What’s new in the pathogenesis and treatment of therapy-related myeloid neoplasms

Abstract

Therapy-related myeloid neoplasms (t-MN) include diseases onsetting in patients treated with chemo- and/or radiotherapy for a primary cancer, or an autoimmune disorder. Genomic variants, in particular in familial cancer genes, may play a predisposing role. Recent advances in deep sequencing techniques have shed light on the pathogenesis of t-MN, identifying clonal hematopoiesis of indeterminate potential (CHIP) as a frequent first step in the multi-hit model of t-MN. CHIP is often detectable prior to any cytotoxic treatment, probably setting the fertile genomic background for secondary leukemogenesis. The evolution pattern towards t-MN is then a complex process, shaped by the type of cancer therapy, the aging process, and the individual exposures, that favor additional hits, such as the acquisition of TP53 mutations and unfavorable karyotype abnormalities. The pathogenesis of t-MN differs from MN associated with environmental exposure. Indeed, the genetic aberration patterns of MN developing in atomic bomb survivors show few mutations in classical DNA methylation genes, and a high prevalence of 11q and ATM alterations, together with TP53 mutations. Survival in t-MN is poor. In addition to the biology of t-MN, the patient's previous disease history and the remission status at t-MN diagnosis are significant factors contributing to unfavorable outcome. New drugs active in secondary leukemias include CPX-351, or venetoclax in combination with hypomethylating agents, monoclonal antibodies as magrolimab, or targeted drugs against pathogenic mutations. Allogeneic stem cell transplantation remains the best currently available therapeutic option with curative intent for fit patients with unfavorable genetic profiles.

Therapy‐related myeloid neoplasms with normal karyotype show distinct genomic and clinical characteristics compared to their counterparts with abnormal karyotype

“…In recent years, the mutational landscape of myeloid neoplasms has been extensively studied. It has been shown that no alteration is exclusive or specific to de novo (dn), secondary or therapy‐related myeloid neoplasms 6 . However, the proportion of specific mutations differs in dn‐MNs versus t‐MNs, pointing towards different pathogenesis and genetic pathways 19 .…”

“…In addition to germline predisposition, recent evidence suggests acquired susceptibility in the form of clonal haematopoiesis of indeterminate potential (CHIP), a condition characterized by the presence of myeloid gene mutations in the absence of morphological or haematological evidence of myeloid neoplasms. In a high proportion of patients who later develop t‐MN, CHIP has been found at the time of the primary tumour diagnosis, prior to receiving any type of cytotoxic treatment 6 …”

“…In a high proportion of patients who later develop t-MN, CHIP has been found at the time of the primary tumour diagnosis, prior to receiving any type of cytotoxic treatment. 6 Most of the t-MNs have an abnormal karyotype (AK) and are categorized into two subsets based on the type of causative therapeutic exposure. [7][8][9] The most common subtype, comprising approximately 70% of all reported t-MNs, is a result of prior treatment with alkylating agents and/or ionizing radiation.…”

“…The prevalence of NK in t-MNs is approximately 30%. 3,6,10,[15][16][17][18] The clinical characteristics, survival data and mutational landscape of this subset of t-MNs have not been well studied. The goal of this study is to investigate the clinical features and genetic alterations of t-MNs with NK and to compare them with those of t-MNs with AK.…”

Characterization of myeloid neoplasms following allogeneic hematopoietic cell transplantation

“…Patients who undergo allogeneic HCT are heavily treated, and this may accelerate the development of MNs. It was also reported that 9%–20% of MNs that occurred after chemotherapy or radiation therapy had germline mutations in BRCA1 , BRCA2 , TP53 , DDX41 , or CHEK2 29–31 . Individual genetic predisposition might further contribute to the early development of recipient‐derived MNs following allogeneic HCT.…”