Diagnostic Oversights Limit Luspatercept Benefits in MDS

As the treatment landscape for myelodysplastic syndromes (MDS) evolves, it is imperative to correctly identify all patients who would benefit from novel agents. This may not currently be happening with luspatercept (Reblozyl; Bristol Myers Squibb), report the authors of a retrospective review in Current Oncology.¹

Specifically, patients with MDS who have ring sideroblasts (MDS-RS) orSF3B1mutations respond to this first-in-class erythroid maturation agent. Analyses of previous trials—MEDALIST and COMMANDS—found that patients with lower-risk MDS-RS had decreased transfusion dependency with luspatercept treatment. Blast count, cytogenetics, and blood counts are all considered when distinguishing lower-risk from higher-risk MDS.

MDS-RS is diagnosed via bone marrow aspiration in the presence of 1 of 2 scenarios: either at least15% RS or 5% to 14% RS and anSF3B1mutation.

Yet, the present team’s results indicate that a significant portion of patients who might benefit from luspatercept are potentially missed when clinicians take only the first morphologic criterion into consideration—RS 15% or greater.

How to rectify this situation? A crucial element, the authors posit, would be widespread clinician use of the revised, and most recent, 2022 definitions drafted by the World Health Organization (WHO) and International Consensus Classification (ICC).^2,3 These definitions “shift toward molecularly defined subtypes of MDS and appropriate testing.”

The authors of this analysis stress the importance of correctly identifying all patients who might benefit from novel agents | Image Credit: natali_mis - stock.adobe.com

These definitions have changed over time, they explained further.

“Early criteria used for RS required the presence of more than 15% RS,” they wrote. “In 2016, the WHO classification defined ≥ 5% RS in the presence of anSF3B1mutation as also being sufficient for a diagnosis of MDS-RS.”

When results of various studies showed that the percentage of RS is not prognostically relevant and that MDS associated withSF3B1 mutation is a distinct MDS subtype, the 2022 WHO Classification and the 2022 ICC, they noted, “moved away from relying on morphologic features and have defined a new genetic subtype: MDS with low blasts andSF3B1mutations (MDS-SF3B1). However, WHO 2022 does allow for the detection of ≥15% RS to substitute for anSF3B1mutation.”

The investigation’s patient pool began with 6817 Canadian patients with suspected hematologic malignancies who had undergone molecular testing between January 2018 and May 2023 using a next-generation sequencing–based genetic assay. Of these, 395 had SF3B1 mutations, but 113 of them had not been seen at the investigators’ institution (London Health Sciences Centre in London, Ontario). That left 282 patients, 39 of whom were classified as having lower-risk MDS.

Of the 39 patients, 19 (48.7%) had an isolatedSF3B1mutation with a mean (SD) variant allele frequency of 35.2% (8.1%), noted the investigators.

“There were 29 (74.4%) patients with ≥ 15% RS, 6 (15.4%) with 5% to 14% RS, 1 (2.6%) with 1% RS, and 3 (7.7%) with no RS.”

From these calculations come 2 related conclusions: A quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15%, and the 6 patients with 5% to 14% RS would have been missed and not qualified for luspatercept funding in the team’s jurisdiction if molecular testing forSF3B1had not been performed.

The study population was evenly divided between male patients (n = 20) and female patients (n = 19), and their median age was 77 (range, 57-92) years.

Given that their findings support the revised 2022 WHO and ICC classifications, “which shift toward molecularly defined subtypes of MDS, [we] suggest molecular testing for patients with an established diagnosis of lower-risk MDS, with or without RS.” However, this doesn’t mean, they added, that they “encourage the indiscriminate use of molecular testing for undiagnosed patients with cytopenias.”

References

1. Mortuza S, Chin-Yee B, James TE, et al. Myelodysplastic neoplasms (MDS) with ring sideroblasts orSF3B1mutations: the improved clinical utility of World Health Organization and International Consensus Classification 2022 definitions, a single-centre retrospective chart review. CurrOncol.2024;31(4):1762-1773.doi:10.3390/curroncol31040134

2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms.Leukemia.2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1

3. Zeidan A. Recent updates in lower-risk MDS. Targeted Oncology™. November 2, 2023. Accessed May 8, 2024. https://www.targetedonc.com/view/recent-updates-in-lower-risk-mds