Addressing MDS Treatment Gap Post Hypomethylating Failure

A close-up of red blood cells flowing through a vein, displaying the characteristic sickle shape Generative AI: © catalin - stock.adobe.com

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by bone marrow dysplasia, cytopenia, and a propensity to progress to acute monocytic leukemia (AML).¹ Treatment decisions in MDS have traditionally been based on various prognostic factors, such as peripheral blood counts, bone marrow blast percentage, and cytogenetics, that predict survival and progression to AML, with the International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R) being the most widely used prognostic systems.^2,3 Although multiple studies have demonstrated the impact of various somatic mutations on prognoses over a decade, it was not until the recently published Molecular IPSS (IPSS-M) that a risk stratification system incorporated molecular patient factors.^4-8

The frontline standard-of-care regimen for patients with higher-risk MDS and some with lower-risk MDS remain hypomethylating agents (HMAs), such as azacitidine (Vidaza), decitabine (Dacogen), and decitabine/cedazuridine (Inqovi).^9-17 The use of these therapeutic agents results in improved cytopenias and survival, but these benefits are transient and modest in magnitude.¹⁸ Patients who are refractory to or progress after responding to HMA therapy are faced with a phenomenon known as HMA failure.¹⁹ The median overall survival for individuals with higher-risk MDS post-HMA failure is approximately 4 to 6 months and approximately 17 months for those with lower-risk HMA failure MDS.^20-22 Furthermore, HMA failure MDS is associated with extremely high health care resource utilization burdens.^23,24

There have been several studies looking at predictive biomarkers for response to HMA, including bone marrow blast percentage, previous treatments, cytogenetics, molecular studies, and gene expression profiles.^25-31 However, these are not readily used, as alternative treatments to HMAs are unavailable. Therefore, the improvement of frontline therapy and the development of novel therapeutics after HMA failure remain urgent and unmet needs in the field of MDS.

Therapeutic Options for HMA Failure MDS

Until recently, there were no FDA-approved therapeutic options for patients with MDS who do not respond to or have lost their response to HMA therapy. Ivosidenib (Tibsovo) recently obtained approval for patients with IDH1-mutated relapsed or refractory MDS after HMAs after demonstrating a complete response rate of 39%.³² However, no other treatments are commercially available for those without IDH1 mutations. Given that IDH1 mutations are extremely rare in MDS (approximately 5% of MDS patients have IDH1/2 mutations^5,33,34), most patients still do not have any FDA-approved therapies.

There are many clinical trials researching novel therapeutics in HMA failure MDS.³⁵ In addition to IDH1/2 inhibitors, these investigational agents can be divided into immune checkpoint, inflammation pathway, antiapoptotic, multikinase, and NEDDylation inhibitors. Therefore, referral to a tertiary care center for clinical trial options is warranted for patients with HMA failure MDS.

Managing HMA Failure MDS

In the case of suspected HMA failure MDS, complete laboratory and bone marrow examination is recommended. Although the IPSS-R was shown to lose predictive power in those who have already been treated with HMA and the IPSS-M does not provide much additional prognostic value at this time,^36,37 having an understanding of the genomic components at this time is paramount, either for clinical trial enrollment or obtaining ivosidenib with IDH1-mutated disease. It is also possible that patients may have transformed to secondary AML³⁸; though outcomes are dismal, more therapies are available in that situation, including induction chemotherapy regimens and BCL2 inhibition with venetoclax (Venclexta).

Fit patients with higher-risk MDS by IPSS-R or lower-risk MDS by IPSS-R with poor-risk genetic features at diagnosis are candidates for allogeneic stem cell transplantation (alloSCT),³⁹ which remains the only curative treatment option. In the case of HMA failure and relapsed/refractory MDS, all fit patients are recommended to undergo alloSCT, as it results in prolonged survival compared with other treatment modalities.²¹ Although there was a higher risk of post-alloSCT relapse in patients with HMA failure MDS compared with those who underwent alloSCT during response,⁴⁰ results are still more encouraging than the dismal survival outcomes detailed above.

Summary Points

• HMA failure MDS is associated with poor survival outcomes.
• The only commercially available treatment option is ivosidenib for patients with IDH1-mutated MDS after HMA failure.
• Referral to a tertiary cancer center for clinical trial options is paramount.
• Consider alloSCT in all fit patients with MDS after HMA failure.

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