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Therapy-Related Myeloid Neoplasms: Predisposition and Clonal Evolution
Emiliano Fabiani1,2, A Cristiano1, H Hajrullaj1
1Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy.
Abstract:
Therapy-related Myeloid Neoplasm (t-MN) represents one of the worst long-term consequences of cytotoxic therapy for primary tumors and autoimmune disease. Poor survival and refractoriness to current treatment strategies characterize affected patients from a clinical point of view. In our aging societies, where newer therapies and ameliorated cancer management protocols are improving the life expectancy of cancer patients, therapy-related Myeloid Neoplasms are an emerging problem. Although several research groups have contributed to characterizing the main risk factors in t-MN development, the multiplicity of primary tumors, in association with the different therapeutic strategies available and the new drugs in development, make interpreting the current data still complex. The main risk factors involved in t-MN pathogenesis can be subgrouped into patient-specific, inherited, and acquired predispositions. Although t-MN can occur at any age, the risk tends to increase with advancing age, and older patients, characterized by a higher number of comorbidities, are more likely to develop the disease. Thanks to the availability of deep sequencing techniques, germline variants have been reported in 15-20% of t-MN patients, highlighting their role in cancer predisposition. It is becoming increasingly evident that t-MN with driver gene mutations may arise in the background of Clonal Hematopoiesis of Indeterminate Potential (CHIP) under the positive selective pressure of chemo and/or radiation therapies. Although CHIP is generally considered benign, it has been associated with an increased risk of t-MN. In this context, the phenomenon of clonal evolution may be described as a dynamic process of expansion of preexisting clones, with or without acquisition of additional genetic alterations, that, by favoring the proliferation of more aggressive and/or resistant clones, may play a crucial role in the progression from preleukemic states to t-MN.
Insights
Therapy-related Myeloid Neoplasms (t-MN) are a serious consequence of cancer treatment, particularly in aging populations. Understanding risk factors like genetic predispositions and Clonal Hematopoiesis of Indeterminate Potential (CHIP) is crucial for managing this emerging health problem.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Therapy-related Myeloid Neoplasms (t-MN) are severe long-term complications of cytotoxic therapies for primary cancers and autoimmune diseases.
- t-MN presents a significant clinical challenge due to poor survival rates and resistance to current treatments, increasingly affecting aging populations with improved life expectancies.
- The complexity of t-MN pathogenesis is influenced by diverse primary tumors, varied therapeutic strategies, and novel drug development.
Purpose of the Study:
- To elucidate the multifaceted risk factors contributing to the development of therapy-related Myeloid Neoplasms.
- To explore the role of genetic predispositions and Clonal Hematopoiesis of Indeterminate Potential (CHIP) in t-MN pathogenesis.
- To understand the dynamic process of clonal evolution in the progression from preleukemic states to t-MN.
Main Methods:
- Review and synthesis of current research on t-MN risk factors.
- Analysis of data from deep sequencing techniques to identify germline variants in t-MN patients.
- Investigation of the association between Clonal Hematopoiesis of Indeterminate Potential (CHIP) and t-MN development.
Main Results:
- Risk factors for t-MN can be categorized into patient-specific, inherited, and acquired predispositions, with risk increasing with age and comorbidities.
- Germline variants are identified in 15-20% of t-MN patients, underscoring their role in cancer predisposition.
- t-MN with driver mutations may emerge from a background of CHIP, influenced by selective pressures from chemotherapy and radiation, with clonal evolution playing a key role.
Conclusions:
- Therapy-related Myeloid Neoplasms represent a growing clinical concern, particularly in aging demographics.
- Genetic factors, including germline variants and CHIP, significantly contribute to t-MN susceptibility and development.
- Understanding clonal evolution is vital for comprehending the progression from preleukemic conditions to overt t-MN.
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