Understanding the Role of Mutations in Staging of Low-Risk MDS

The division of myelodysplastic syndromes (MDS) into low-risk and high-risk categories guides prognosis and treatment, with patients who have lower-risk disease typically receiving therapies that manage anemia and other symptoms. During a Case-Based Roundtable event in Charlestown, South Carolina, Praneeth Baratam, MBBS, associate professor in the Department of Medicine at the Medical University of South Carolina, discussed how the classification of MDS now expands on the Revised International Prognostic Scoring System (IPSS-R) to incorporate molecular features and mutations. Because of the prognostic value of mutations, blood-based testing can delay the need for a biopsy. Using these tools can improve the treatment paradigm for low-risk disease and enable physicians to counsel patients more easily on what to expect after a difficult disease diagnosis.

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Targeted Oncology: How has molecular analysis affected the classification of low-risk MDS?

Praneeth Baratam, MD: The classification of low-risk MDS is evolving. It’s changing with time, and that’s great because previously it was whether the patient had blasts or no blasts; that was the only way we distinguished different types of MDS. Now there are different ways of genetically defining MDS.¹ SF3V1 is an important mutation; you should check next-generation sequencing [NGS] on every patient with MDS because detection of an SF3V1 [mutation] has survival value and predictive value for treatment. It predicts whether they respond to certain treatment or not. [It is] the same thing with 5q [deletion, which is] only present in about 5% of patients with MDS, but…5q deletion is targetable with lenalidomide [Revlimid]. It works remarkably well in about 50% to 70% of patients. These patients remain transfusion independent for years if you treat them with lenalidomide. Another genetic marker is TP53…these patients don’t do well. They will die from MDS within 6 to 12 months. So, it orients your compass in directing the patient towards appropriate [treatment]; maybe a referral to an [academic] center, or if the patient is too frail, then palliating them rather than giving them hope about treatment of low-risk MDS.

There is a distinction between biallelic TP53 and monoallelic TP53. If they have less than 50% variant allele frequency [VAF], it’s typically monoallelic, meaning only one of the copies of TP53 is affected. But if it’s 70% [to] 90%, that means one of the copies of the TP53 is mutated, and the other copy is usually lost. That’s where there’s a loss of balance between a mutated and unmuted copy of their TP53. The patients who do poorly are the ones who have biallelic TP53.

How has mutational profile been incorporated into staging?

[Whether] there are excess blasts or low blasts is the classification of MDS, practically speaking.¹ [However], there has been a switch. The International Prognostic Staging System-Molecular [IPSS-M] is a molecular prognostic scoring that’s a new resource.² [You can] type in IPSS-M on Google and the calculator pops up. It uses not just the IPSS-R classification but adds mutational profile to that. IPSS-R looks at how many cytopenias [there are and] if blasts are present. It looks at cytogenetic profile, meaning whether they have 1 or 2 deletions, or 5q or 7q deletion.³ IPSS-M adds the mutational profile. It changes the risk stratification in about half of patients, so half of the patients who have been characterized by IPSS-R will be either upstaged or downstaged.² You might be thinking that a patient has bad disease, but they might be downstaged by IPSS-M, and then you can give them a more favorable prognosis. It’s a very quick calculator. It will help in prognosticating these patients. The IPSS-M categories go from very low risk, low risk, moderate low risk, moderate high risk, high risk and very high risk. The distinction between all these survival curves is very stark, so when you calculate an IPSS-M, it makes a very accurate prediction of who falls where, and it‘s much better than IPSS-R.⁴

When is a bone marrow biopsy needed for suspected low-risk MDS?

The question is, if they’re not transfusion dependent, why care about a diagnosis? What I tend to see, at least in our classical hematology group or benign hematology group, is they tend to run an…NGS panel on the blood, which is a useful resource when you don’t know what’s going on, when you’re suspecting some sort of marrow disorder [but] you don‘t know what it is. We’ve shown that the concordance between blood testing and marrow testing is pretty high. If you ran [NGS] on the blood and it comes back abnormal, then you do a marrow [biopsy]. You don’t need to repeat it on the marrow [later]. You can do NeoGenomics testing on blood, or whatever is available at your clinic. That’s the quick way of proving somebody has clonal hematopoiesis, and if they have clonal hematopoiesis, I would then suggest doing a marrow [biopsy]. There are 3 mutations: DNMT3A, ASXL1, and TET2. These are called DTA mutations. If there are DTA mutations, you might avoid a marrow [biopsy] and say [the patient] seems to have clonal hematopoiesis. Until treatment is needed, you may not need a marrow [biopsy]. But if it’s more than the DTA mutations, that’s where I would say a marrow [biopsy] is probably indicated. So I would start with NGS on those patients.

How do treatment goals differ for low-risk and high-risk MDS?

In general, there are 2 kinds of MDS treatments, and this is how I explain them to my patients. One basket of treatment is to improve your symptoms, fatigue, and [blood cell] counts. They only change what on the surface. They don’t change the disease pattern or the natural history. The second basket of treatments are the treatments like chemotherapies [such as] hypomethylating agents, which change the natural history of the disease. By convention, we tend to pick the topical treatments for low-risk MDS, and we tend to pick the disease-modifying treatments for high-risk MDS. That has been the paradigm which hasn’t changed in a long time.

The one place where I would insert a change in the classic paradigm is that if you have a patient with lower-risk MDS, and they have tried a few treatments and they’re not responding, a stem cell transplant is not unreasonable. If they if they’re robustly healthy, [such as] a 60-year-old who plays tennis and has a hemoglobin of 7 g/dL and they’re getting transfusions 5 or 6 times a year or more than that, after trying everything, and their lifestyle is affected, I would not hesitate to offer them a stem cell transplant.

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DISCLOSURES: Baratam previously reported honoraria from Rigel and GSK, and advisory board participation with Incyte, KITE, Ono Therapeutics, and Protagonist Therapeutics.

REFERENCES

1. 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

2. Sauta E, Robin M, Bersanelli M, et al. Real-world validation of molecular international prognostic scoring system for myelodysplastic syndromes. J Clin Oncol. 2023;41(15):2827-2842. doi:10.1200/JCO.22.01784

3. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850

4. Bernard E, Tuechler H, Greenberg PL, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid. 2022;1(7):EVIDoa2200008. doi:10.1056/EVIDoa2200008