TOPLINE

Researchers used germline variants to stratify therapy-related myeloid neoplasms (t-MNs) into molecularly and prognostically distinct subgroups beyond treatment-based classifications. They found that germline mutations in cancer predisposition genes identified a high-risk subgroup of t-MNs characterized by complex karyotypes and poor survival. Patients with myeloid-related germline variants or no germline mutations had more favorable outcomes. 

METHODOLOGY

• t-MNs that arise after cytotoxic exposure account for 10%-20% of new diagnoses related to myelodysplastic syndromes/acute myeloid leukemia and often carry high-risk cytogenetic and mutational features. Because current classification relies mainly on treatment history and makes limited use of germline information, this study examined whether genomic profiling could better refine biologic subgroups and prognosis.
• Researchers conducted a comprehensive genomic analysis of 100 patients with post-cytotoxic therapy MNs, integrating clinical characteristics, prior treatment regimens, and genomic profiling. The mean age at onset of the primary disease was 63.2 years, and the mean age at t-MN diagnosis was 70.3 years.
• Somatic and germline variants were identified using targeted next-generation sequencing (NGS) in 33 patients and whole-exome sequencing (WES) in 67 patients, with bone marrow samples obtained at t-MN diagnosis and paired peripheral blood samples collected at the time of primary disease and t-MN diagnosis. CD3+ T cells from peripheral blood served as a source of germline DNA, and variant allele frequency thresholds were set at ≥ 2% for targeted NGS and ≥ 5% for WES.
• Researchers categorized acquired alterations according to germline status, karyotype complexity, and clinical features to examine links between genetic patterns and disease presentation. Overall survival was analyzed across different germline and somatic mutation scenarios, with a median follow-up duration of 24 months.
• Among evaluable patients, 32.3% harbored germline pathogenic or likely pathogenic variants, including 19.8% with cancer predisposition gene variants and 14.6% with myeloid-related variants; overall, 89.8% had acquired cytogenetic and/or molecular abnormalities, and 64.6% had somatic mutations in myeloid-related genes.

TAKEAWAY

• Patients with vs without germline mutations in cancer-related genes had significantly worse overall survival (median, 10 vs 48 months; P = .0063). This subgroup was also enriched for complex karyotypes and somatic TP53 mutations.
• Patients with germline mutations in myeloid-related genes more often had normal karyotypes and recurrent somatic TET2 and DNMT3A mutations. Their outcomes were favorable and did not differ significantly from those of patients without germline mutations.
• Germline-stratified subgroups differed significantly in karyotype complexity (P = .0061), the number of chromosomal alterations (P = .0038), and the frequency of somatic TP53 mutations (P = .0440). These differences were mainly driven by patients with germline mutations in cancer-related genes.
• Chemotherapy was associated with the highest number of chromosomal abnormalities (mean, 2.7), whereas immunotherapy was associated with the lowest (mean, 1.1). Latency also differed by treatment group (P = .0004), with combined chemotherapy plus radiotherapy showing longer latency than chemotherapy alone. Combination therapy was also associated with fewer karyotypic abnormalities and longer median overall survival (48 vs 17 months) than chemotherapy alone.
• Among patients with TP53 mutations, survival was poor regardless of mutation origin. Median overall survival was 7 months for patients with germline TP53 mutations and 9 months for patients with somatic TP53 mutations compared with 48 months for patients with wild-type TP53 (P < .0001).

IN PRACTICE

“Overall, our data underscore the interplay between germline susceptibility and t-MN development and support the existence of biologically distinct yet clinically homogeneous subgroups with different prognosis. Cytotoxic therapy may, therefore, play a secondary role in disease initiation and progression. Consistently, germline-based stratification reduced apparent heterogeneity, with patients lacking cancer-related germline mutations showing more favorable outcomes than previously reported,” the authors wrote.

“These results challenge the traditional classification of t-MN based solely on prior cytotoxic exposure and emphasize the germline landscape as a key determinant of disease biology,” they added.

SOURCE

The study, led by Oriol Calvete, MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona in Badalona, Spain, was published online on July 13, 2026, in Blood Advances.

LIMITATIONS

Subgroup analyses were limited by the small cohort size, reducing statistical power and necessitating cautious interpretation of findings as exploratory. The detection of germline mutations in myeloid genes with variant allele frequency less than 20% in CD3+ T cells raises questions about their origin as some variants may have been acquired in early hematopoietic progenitors before myeloid-lymphoid divergence rather than being true germline mutations.

DISCLOSURES

This study was supported partly by grants from the Instituto de Salud Carlos III. The authors disclosed no competing financial interests or relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.