Assessing Therapy-Related Myeloid Neoplasm Risk Through Clonal Hematopoiesis and Treatment Exposure Integration

Abstract

Therapy-related myeloid neoplasms (t-MNs), encompassing therapy-related acute myeloid leukemia (t-AML) and therapy-related myelodysplastic syndromes (t-MDS), represent a significant complication of cytotoxic treatments for cancer and non-malignant conditions. Recent evidence highlights the pivotal role of clonal hematopoiesis (CH), particularly clonal hematopoiesis of indeterminate potential (CHIP), as a determinant of t-MN risk following exposure to chemotherapy and/or radiotherapy. This review synthesizes current data on the epidemiology, pathophysiology, and clinical management of t-MNs, with an emphasis on integrating CH status with treatment exposure to refine risk stratification and inform clinical decision-making. Key advances in molecular profiling, risk-adapted surveillance, and emerging therapeutic strategies are explored, underscoring the necessity for personalized approaches to mitigate t-MN risk and improve outcomes for cancer survivors.

Introduction

Therapy-related myeloid neoplasms are increasingly recognized as a severe and often fatal complication arising after exposure to cytotoxic therapies, including chemotherapy and radiotherapy, administered for primary malignancies or certain non-malignant diseases. The incidence of t-MNs is rising in parallel with improvements in cancer survivorship, making their prevention and early detection a pressing clinical concern. Integrating emerging knowledge of clonal hematopoiesis with traditional risk factors has the potential to revolutionize risk assessment and guide the development of tailored surveillance and intervention strategies for at-risk individuals.

Epidemiology / Disease Burden

t-MNs account for approximately 10%–20% of all cases of AML and MDS. The risk of developing t-MN varies widely depending on the type and intensity of prior therapy, underlying patient characteristics, and genetic predisposition. The overall prognosis for t-MNs remains poor, with median overall survival ranging from 6 to 12 months, largely due to the adverse cytogenetic and molecular features that typify these neoplasms. The growing population of cancer survivors amplifies the absolute number of t-MN cases, imposing significant clinical and health economic burdens.

Pathophysiology

The development of t-MNs reflects the intersection of genotoxic stress from cytotoxic therapy and pre-existing or therapy-induced clonal hematopoiesis. CH, particularly CHIP, is characterized by the expansion of hematopoietic clones harboring somatic mutations in genes such as DNMT3A, TET2, and ASXL1, in the absence of overt hematologic malignancy. Exposure to chemotherapy or radiotherapy exerts selective pressure that can preferentially expand these mutated clones, especially those with defects in TP53 or PPM1D, which confer a survival advantage in the face of DNA damage. The accumulation of additional genetic lesions over time, in conjunction with environmental and host factors, precipitates the transition from clonal hematopoiesis to overt t-MN.

Risk Factors

Risk stratification for t-MN incorporates several factors: the cumulative dose and type of cytotoxic agent (notably alkylating agents and topoisomerase II inhibitors), radiation exposure, age, underlying genetic susceptibility, and, critically, the presence of CHIP. Recent prospective studies have demonstrated that individuals with detectable CHIP prior to therapy have a markedly increased risk of developing t-MN post-treatment, with certain mutations (e.g., TP53, PPM1D) conferring the highest risk. Family history of hematologic malignancies and inherited bone marrow failure syndromes further amplify the risk.

Clinical Features

t-MNs often present with cytopenias, fatigue, infections, and hemorrhagic manifestations, typically within a latency period of 1–10 years after exposure to cytotoxic therapy. Compared to de novo AML/MDS, t-MNs are more likely to exhibit complex karyotypes, monosomy 5/7, and mutations in TP53, indicative of a particularly aggressive clinical course. The clinical presentation can be subtle, necessitating a high index of suspicion in at-risk populations, especially those with prior CHIP and high-risk exposures.

Diagnosis

Diagnosis of t-MN requires integration of clinical, morphologic, cytogenetic, and molecular data. Bone marrow examination reveals dysplasia and increased blasts, while cytogenetic analysis frequently identifies complex aberrations. Next-generation sequencing (NGS) is increasingly employed to detect mutations in genes associated with CHIP and t-MN. The identification of high-risk mutations in previously archived samples can help establish the chronology of clonal evolution and inform risk assessment.

Treatment & Management

Treatment options for t-MNs are limited and outcomes remain poor. Intensive chemotherapy regimens yield low remission rates, and allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative approach for eligible patients. However, the feasibility of HSCT is often constrained by comorbidities and prior treatment toxicity. Supportive care, including transfusions and infection prophylaxis, is essential. Recent interest has focused on the use of hypomethylating agents, particularly in patients unfit for intensive induction therapy.

Recent Advances / Emerging Therapies

The advent of high-throughput sequencing has elucidated the molecular underpinnings of t-MN risk and paved the way for precision medicine approaches. Pre-therapy screening for CHIP, especially high-risk variants, is being evaluated as a strategy to personalize treatment regimens and modify exposure to genotoxic agents. Novel agents targeting mutant p53, DNA repair pathways, and the clonal hematopoietic compartment are under investigation. Additionally, the use of less leukemogenic treatment modalities in CHIP-positive individuals is a growing area of research, aiming to reduce the incidence of t-MN without compromising cancer efficacy.

Guideline Recommendations

Current guidelines emphasize the importance of risk assessment and informed consent regarding t-MN risk when planning cytotoxic therapy. The integration of molecular data, including CHIP status, into standard risk models is advocated in recent expert consensus statements. Surveillance protocols for high-risk survivors, particularly those with pre-existing clonal hematopoiesis and substantial treatment exposures, are being refined to enable earlier detection and intervention. Multi-disciplinary collaboration is crucial, involving hematologists, oncologists, and genetic counselors to optimize patient outcomes.

Conclusion

The integration of clonal hematopoiesis status with treatment exposure represents a paradigm shift in assessing and mitigating the risk of therapy-related myeloid neoplasms. Personalized risk stratification, molecular surveillance, and judicious selection of cytotoxic therapies are essential to reduce the burden of t-MNs in cancer survivors. Ongoing research into the biology of clonal hematopoiesis and innovative therapeutic strategies holds promise for improving the prognosis of affected individuals and guiding clinical practice in the era of precision oncology.