This study builds on previous evidence for lenalidomide-induced selective advantage for TP53-mutant clones.
Current data from real-world settings indicate treatment initiation with lenalidomide and disease monitoring in patients with myelodysplastic syndrome with del(5q) (MDS-del[5q]) greatly vary, highlighting the need for monitoring mutations at diagnosis and during the disease course regardless of specific treatment, according to correspondence published in Blood Cancer Journal.
MDS with del(5q) is a specific type of MDS that does not have excess blasts and is characterized by the presence of an often-isolated del(5q) cytogenetic abnormality. Additionally, patients with MDS-del(5q) often harbor other somatic mutations, with frequent ones being TP53 and SF3B1; these 2 mutations are particularly prevalent in the leukemic phase of disease, suggesting a contribution to leukemic progression.
The current study aimed to observe a cohort of 10 Mayo Clinic patients with MDS-del(5q) before and after treatment with lenalidomide. Selection of patients was done according to whether next-generation sequencing (NGS) information was available, according to the investigators.
The median time from initial diagnosis of MDS-del(5q) to the first NGS study was 16 (range, 0-80) months. At baseline, mutation profiling disclosed 1 patient with monoallelic TP53 mutation (variant allele frequency [VAF], 19%) and 2 other patients with SF3B1 mutation (VAF 8% and 14%), the investigators found. Additionally, one of the patients with SF3B1 mutation had an ASXL1 mutation (VAF, 37%).
A second NGS study was performed during lenalidomide therapy in all 10 patients at a median of 27 (range, 10-58) months from the time of the first NGS study. Analysis revealed that new TP53 mutations emerged in 3 of 9 patients in whom the mutation was not detected at baseline. Among these 3 patients, 2 had SF3B1 mutations at baseline.
Cytogenetic information provided at the time of diagnosis showed sole del(5q) in 8 patients and another cytogenetic abnormality in 2 patients. Similar information was observed at the time of the second NGS study—available in 9 patients—and revealed no changes in 7 cases but a disappearance of del(5q) in 2 patients.
Along with this data, the investigators noted that both patients with lenalidomide treatment–associated disappearance of del(5q) each started with just 2 abnormal metaphases at baseline.
Importantly, at the final follow-up point, the 3 patients with treatment-emergent TP53 mutations were alive at 10, 52, and 44 months post treatment with lenalidomide therapy, according to the investigators. None of these patients had exposure to chemtherapy or radiotherapy, and there was no leukemic transformation observed.
The data gathered from this investigation confirm previously published observations about treatment-emergent TP53 mutations in patients with MDS-del(5q) receiving lenalidomide therapy, the investigators discussed. In the current study, the investigators were able to show a correlation between TP53 clonal evolution and disease progression.
In one previous study where 416 patients with therapy-related myeloid neoplasms were observed, the study authors described an association between TP53 mutations and prior treatment with lenalidomide, providing evidence for lenalidomide-induced selective advantage for TP53-mutant clones.
The authors of the current study suggested that their observations suggest lenalidomide-enhanced expansion of preexisting mutant TP53 clones that may be less sensitive to lenalidomide-induced clonal suppression in MDS-del(5q). At the same time, they cautioned that the previously mentioned studies were not controlled, do not prove cause and effect, and the phenomenon observed may represent clonal evolution as an intrinsic disease biology.
“The observations from the current study underline the need for monitoring of mutations both at diagnosis (preferably using highly sensitive assays) and during the disease course, in patients with MDS-del(5q), regardless of specific treatment,” the investigators concluded.
Reference
Abdallah M, Reichard K, Gangat N, et al. Treatment-emergent mutations in myelodysplastic syndrome with del(5q) – lenalidomide related or disease-intrinsic clonal evolution? Blood Cancer J. 14, 49 (2024). doi:10.1038/s41408-024-01027-5
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