Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell abnormalities characterized by peripheral blood cytopenias, dysplastic hematopoietic progenitors, hyper- or hypocellular bone marrow, and a high probability of the development of acute myeloid leukemia (AML). The symptoms are related to the most-affected cell line and can include weakness, fatigue, pallor (due to anemia), infection and fever (neutropenia-related), and bleeding and bruising (thrombocytopenia-related).¹

Complete blood cell counts, peripheral blood smears, and bone marrow aspiration and biopsy are used to make the diagnosis. Hypomethylating drugs such as Vidaza^® (azacitidine) and Dacogen^® (decitabine), which are the mainstay of treatment, may lessen symptoms and slow progression to AML. The only curative treatment is stem cell transplant, which is the preferred option for individuals who are younger and medically fit.¹ 

In an effort to improve treatments for MDS, the following trials are in progress. 

Verona

For individuals unable to undergo chemotherapy, treatment with Venclexta® (venetoclax), a medication approved for AML, has become standard in combination with hypomethylating drugs. It is also being evaluated for MDS, and phase 1/2 trials have shown promising results, nearly doubling response and remission rates.²

This therapy is currently being evaluated in Verona (NCT04401748), a randomized, double-blind phase 3 clinical trial in which Venclexta is administered in tablet form together with intravenous or subcutaneous Vidaza.³ The study aims to compare the safety and efficacy of Venclexta/Vidaza with that of placebo/Vidaza in patients with newly diagnosed, high-risk MDS. Participants in one arm will receive oral Venclexta and intravenous or subcutaneous Vidaza. Participants in another arm will receive oral placebo and intravenous or subcutaneous Vidaza.³

The study is estimated to be completed in February of 2025.³

Read more about MDS treatment

ENHANCE

A humanized anti-CD47 IgG4 antibody called magrolimab (Hu5F9-G4) targets CD47 in AML. AML cells that overexpress CD47 are associated with a poor prognosis.⁴ In a phase 1 clinical trial, the combination of magrolimab and Vidaza showed promising results (doubled response rates and higher complete remission rates).^2,5

ENHANCE (NCT04313881), a randomized, double-blind, multicenter phase 3 clinical trial of magrolimab, is ongoing. The primary goal of this trial is to compare the effectiveness of the combination of magrolimab and Vidaza with that of Vidaza plus placebo in patients with previously untreated intermediate-, high-, or very high-risk MDS as assessed by the Revised International Prognostic Scoring System (IPSS-R).⁶ 

The study is expected to be completed in December 2026.⁶

Read more about MDS prognosis

SELECT MDS-1

Tamibarotene (previously known as SY-1425) is an orally administered selective retinoic acid receptor alpha (RARα) agonist in development by Syros Pharmaceuticals. Almost 50% of patients with MDS overexpress the RARA gene. By attaching to RAR, tamibarotene promotes myeloid differentiation and the restoration of normal gene expression.⁷

SELECT MDS-1 (NCT04797780) is a randomized, double-blind, placebo-controlled phase 3 clinical trial in which the efficacy of tamibarotene plus Vidaza is being compared with that of Vidaza plus placebo in adult patients with newly diagnosed, RARA-positive, higher-risk MDS who have not received treatment. The primary aim of the trial is to compare the complete remission rates in the 2 treatment arms.⁸

The study is estimated to finish in February 2029.⁸

STIMULUS MDS-US

Sabatolimab is a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor that works in the immune system and attacks leukemic cells. It has shown promising results in terms of durability of response and is being tested in the randomized phase 2 STIMULUS MDS-US (NCT04878432) trial. If the phase 2 trial results are positive, a phase 3 trial will be conducted.²

The primary goal of the study is to evaluate the safety and effectiveness of sabatolimab in combination with Dacogen, Vidaza, or Inqovi^® (decitidine/cedurazidine) in patients with intermediate-, high-, or very high-risk MDS per IPSS-R criteria.⁹ 

The study is estimated to be completed in March 2025.⁹

Read more about MDS therapies

Imetelstat (GRN163L)

Imetelstat (GRN163L) is a synthetic lipid-conjugated, 13-mer oligonucleotide N3′-P5′-thio-phosphoramidate with strong antineoplastic activity. Imetelstat causes telomere shortening in tumor cells by inhibiting the function of telomerase, resulting in cell cycle arrest or apoptosis.¹⁰ 

A phase 2/3 clinical trial (NCT02598661) is assessing imetelstat in transfusion-dependent patients with low- or intermediate 1-risk MDS per IPSS criteria.¹¹ 

Part 1 of the study is evaluating the effectiveness and safety of imetelstat in transfusion-dependent subjects with low- or intermediate 1-risk MDS that is relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment. Part 2 of the study is comparing the efficacy of imetelstat with that of placebo in terms of red blood cell transfusion independence in patients with low- or intermediate 1-risk MDS that is relapsed or refractory to ESA treatment. Participants who benefit from imetelstat may continue to receive treatment, and an extension phase will continue to evaluate long-term safety, overall survival, and AML development in transfusion-dependent subjects.¹¹ 

The study is expected to be completed in October 2026.¹¹ 

R289 

R289 is a potent oral drug that selectively inhibits interleukin receptor-associated kinases 1 and 4 (IRAK1/4). R289 inhibits the production of inflammatory cytokines in response to toll-like receptor (TLR) and interleukin-1 receptor family (IL-1R) signaling. Persistent cytopenias in patients with lower-risk MDS are thought to be caused by a pro-inflammatory milieu in the bone marrow that is due to the chronic stimulation of both receptor systems.¹² 

An open-label phase 1b clinical trial of R289 (NCT05308264) is studying patients with lower-risk MDS that is refractory or resistant to prior treatments. The goal of the study is to evaluate the tolerability and preliminary efficacy of R289 in patients who have low-risk MDS that is relapsed or resistant/refractory to prior treatments (erythropoietin, thrombopoietin, Reblozyl^® [luspatercept], or hypomethylating agents) or who cannot tolerate these treatments.¹³

The trial is expected to be completed in May 2024.¹³

Read more about MDS experimental therapies

References

1. Emadi A, Law JY. Myelodysplastic syndrome (MDS). MSD Manual, professional version. Reviewed/revised June 2022. Modified September 2022. Accessed June 22, 2023.
2. Ryan D. Novel combinations could spark shift in treatment paradigm for higher-risk MDS. News release. OncLive; August 30, 2022.
3. Study of venetoclax tablet with intravenous or subcutaneous azacitidine to assess change in disease activity in adult participants with newly diagnosed higher-risk myelodysplastic syndrome (Verona). ClinicalTrials.gov. September 10, 2021. Updated April 26, 2023. Accessed June 22, 2023.
4. Gallazzi M, Ucciero MAM, Faraci DG, et al. New frontiers in monoclonal antibodies for the targeted therapy of acute myeloid leukemia and myelodysplastic syndromes. Int J Mol Sci. 2022;23(14):7542. doi:10.3390/ijms23147542
5. Magrolimab monotherapy or magrolimab in combination with azacitidine in participants with hematological malignancies. ClinicalTrials.gov. September 8, 2017. Updated June 18, 2023. Accessed June 22, 2023.
6. Magrolimab + azacitidine versus azacitidine + placebo in untreated participants with myelodysplastic syndrome (MDS) (ENHANCE). ClinicalTrials.gov. September 9, 2020. Updated June 9, 2023. Accessed June 22, 2023.
7. Tamibarotene for MDS and AML. Syros Pharmaceuticals. Accessed June 22, 2023.
8. Tamibarotene plus azacitidine in participants with newly diagnosed RARA-positive higher-risk myelodysplastic syndrome. ClinicalTrials.gov. February 8, 2021. Updated May 16, 2023. Accessed June 22, 2023.
9. STIMULUS MDS-US: Sabatolimab added to HMA in higher risk MDS. ClinicalTrials.gov. March 17, 2022. Updated December 7, 2022. Accessed June 22, 2023.
10. Imetelstat (GRN163L). HemOnc.org. Edited June 1, 2023. Accessed June 22, 2023.
11. Study to evaluate imetelstat (GRN163L) in subjects with International Prognostic Scoring System (IPSS) low or intermediate-1 risk myelodysplastic syndrome (MDS). ClinicalTrials.gov. November 24, 2015. Updated May 31, 2023. Accessed June 22, 2023. 
12. Rigel’s investigational candidate, R289, is an oral, potent and selective inhibitor of interleukin receptor-associated kinases 1 and 4 (IRAK1/4). Rigel. Accessed June 22, 2023.
13. Study of R289 in patients with lower-risk myelodysplastic syndromes (LR MDS). ClinicalTrials.gov. September 12, 2022. Updated March 15, 2023. Accessed June 22, 2023.

Reviewed by Kyle Habet, MD, on 6/25/2023.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.