HSCT for older patients with MDS: Seizing the window of opportunity for high-risk patients
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Myelodysplastic syndrome predominantly affects older adults, with median age of onset of 70 years.
Moreover, older patients more commonly have higher-risk disease from clonal hematopoiesis, antecedent chemoradiation therapy, and age-related immune dysregulation leading to treatment refractoriness, rapid progression to acute myeloid leukemia and early death.
Despite recent advances in drug therapy, allogeneic hematopoietic cell transplantation remains the only curative option for myelodysplastic syndrome (MDS). However, it is underutilized among older patients due to age and socioeconomic barriers, multiple morbidities and frailty, and uncertain benefits for high-risk patients.
The landmark BMT CTN 1102 study is a practice-changing study in this perspective.
In this multicenter study, older patients aged 50 to 75 years with intermediate-2 to high-risk de novo MDS were assigned to the transplant arm if they had a matched related or unrelated donor, and they were assigned to a hypomethylating chemotherapy arm if they did not.
The primary endpoint of 3-year OS overwhelmingly favored the transplant arm (47.9% vs. 26.6%; P = .0001).
Two subsequent companion studies focusing on quality of life and cost-effectiveness further supported the use of HSCT by showing the survival advantage did not come at a cost of quality of life or financial toxicities.
These studies established that older patients with higher-risk MDS should be referred earlier to a transplant center for consideration of curative-intent HSCT.
More recently, the impact of molecular mutations on MDS treatment response has been illustrated. The subgroup of patients with TP53 mutations — especially those associated with complex karyotypes — have dismal outcomes.
These patients often have antecedent chemotherapy and/or radiation therapy; are commonly refractory to chemotherapy; and have increased risk for relapse after HSCT.
Do these ultra-high-risk subgroups of older patients with MDS benefit from allogeneic HSCT? This question is answered in an elegant molecular correlative study in which researchers used banked specimens from the BMT CTN 1102 study and performed targeted next-generation sequencing to identify mutations associated with all primary and secondary outcomes.
Not surprisingly, TP53 was the most common mutation identified among these older patients, and they had the worst outcome with OS of 21% at 3 years.
However, allogeneic HSCT still provided a significant survival advantage with regard to 3-year OS (23% vs. 11%; P < .001).
Similarly, other high-risk molecular mutation groups benefited from HSCT. These results provided further support to offer transplant for selected older adults with MDS, even among the ultra-high-risk groups with TP53 mutation as in the case of AML.
However, 23% long-term survival after transplant for TP53-mutated MDS is hardly something we should be excitedly about.
The keys for future improvement in outcomes for this group of older patients would be: 1) identify and optimize most appropriate older candidates incorporating geriatric assessment and management, and 2) identify strategies that reduce the risk for relapse prior to and following HSCT.
With time, we shall widen this curative window of opportunities for older patients with MDS.
For more information:
Richard J. Lin, MD, PhD, is a hematopoietic cell transplant and cellular therapy specialist at Memorial Sloan Kettering Cancer Center.
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