Higher-Risk Myelodysplastic Syndromes: Lacking Treatment Advances in Over a Decade


Continued research is critical to potentially bring a targeted therapeutic option to patients with higher-risk myelodysplastic syndromes, to improve overall survival, manage symptoms, and preserve quality of life.

Myelodysplastic syndromes (MDS) are a heterogenous, molecularly-driven group of rare bone marrow cancers that occur when the blood-forming cells in the marrow become abnormal, or dysplastic, and are unable to correctly make new blood cells.1 It is estimated that there are 14,000 new cases of MDS reported every year in the U.S., with most cases diagnosed in people aged 60 or older.2

There are several roadblocks to diagnosing MDS, mostly related to symptoms being vague and attributed to other, less serious illnesses. This can cause the diagnosis and subsequent treatment to be delayed, which can result in disease progression. Symptoms include fever, easy bruising or bleeding, loss of appetite, fatigue, weakness, shortness of breath, pale skin and frequent or severe infections.3

MDS can be initially identified by a complete blood count (CBC) with differential test, and a peripheral blood smear, which detect signs of MDS like anemia, abnormal myeloblasts (“blasts”) or other abnormalities. A diagnosis is then confirmed by the presence of persistent cytopenias and the identification of cytogenetic abnormalities, dysplasia or increased blasts (less than 20%) in the bone marrow as determined by a bone marrow aspiration and biopsy test.4

A risk score is then determined, most often by the Revised International Prognostic Scoring System (IPSS-R), to help determine a patient’s prognosis and the appropriate treatment option.5 The risk score is based on the percentage of blasts and the chromosomal abnormalities present in the bone marrow cells, combined with the severity of cytopenias, and it ranges from very low-risk to very high-risk. Patients with “higher-risk” disease — defined as intermediate, high or very high on the IPSS-R scale – account for 43% of people diagnosed with MDS.6-7

There has historically been a lack of consensus regarding the classification of MDS, with some considering MDS to be more of a bone marrow disorder than a cancer. While lower-risk MDS can sometimes behave indolently and be observed without treatment, it is important to realize that higher-risk MDS (HR-MDS) is a fatal bone marrow cancer that is progressive in nature, and fast diagnosis and intervention is critical.

Because higher-risk patients have more severe symptoms, and ultimately lower rates of overall survival (OS), prompt diagnosis and treatment is critical. Current treatment options do not provide benefit for all patients, and survival is limited with the currently approved therapies. If left untreated, the median survival rate is 9.6 months to 3 years upon diagnosis.8 Furthermore, approximately 40% of people living with HR-MDS will transform to acute myeloid leukemia (AML), another aggressive blood cancer with poor survival outcomes. AML progresses rapidly and is typically fatal within weeks or months if untreated.9-12

There have been significant advances in the development of targeted treatment options for other cancers. However, there are no targeted therapies available to patients with HR-MDS.

Recent research shows that overall cancer mortality rates have declined by 29% from 1991 to 2017, especially in lung, colorectal, breast and prostate cancers, as well as melanoma, lymphoma and some types of leukemia. For patients living with these cancers, early detection has been a key component of improved survival rates. An equally critical component has been the scientific community’s dedication to researching, developing and bringing innovative medicines to patients that specifically target and attack certain types of cancer cells in malignancies like lung cancer, melanoma, lymphoma and certain types of leukemia.13

The ultimate goal of HR-MDS treatment is to induce remission, slow disease progression and to manage symptoms to help maintain quality of life. However, there is room to improve upon the current standard of care — hypomethylating agent (HMA) monotherapy – which provides limited benefit in most patients. Specifically, not every patient responds to HMA monotherapy, and most of the patients that do respond will eventually experience disease progression or lose their response.14

Other options like allogeneic stem cell transplantation (ASCT) have the potential to cure HR-MDS, but many patients may not be eligible because they may be too frail or sick to tolerate the procedure or may not have a suitable donor.15-16 Due to age or comorbidities, only 6% to 14% of people living with HR-MDS undergo ASCT. Even patients who are eligible to receive ASCT have relatively poor outcomes, as transplant-related mortality ranges from 20% to 37%.17-18

In the event that neither chemotherapy nor ASCT are options, supportive care alternatives, such as transfusions or blood cell growth factors can help manage symptoms, but have no efficacy against the disease itself.15,19

A significant need remains for targeted therapies for those living with HR-MDS.

For over a decade, there has been little advancement in treatment options for people living with HR-MDS despite poor patient outcomes.

Continued research is critical to potentially bring a targeted therapeutic option to HR-MDS patients, to not only improve OS, but also to manage symptoms and preserve quality of life. Though there has been little progress in HR-MDS treatment options over the last decade, late-stage clinical studies are actively investigating novel agents in combination with HMAs to improve efficacy and patient outcomes while maintaining safety and tolerability. Due to its aggressive nature and poor survival rates, people living with HR-MDS urgently require new treatment options that are more effective at inducing remission and slowing or preventing disease progression to ultimately improve the survival and quality of life of patients living with this disease.

Author Disclosure: Dr. Watts has received consultancy fees from Takeda/Millennium Pharmaceuticals, Genentech, Jazz Pharmaceuticals, and Rafael Pharmaceuticals.

Acknowledgements: The author would like to acknowledge W2O Group for their writing support, which was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Sponsored by Takeda Oncology.


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