 HMAs are cytidine nucleoside analogues that are administered parenterally for 5 to 7 days per 28-day treatment cycle.7
Dacogen is an FDA-approved medication for the treatment of adult patients with MDS previously treated and untreated, de novo and secondary MDS. The active ingredient of this therapy is decitabine, a nucleoside metabolic inhibitor that hypomethylates DNA to cause cellular differentiation and/or apoptosis.7
There are two dosing regimens that may be followed for Dacogen administration. In the first, the recommended dose of Dacogen is 15mg/m2 administered by continuous intravenous infusion over 3 hours and repeated every 8 hours for 3 days. This cycle is repeated every 6 weeks. In the second option, Dacogen is administered at 20 mg/m2, also by continuous intravenous infusion over one hour and repeated daily for 5 days. This cycle is repeated every 4 weeks.8
Dacogen was evaluated in a randomized open-label, multicenter, controlled phase 3 clinical trial that enrolled 170 patients with MDS. Patients were randomized to receive Dacogen plus supportive care and supportive care alone. The endpoints in this study consisted of the overall response rate and time to AML or death. The overall response rate in Dacogen-treated patients who were considered evaluable for response was 21%. An additional benefit, hematologic improvement, was also observed in patients treated with this therapy. Three other open-label, single-arm, multicenter studies were performed to evaluate both safety and efficacy of Dacogen in MDS patients, reporting similar results to the controlled trial.8
Read more about MDS treatment
Inqovi® (decitabine and cedazuridine) is an innovative treatment for MDS that was approved by the US Food and Drug Administration (FDA) in 2020 and is marketed by Taiho Oncology. The drug is a combination of decitabine plus the cytidine deaminase inhibitor cedazuridine.7,9 Although decitabine has known efficacy in MDS, its oral bioavailability is limited. Cedazuridine prevents the rapid degradation of decitabine in the gastrointestinal tract, allowing oral administration and improving exposure to decitabine.7
Inqovi is indicated for the treatment of MDS in adult patients, including those with previously treated or untreated de novo or secondary MDS. The recommended dosage of this medication is 1 tablet (35 mg of decitabine and 100 mg of cedazuridine) orally once per day on days 1 through 5 of each 28-day cycle.9
The clinical studies ASTX727-01-B (NCT02103478) and ASTX727-02 (NCT03306264) demonstrated the non-inferiority of Inqovi to intravenous decitabine in terms of complete response rates.7
Read more about MDS experimental therapies
Vidaza® (azacitidine) was approved by the FDA in 2004 for the treatment of adult patients with MDS.10 This was the first medication approved by the FDA for managing MDS.11
The active ingredient in Vidaza is the nucleoside metabolic inhibitor azacitidine. Vidaza is administered via subcutaneous injection once per day for 7 consecutive days in a 28-day treatment cycle.10
The mechanism of action of azacitidine involves the hypomethylation of DNA and direct cytotoxic effects on abnormal hematopoietic cells in the bone marrow.10 The efficacy of this drug in improving survival and reducing transfusion dependence in patients with higher-risk MDS was demonstrated by overall response rates in a randomized, controlled clinical trial that compared azacitidine administered subcutaneously with supportive care and in 2 single-arm studies in which azacitidine was administered subcutaneously and intravenously. The same dose of azacitidine was evaluated in all 3 studies. Response rates in the azacitidine groups ranged from 13% to 19%. Common adverse events included nausea, vomiting, diarrhea, neutropenia and thrombocytopenia, fever, arthralgia, headache, and dizziness.11
Read more about MDS pathophysiology
- Dotson JL, Lebowicz Y. Myelodysplastic syndrome. StatPearls [Internet]. Updated July 18, 2022. Accessed June 10, 2023.
- Cazzola M. Myelodysplastic syndromes. N Engl J Med. 2020;383(14):1358-1374. doi:10.1056/NEJMra1904794
- Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood.2013;122(17):2943-64. doi:10.1182/blood-2013-03-492884
- REBLOZYL® (luspatercept-aamt). Highlights of prescribing information. Bristol Myers Squibb. Revised September 2022.
- Patel B, Moosavi L. Luspatercept. StatPearls [Internet]. Updated November 16, 2022. Accessed June 10, 2023.
- Cappellini MD, Viprakasit V, Taher AT, et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2020;382(13):1219-1231. doi:10.1056/NEJMoa1910182
- Dhillon S. Decitabine/cedazuridine: first approval. Drugs. 2020;80(13):1373-1378. doi:10.1007/s40265-020-01389-7. Erratum in: Drugs. 2021;81(1):179. doi:10.1007/s40265-020-01453-2
- DACOGEN® (decitabine). Highlights of prescribing information. Ensai Inc. Revised March 2010.
- INQOVI® (decitabine and cedazuridine). Highlights of prescribing information. Taiho Oncology. Revised March 2022.
- VIDAZA® (azacitidine for injection). Highlights of prescribing information. Bristol Myers Squibb. Revised September 2022.
- Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005;10(3):176-182. doi:10.1634/theoncologist.10-3-176
Reviewed by Hasan Avcu, on 6/12/2023.