Next-generation sequencing to impact all aspects of care for myelodysplastic syndrome
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Incorporation of next-generation sequencing into standard of practice will be required for patients with myelodysplastic syndrome and will impact all facets of care, according to a speaker at Chemotherapy Foundation Symposium.
Cost may be a consideration, and reducing turnaround times is important, David A. Sallman, MD, assistant member of the department of malignant hematology at Moffitt Cancer Center, said during his presentation.
“Right now, clinical prognostic systems are lower vs. higher risk, but the incorporation of mutations can really help significantly stratify outcomes based on the underlying mutations,” Sallman said. “These will not only predict outcomes but will piece out very important groups.”
The impact of next-generation sequencing on diagnosis will continue to evolve and already has been evidenced by the incorporation of SF3B1 mutation presence to help diagnose myelodysplastic syndrome with ringed sideroblasts, he said.
Researchers have used factors such as age, peripheral blood blasts and red blood cell transfusion dependence to further risk-stratify patients deemed intermediate risk according to the revised International Prognostic Scoring System. However, an optimal molecular model will be used to personalize the prognosis of patients at diagnosis and sequentially over time, Sallman said.
Sallman highlighted TP53 mutations to show the importance of personalization, particularly for subgroups that respond poorly to standard-of-care therapy. He cited research that identified TP53 mutation status and variant allele frequency as predictors of survival among patients with myelodysplastic syndrome and secondary acute myeloid leukemia. The very adverse-risk group, which represents the majority of patients, consists of those with a high variant allele frequency of 40%, complex karyotype or more than one mutation, or a mutation in the setting of TP53.
“It’s not as straightforward as yes/no with mutations,” Sallman said. “I think this may continue to get teased out with other mutations, as well.”
In addition, clearance of all mutations at any time tightly correlates with overall quality of response, he said.
“We really think going forward, particularly in the setting of novel therapy, that achievement of p53 clearance, as low as possible, potentially at that point then bridging to transplant, may be the ultimate approach,” Sallman said.
Clinicians can wait for results of sequencing panels for the vast majority of patients with myelodysplastic syndrome, Sallman said, adding that turnaround time continues to improve. Meanwhile, other factors that can provide a high pretest probability of whether a patient may have a TP53 mutation include therapy-related history, multiple abnormalities, refractory anemia excess blasts with increased ringed sideroblasts and p53 immunohistochemistry.
To improve outcomes for this molecular subset of patients, researchers are investigating eprenetapopt (APR-246, Aprea Therapeutics), a first-in-class p53 reactivator. Results of a phase 2 study showed the agent in combination with azacitidine induced responses in more than 70% of patients, with complete remission rates of 40% to 50%, Sallman said. The phase 3 study, however, did not meet its primary endpoint of improved complete remission, he said, adding other trials of novel combinations that include the agent are ongoing and he remains hopeful.
In a separate study, magrolimab (Gilead) — a first-in-class macrophage immune checkpoint inhibitor that targets CD47 — in combination with azacitidine demonstrated high rates of overall response and complete remission among patients with AML, with similar responses among patients with TP53-mutated disease. With median follow-up of 4.7 months, median OS among 47 patients with TP53-mutant disease was about 12.9 months, which Sallman said is double what would be expected, including with novel therapies such as hypomethylating agent and venetoclax (Venclexta; AbbVie, Genentech) combinations.
Other mutations that potentially could be targeted include IDH1 and IDH2 mutations, which are rare in myelodysplastic syndrome, and splicing mutations.
“Overall, we have several mutations that we can already target,” Sallman said. “P53, which I hope to have shown you today, really requires clinical trials if at all possible, but there are other mutations.”
References:
Sallman DA. Incorporating mutational panel testing for MPNs/MDS into your practice. Presented at: Chemotherapy Foundation Symposium, Nov. 3-5, 2021.
Sallman DA, et al. J. Clin Oncol. 2021;doi:10.1200/JCO.20.02341.
Sallman DA, et al. Abstract 187. Presented at: European Hematology Association Annual Congress (virtual meeting), June 11-21, 2020.
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Sallman DA. Incorporating mutational panel testing for MPNs/MDS into your practice. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
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