Annual Clinical Update on MDS Sees Hope in Precision Medicine, Use of Oral Therapy

The Annual Clinical Update in Hematological Malignancies, appearing online in early June and now publishing in the August issue of the American Journal of Hematology (AJH), includes an update on myelodysplastic syndromes by Guillermo Garcia-Manero, MD, who leads the MDS Section in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.

“Better understanding of the pathobiology of MDS is resulting in newer approaches for patients,” Garcia-Manero states. “As a consequence, the treatment landscape for patients with MDS is starting to change.”

The update notes that patients’ prognosis is classified with different scoring methods, which all include an evaluation of the percentage of blasts in the bone marrow, peripheral cytopenias, cytogenic characeterics. A newer methodology also incorporates genomic data, which can also aid in diagnosis.

The article presents a treatment algorithm based on lower-risk or higher-risk classification, but it does call for next-generation sequencing at baseline “and each time a therapeutic decision is going to be made,” because there is no other way to identify small subsets of patients who are more likely to have a response to specific treatments, such as allogeneic stem cell transplant (alloSCT), based on their genomic profile.

Garcia-Manero cited a report on a small group of patients at MD Anderson with very high response rates based on this approach.

Early-stage conditions. The article distinguishes betweenclonal cytopenia of undetermined significance (CCUS), clonal hematopoiesis of indeterminate potential (CHIP), and idiopathic cytopenia of undetermined significance (ICUS), in which dysplasia is not seen but the potential for progression to MDS exists. At this stage, Garcia-Manero writes, “Patients with ICUS/CHIP/CCUS should not be treated but followed preferentially in a dedicated ‘CHIP’ clinic.

Attention should be paid to the care of comorbidities. Clinical trials could be considered if available.”

Lower-risk MDS. Garcia-Manero hedges his recommendations in this section by noting that things could change with results from the COMMANDS trial, which he presented at the American Society of Clinical Oncology (ASCO) just as his update went to press. COMMANDS found that luspatercept, approved for other populations in 2020, allowed 58.5% of the lower-risk patients treated first-line to avoid transfusions for at least 12 weeks while increasing hemoglobin, compared with 31.2% of patients receiving epoetin alfa, an erythropoiesis-stimulating agent (ESA).

The article’s section on lower risk MDS also discusses use of lenalidomide and azanucleosides, including oral decitabine/cedazuridine (oral dec/ced), approved in 2020. Garcia-Mareno said use of these agents in the US is mainly in second-line treatment and different from use in Europe. He discusses at length the importance of proper dosing; at MD Anderson, investigators designed a series of clinical trials investigating attenuated doses and schedules of both azacytidine and decitabine. When these trial designs were criticized for not including comparisons of hypomethylating agents (HMAs), a third study was designed and is accruing patients.

Garcia-Mareno notes that use of HMAs in lower-risk MDS is better facilitated with the availability of oral agents; the recommendation sees more use of oral agents in the future. Thus far, data on oral dac/ced and oral azacytidine have been published, although the latter is not approved in MDS. He notes that the phase 3 trial for oral dec/ced directly compared patients to intravenous decitabine, and “This allowed for intrapatient PK comparison. Results presented at [American Society of Hematology] 2019 demonstrated virtually identical pharmacokinetic (PK) profile between both IV decitabine and the oral version.” The article outlines ongoing studies in both agents.

He mentioned the phase 2/3 iMerge trial (NCT02498661), also presented at ASCO, in which imetelstat, a telomerase inhibitor, produced a significantly higher rate of 8-week transfusion independence than placebo. Since then, FDA has granted a new drug application for imetelstat to be used for patients with transfusion-dependent anemia in patients with low- to intermediate–risk MDS.

Another section of the paper addresses treatment of patients with lower-risk MDS and thrombocytopenia.

Higher-risk patients. Garcia-Mareno writes that options for patients diagnosed with higher-risk MDS “have not evolved significantly” since the last AJH update, and that “azanucleosides remain the standard of care of a majority of patients.” He wrote that final results for the study (NCT03306264) on oral dec/ced will come this year; the last update was reported on clinicaltrials.gov. on May 31, 2023. Garcia-Mareno said the report may answer questions about interim data that suggest better responses for patients with certain p53 mutations.

Although the paper notes that “no study has compared 5-azacitidine vs decitabine” and response rates appear similar, “only 5-azacitidine has been associated with improvement of survival in a randomized trial. Based on this, we consider 5-azacitidine standard therapy for front-line treatment in higher risk MDS.”

Garcia-Mareno goes on to outline when patients should be considered for therapy similar to that used to treat patients with acute myeloid leukemia, such as an allogeneic stem cell transplant (alloSCT); for lower-risk MDS, generally younger, fitter patients would be considered. The algorithm for higher-risk patients distinguishes between those older and younger than aged 70 to 75, when an individual’s ability to tolerate various treatment approaches must be weighed against possible benefits. Recommendations regarding alloSCT are very specific in the higher-risk population: “Although alloSCT should be considered for patients with higher-risk MDS this may not be the case in patients with high risk mutations such as TP53, in whom, in our opinion, transplant may have to be considered only if an optimal donor is available.”

Still, the challenge of what to do for patients who fail HMAs is a daunting one, and Garcia-Mareno concludes with a discussion of the “total therapy” approach alongside alloSCT, including the debate over bridging therapy. "The advent of powerful new combinations with magrolimab or venetoclax argue for total therapy that could render patients [minimal residual disease]-negative pre transplant followed with post-transplant maintenance therapy, either with targeted approaches of HMAs. Further studies are needed in this area.”

Reference

Garcia-Manero G. Myelodysplastic syndromes: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(8):1307‐1325. doi:10. 1002/ajh.26984