Additional Research Efforts Required to Establish New Therapeutic Options for Low-Risk MDS

Uwe Platzbecker, MD

Because standardized treatment approaches have not been established for patients with low-risk myelodysplastic syndromes (MDS) and limited options are available to those with erythropoietin (EPO) failure, the need for varied clinical trials is underscored, Use Platzbecker, MD, said during a presentation at the Society of Hematology Oncology 2021 Annual Conference.

At the meeting, Platzbecker, director of the medical clinic at the university hospital in Leipzig, Germany, gave a presentation on the new approaches that are being looked at for patients with low risk MDS and which can be considered the most effective. Platzbacker had previously written on the current challenges for this patient group describing them as, “a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia.”²

He added that most patients in this patient group are also characterized by being affected by anemia and anemia-related syndrome and even though they have lower risk disease, compared to others that have progressed to leukemia, there is no standard of care for them. Existing treatments are not curative for many patients and many patients can also expect to relapse and develop resistance to most first-line therapies. Yet new advances in molecular diagnostics have provided clinicians a deeper understanding of MDS’ pathogenesis, and these new advances and studies have shown that the disease is heavily characterized by genetic abnormalities that drive MDS. In response, according to Platzbecker, a complex and personalized approach has to be developed for these patients.

However, he also noted that clinicians do need to consider to the order of treatment for patients with MDS before moving on to newer treatments. One such consideration was for patients with anemia or thrombocytopenia. According to Platzbecker, about 80% of eligible patients for treatment have EPO levels of 200 IU/L, whereas approximately 10% of patients have levels of EPO greater than 500 IU/L. . As a result, approximately 90% of patients with low risk MDS (LR-MDS) anemia are eligible to receive erythropoietin stimulating agents (ESAs) according to current guidelines. Ten to 20% of these patients however are unlikely to respond to ESAs, which after failure happens Platzbecker recommends that patients should move right to a clinical trial.

“At all stages, the patient should be evaluated for a potential clinical trial option. Luspatercept-aamt [Reblozyl] may become a second-line option soon, while thrombopoiesis-stimulating agents are a potential first-line option in patients with clinically meaningful thrombocytopenia,” he said.

Moving patients with LR-MDS to clinical trials is a next step considered in all the different LR-MDS groups that Platzbecker discussed in his presentation. These included patients with LR-MDS who had thrombocytopenia, anemia, and anemia in non del(5q).

Luspatercept is one of the potential treatments that had been in development for some time with a study first initiated in 2011 and approved in 2020.³ Based off the MEDALIST phase 3 trial (NCT02631070) luspatercept acts similar to an ESA in promoting erythroid maturation to treat patients with MDS. In this trial, it showed promising clinical activity in this patient group but in the subgroup of patients with RS luspatercept showed high clinical activity for the treatment of anemia, which made it an enticing option for patients to move to clinical trial and now use in the first-line setting of treatment. This ability for clinicians to test this drug on clinical trials and acquire an approval to it was what Platzbecker pointed to in his presentation that was so important to the expansion of treatment for this patient population. Furthermore, he was hoping for more of the clinical trials to expand and find similar success to luspatercept.

“An overload may also cause inflammatory and oxidative stress in the bone marrow of these patients and may therefore be responsible at least in part for the impaired maturation differentiation,” said Platzbecker when discussing the use of hypomethylating agents (HMAs) in patients with low risk MDS. Another treatment option that can be considered in the first line setting and under further investigation.

Management of cytopenias in these patients often makes it difficult for an effective treatment. Median duration for this patient population was 11.1 months on oral azacytidine compared to 5.0 months for those on placebo in a phase 3 trial looking at 216 patients.⁴ One-hundred and seven of these patients received azacytidine compared with 109 who received placebo. The median age of these patients with low risk MDS was 74 years old with a median platelet count of 25 x 10⁹/L. In this study researchers concluded that azacytidine significantly improved the RBC-TI rate with 31% of patients achieving RBC-TI (P = .0002) and that the drug induced durable bilineage improvements in patients with LR-MDS. However, more early deaths occurred in the drug arm, along with most infections in patients being related with significant pretreatment neutropenia. Ultimately, further evaluation of azacytidine in MDS is needed, according to researchers.

“With regards to licensed agents in the European Union and across the Atlantic, I think it needs to be just the beginning because many of our patients are in need (of treatments), especially second-line treatments,” Platzbecker concluded in his talk. “I think the era of targeted therapy has been started in patients with low risk MDS, and it’s a major step forward, but I think definitely we need more studies and agents.”

References

1. Platzbecker U. New Approaches for low risk disease in MDS. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Abstract 266. Accessed September 8, 2021.
2. Platzbecker U, Kubasch AS, Homer-Bouthiette C, Prebet T. Current challenges and unmet medical needs in myelodysplastic syndromes. Leukemia. 2021 Aug;35(8):2182-2198. doi: 10.1038/s41375-021-01265-7
3. Kubasch AS, Fenaux P, Platzbecker U. Development of luspatercept to treat ineffective erythropoiesis. Blood Adv. 2021 Mar 9;5(5):1565-1575. doi: 10.1182/bloodadvances.2020002177
4. Garcia-Manero G, Santini V, Almeida A, et al. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes. J Clin Oncol. 2021 May 1;39(13):1426-1436. doi: 10.1200/JCO.20.02619