The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution.

Abstract

Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with "Very low" or "Low" Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.

• Authors: Deepak Singhal, Li Yan A Wee, Monika M Kutyna, Rakchha Chhetri, Joel Geoghegan, Andreas W Schreiber, Jinghua Feng, Paul P-S Wang, Milena Babic, Wendy T Parker, Smita Hiwase, Suzanne Edwards, Sarah Moore, Susan Branford, Teodora Kuzmanovic, Nimit Singhal, Raghu Gowda, Anna L Brown, Peer Arts, Luen B To, Peter G Bardy, Ian D Lewis, Richard J D'Andrea, Jaroslaw P Maciejewski, Hamish S Scott, Christopher N Hahn, Devendra K Hiwase
• Journal: Leukemia (Leukemia) Vol. 33 Issue 12 Pg. 2842-2853 (12 2019) ISSN: 1476-5551 [Electronic] England
• PMID: 31089247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers

Topics

• Adult
• Aged
• Aged, 80 and over
• Alleles
• Biomarkers
• Biopsy
• Chromosome Aberrations
• Cytogenetic Analysis
• Diagnosis, Differential
• Female
• Humans
• Leukemia, Myeloid (diagnosis, etiology, mortality)
• Male
• Middle Aged
• Mutation
• Mutation Rate
• Myelodysplastic Syndromes (diagnosis, genetics, mortality)
• Neoplasms, Second Primary (diagnosis, etiology, mortality)
• Prognosis
• Young Adult