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Therapy-Related MDS/AML and the Role of Environmental Factors

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Pathogenesis and Treatment of Leukemia

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Abstract

Therapy-related myeloid neoplasms (t-MNs) include acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), onsetting in patients treated with cytotoxic therapy (chemotherapy and/or radiation therapy) for a primary cancer or an autoimmune disorder.

t-MN accounts for approximately 10–20% of newly diagnosed cases of AML or MDS and can occur at any age. The risk of developing a t-MN is determined by complex interactions between the nature and dose of the chemotherapy agents and radiation intensity. Inherited risk factors and environmental exposures may then contribute to the accumulation of somatic mutations in hematopoietic stem cells and t-MN onset. 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 at the time of the primary cancer diagnosis prior to any cytotoxic treatment, probably setting the fertile genomic pre-malignant state for secondary leukemogenesis. The pathogenesis of t-MN is then a multifactoral process, where the type of cancer therapy, the aging process, and the individual exposures may favor additional hit development, such as the acquisition of TP53 mutations and unfavorable karyotype abnormalities.

Patients with t-MN generally have poor prognosis (5-year overall survival <10%) and are often refractory to standard treatment strategies, with the exceptions of t-AML with recurrent translocations, including t-APL (acute promyelocytic leukemia) and core-binding factor t-AML, who should receive conventional treatment according to age and performance status. Other t-MN patients should be considered candidates for HSCT, if eligible, since this is the only potentially curative treatment. However, not all patients may benefit from transplantation, such as patients with TP53 mutations, that account for about 30–40% of all t-MN cases. The unfavorable prognosis of t-MN indicates the need for new pharmacological approaches, such as CPX-351, or venetoclax in combination with hypomethylating agents, monoclonal antibodies as magrolimab, or targeted drugs against pathogenic mutations.

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Abbreviations

AML:

Acute myeloid leukemia

ASXL1:

Additional sex combs like 1

BM:

Bone marrow

BMM:

Bone marrow microenvironment

CHIP:

Clonal hematopoiesis of indeterminate potential

CNA:

Copy number alterations

cnLOH :

Copy neutral loss of heterozygosity

CR:

Complete response

DAMP:

Damage-associated molecular pattern

DE:

Distally exposed

DNMT3A:

DNA methyltransferase 3A

HSC:

Hematopoietic stem cells

HSCT:

Hematopoietic stem cell transplantation

HSPC:

Hematopoietic stem/progenitor cells

KMT2A:

Histone-lysine N-methyltransferase 2A

MDS:

Myelodysplastic syndromes

MDS/MPN:

Myelodysplastic/myeloproliferative neoplasms

MSC:

Mesenchymal stem cells

OS:

Overall survival

PE:

Proximally exposed

RUNX1:

Runt-related transcription factor 1

SF3B1:

Splicing factor 3B subunit 1

SIR:

Standardized incidence ratio

SNP:

Single nucleotide polymorphisms

SNV:

Single nucleotide variants

TET2:

Tet methylcytosine dioxygenase 2

TLR4:

Toll-like receptor 4

t-MN:

Therapy-related myeloid neoplasms

TP53:

Tumor protein p53

VAF:

Variant allele frequency

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  1. Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy

    Maria Teresa Voso & Giulia Falconi

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  1. Maria Teresa Voso
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    Harinder Gill

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    Yok-Lam Kwong

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Voso, M.T., Falconi, G. (2023). Therapy-Related MDS/AML and the Role of Environmental Factors. In: Gill, H., Kwong, YL. (eds) Pathogenesis and Treatment of Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-99-3810-0_29

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