An insight into the biology of MDS in younger adults: a unique clinical challenge

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Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, leading to peripheral cytopenias and an increased risk of progression to acute myeloid leukemia (AML).¹ Although MDS primarily affects older adults, with a median age of onset around 70, it can also occur in younger individuals. Cases in younger adults (under the age of 50) are estimated to account for less than 10% of all MDS diagnoses, making it a rare but significant clinical entity^1,2. Few studies have investigated molecular alterations in younger patients with MDS, with research primarily focusing on germline variants, inherited bone marrow failure syndromes (BMFS), and/or genetic predisposition to MDS.³

Epidemiology, risk factors and clinical presentation

There are several differences in disease characteristics between older and younger patients with MDS. While age-related somatic mutations play a role in MDS acquisition in older adults, MDS in younger adults is more commonly associated with germline genetic predisposition.⁴ Germline mutations in genes such as GATA2, RUNX1, and DDX41 have been linked to familial MDS, and are more commonly observed in younger populations, with germline GATA2 mutations accounting for approximately 15% of advanced primary MDS cases and 7% of all cases.⁵

Environmental risk factors, such as chemotherapy exposure, radiation therapy, and toxins such as benzene are also significant contributors. Younger adults with a history of cancer treatment, particularly those who have received alkylating agents or topoisomerase II inhibitors, are at increased risk of developing therapy-related MDS (t-MDS), a subtype associated with poor outcomes.^1,6

As more genes and pathways are identified in MDS predisposition, revisiting diagnostic assessment and incorporating additional genetic testing may be beneficial.⁷

The clinical presentation of MDS is variable, with many patients presenting with fatigue, recurrent infections, and bruising or bleeding due to cytopenias. Although data specifically on younger patients are lacking, younger individuals may exhibit fewer comorbidities and better overall physical health, which could impact patient survival and treatment choice.^8,9 Additionally, younger adults are more likely to present with hypoplastic MDS, a subtype characterized by bone marrow hypocellularity, which requires careful differentiation from aplastic anemia.^10,11

Treatment options

While there are established guidelines for managing older adults with MDS/AML, treatment approaches for younger adults are lacking, with published literature primarily focused on evaluation and therapeutic algorithms for patients with BMFS.⁷ Therapeutic approaches for MDS in older adults that can be used in younger patients include supportive care, immunosuppressive therapy (IST), and allogeneic stem cell transplantation (alloSCT).

Supportive care and monitoring

For patients with an MDS/AML predisposition, genetic counseling and genetic testing for family members should be offered. For those identified with an underlying predisposition syndrome before the development of MDS or AML, management should include regular hematologic and bone marrow monitoring, as well as syndrome-specific cancer surveillance.⁷

IST

IST is a recognized treatment option for patients with lower-risk MDS; however, the use of various immunosuppressive regimens, coupled with the lack of high-quality studies and validated predictive biomarkers, presents significant challenges.¹² Research has shown that treatment with immunosuppressive agents, such as antithymocyte globulin and cyclosporin A, may improve cytopenia in a small proportion of younger patients with such hypoplastic MDS.¹³

Stem cell transplantation

AlloSCT is the only treatment with curative potential for MDS and is the treatment of choice for younger patients with high-risk disease.¹⁴Advances in donor matching, conditioning regimens, and post-transplant care have improved outcomes, although challenges including treatment-related toxicities, graft-versus-host disease (GvHD), infectious complications, and the risk of relapse persist.¹⁵

We recently heard from Matteo Della Porta, MD, IRCCS Humanitas Research Hospital, Milan, Italy, who shared some insights into the rarity of MDS in younger patients and the curative potential of alloSCT.

Conclusion and future outlooks

Advances in genomic profiling have revolutionized our understanding of MDS biology, revealing distinct mutational landscapes in younger patients. MDS in younger adults represents a unique subset of the disease that warrants specialized attention. Whilst several management approaches can be used, increased awareness, as well as ongoing research and collaboration between clinicians and researchers are essential to advance our understanding of MDS in younger adults and develop more effective treatments for this patient population.