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Therapy-related myeloid neoplasms (t-MNs) encompass a specific sub-group of myeloid malignancies arising after exposure to radio/cytotoxic agents for the treatment of unrelated diseases. Such malignancies present unique features, including advanced age, high comorbidities burden, and unfavorable genetic profiles. All these features justify the need for a specific diagnostic work-up and dedicated treatment algorithms. However, as new classification systems recognize the unique clinical characteristics exhibited by t-MNs patients, how to assess fitness status in this clinical setting is largely unexplored. Optimizing fitness assessment would be crucial in the management of t-MNs patients, considering that factors usually contributing to a worse or better outcome (like age, comorbidities, and treatment history) are patient-specific. In the absence of specific tools for fitness assessment in this peculiar category of AML, the aim of this review is to describe all those factors related to patient, treatment and disease that allow planning treatments with an optimal risk/benefit ratio.

Therapy-related myeloid neoplasms (t-MNs) encompass a specific sub-group of myeloid malignancies arising after exposure to radio/cytotoxic agents for the treatment of unrelated diseases. Such malignancies present unique features, including advanced age, high comorbidities burden, and unfavorable genetic profiles. All these features justify the need for a specific diagnostic workup and dedicated treatment algorithms. However, as new classification systems recognize the unique clinical characteristics exhibited by t-MN patients, how to assess fitness status in this clinical setting is largely unexplored. Optimizing fitness assessment would be crucial in the management of t-MN patients, considering that factors usually contributing to a worse or better outcome (like age, comorbidities, and treatment history) are patient-specific. In the absence of specific tools for fitness assessment in this peculiar category of AML, the aim of this review is to describe all those factors related to patient, treatment, and disease that allow planning treatments with an optimal risk/benefit ratio. [ABSTRACT FROM AUTHOR]

Progress always comes at a price: the field of oncology has seen unprecedented progress in treatment options recently for many solid and hematologic cancers. Unfortunately, these long-term survivors of prior cancer and cytotoxic therapy exposure are at higher risk of therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML.) T-MDS/AML is a myeloid malignancy which occur after exposure to chemotherapy or radiation therapy for unrelated malignancy. T-MDS/AML is associated with adverse cytogenomic features and poor prognosis. While advances in the field of clonal hematopoiesis and germline variants has unraveled the molecular underpinnings of t-MDS/AML, we have miles to go in terms of t-MDS/AML directed therapy and improvement in outcomes. In this review, we discuss the epidemiology of t-MDS/AML, clinical and biological insights, evolution of t-MDS/AML and available treatment options., Competing Interests: Declaration of competing interest SV No disclosures. AED participated in advisory boards, and/or had a consultancy with and received honoraria from Celgene/BMS, Agios, Novartis,Appellis Gilead. AED served on clinical trial committees or DSMB for Novartis, Abbvie, Kura, Geron, Servier, Keros, Shuattuck labs and Celgene/BMS., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2A) genes. The formation of chromosomal translocation depends on the spatial proximity of translocation partners and the mobility of the DNA ends. It is unclear which of these two factors might be decisive for recurrent t-AML translocations. Here, we used fluorescence in situ hybridization (FISH) and chromosome conformation capture followed by sequencing (4C-seq) to investigate double-strand DNA break formation and the mobility of broken ends upon etoposide treatment, as well as contacts between translocation partner genes. We detected the separation of the parts of the broken AML1 gene, as well as the increased mobility of these separated parts. 4C-seq analysis showed no evident contacts of AML1 and MLL with loci, implicated in recurrent t-AML translocations, either before or after etoposide treatment. We suggest that separation of the break ends and their increased non-targeted mobility—but not spatial predisposition of the rearrangement partners—plays a major role in the formation of these translocations. [ABSTRACT FROM AUTHOR]

Abstract Therapy-related myeloid neoplasms are a life-threatening and often fatal complication, associated with poor prognosis outcomes and with high-risk unfavorable cytogenetic abnormalities including complex karyotype. They occur after the treatment of primary malignancies using chemotherapy and/or radiation therapy. Such therapy is not specific to cancer cells, and also damages the deoxyribonucleic acid (DNA) of normal cells, resulting in unbalanced and balanced translocations. There are eight genetic pathways, whose details are summarized in this review, depending on the cytogenetic abnormalities induced. This abnormality is the major contributor to the development of therapy-related myeloid neoplasms. The etiology of these neoplasms depends on the complex interaction between the nature and dose of the cytotoxic agent, the environment, and the presence of subsequent inherited mutations. This review aims to elaborate upon recent knowledge regarding the etiology, pathogenesis, and genetic pathways of therapy-related myeloid neoplasms. A deeper understanding of their etiology would aid physicians in more careful monitoring of patients during or after cytotoxic therapy for hematological malignancy. Ultimately, this knowledge could influence initial treatment strategies, with the aim of reducing both the incidence and serious complications of neoplasms. Therefore, early detection of DNA lesions is vital. The authors recommend that primary malignancy be treated with targeted therapy.

Therapy-related myeloid neoplasms are a life-threatening and often fatal complication, associated with poor prognosis outcomes and with high-risk unfavorable cytogenetic abnormalities including complex karyotype. They occur after the treatment of primary malignancies using chemotherapy and/or radiation therapy. Such therapy is not specific to cancer cells, and also damages the deoxyribonucleic acid (DNA) of normal cells, resulting in unbalanced and balanced translocations. There are eight genetic pathways, whose details are summarized in this review, depending on the cytogenetic abnormalities induced. This abnormality is the major contributor to the development of therapy-related myeloid neoplasms. The etiology of these neoplasms depends on the complex interaction between the nature and dose of the cytotoxic agent, the environment, and the presence of subsequent inherited mutations. This review aims to elaborate upon recent knowledge regarding the etiology, pathogenesis, and genetic pathways of therapy-related myeloid neoplasms. A deeper understanding of their etiology would aid physicians in more careful monitoring of patients during or after cytotoxic therapy for hematological malignancy. Ultimately, this knowledge could influence initial treatment strategies, with the aim of reducing both the incidence and serious complications of neoplasms. Therefore, early detection of DNA lesions is vital. The authors recommend that primary malignancy be treated with targeted therapy. [ABSTRACT FROM AUTHOR]

For decades, the standard induction for patients with acute myeloid leukemia (AML) has been the combination of cytarabine with anthracycline (7 + 3 regimen). In August 2017 the US FDA approved CPX-351 (vyxeos), a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML (t-AML). This is the first approved treatment specifically for patients with this subgroup of AML. The approval was based on findings from a multicenter, randomized, open-label, phase III study of CPX-351 Versus 7 + 3 in patients 60–75 years old with newly diagnosed AML-MRC or t-AML. In this study CPX-351 had a higher median OS than 7 + 3 (9.56 vs 5.95 months, HR 0.69; 95% CI: 0.52 to 0.90, p = 0.005). In this profile, we review preclinical and clinical data, and discuss limitations and future directions with CPX-351 use in AML. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Therapy related acute myeloid leukemia (t-AML) is a potential late complication of cytotoxic therapy, and it is of particular concern in the treatment of patients with epithelial ovarian carcinoma (EOC) exposed to multiple courses of chemotherapy during the course of their disease. This study examines the incidence, characteristics and clinical outcomes of patients who developed secondary myeloid-type leukemia after a diagnosis of EOC. Methods: National Cancer Institute''s Surveillance, Epidemiology and End Results database was pooled for diagnosis of secondary myeloid leukemia after an initial diagnosis of EOC. This group of patients was compared to patients with de novo AML, and to EOC patients who did not develop secondary myeloid leukemia. Demographic, cytopathological and survival data were recorded. Cox Proportional Hazards model was used to calculate hazard ratios (HR) for developing secondary leukemia and to determine the statistically significant variables impacting survival. Kaplan–Meier estimates of survival were obtained and comparisons between the groups were performed using log-rank test. Results: One hundred and nine myeloid leukemia cases were identified among 63,359 patients with a prior diagnosis of EOC for an overall incidence of 0.17%. The median latency to development of leukemia was 4years (range 0–27years). Median survival from the time of secondary leukemia diagnosis was 3months and significantly worse than the 6month median survival in patients with de novo AML (p <0.001). Age at leukemia diagnosis greater than 65 and development of secondary vs. de novo leukemia had a statistically worse prognosis on multivariate analysis (HR of 2.69, 95%CI 2.60–2.78 and 1.81, 95%CI 1.49–2.20 respectively). The development of secondary leukemia was more common with EOC diagnosis made prior to the platinum/taxane era (HR 6.70, 95%CI 3.69–12.18). There was no difference in median survival between EOC patients who developed AML and those who did not. Conclusion: Development of t-AML is a rare but lethal event among EOC patients, and its incidence has decreased significantly since the use of platinum/taxane-based chemotherapy became the standard of care. [Copyright &y& Elsevier]

BRCA1 plays a pivotal role in the repair of DNA damage, especially following chemotherapy and ionising radiation. We were interested in the regulation of BRCA1 expression in acute myeloid leukaemia (AML), in particular in therapy-related forms (t-AML). Using real-time PCR and Western blot, we found that BRCA1 mRNA was expressed at barely detectable levels by normal peripheral blood granulocytes, monocytes and lymphocytes, whereas control BM-mononuclear cells and selected CD34+ progenitor cells displayed significantly higher BRCA1 expression (P=0.0003). Acute myeloid leukaemia samples showed heterogeneous BRCA1 mRNA levels, which were lower than those of normal bone marrows (P=0.0001). We found a high frequency of hypermethylation of the BRCA1 promoter region in AML (51/133 samples, 38%), in particular in patients with karyotypic aberrations (P=0.026), and in t-AML, as compared to de novo AML (76 vs 31%, P=0.0002). Examining eight primary tumour samples from hypermethylated t-AML patients, BRCA1 was hypermethylated in three of four breast cancer samples, whereas it was unmethylated in the other four tumours. BRCA1 hypermethylation correlated to reduced BRCA1 mRNA (P=0.0004), and to increased DNA methyltransferase DNMT3A (P=0.003) expression. Our data show that reduced BRCA1 expression owing to promoter hypermethylation is frequent in t-AML and that this could contribute to secondary leukaemogenesis.British Journal of Cancer (2006) 95, 1108–1113. doi:10.1038/sj.bjc.6603392 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Amplification or duplication of the AML1 gene at chromosome band 21q22 was detected by FISH using a locus-specific probe in three out of 171 unselected patients with therapy-related myelodysplasia (t-MDS) or t-AML (1.7%). In two patients AML1 signals were located tandemly on derivative chromosomes, in one patient on a dic(9;21) and in the the other patient on a derivative chromosome 18 made up of interchanging layers of material from chromosomes 9, 14, 18, and 21. In the third patient three single supernumerary copies of AML1 were located on derivatives of chromosomes 19 and 21. All three patients were older, had previously received therapy with alkylating agents without topoisomerase II inhibitors, had complex karyotypes including abnormalities of chromosomes 5 or 7, and presented acquired point mutations of the TP53 gene. No point mutations of the AML1 gene were observed. The results support a pivotal role of impaired TP53 function in the development of gene amplification or duplication in t-MDS and t-AML.Leukemia (2005) 19, 197-200. doi:10.1038/sj.leu.2403612 Published online 23 December 2004 [ABSTRACT FROM AUTHOR]

Increased risk for the development of therapy-induced myeloid leukemia following the treatment of breast cancer has typically been associated with the use of regimens containing anthracyclines or alkylating agents. We present two cases of estrogen receptor-positive/progesterone receptor-positive/human epidermal growth factor receptor 2-positive (ER+/PR+/HER2+) breast cancer patients, treated with a non-anthracycline, non-alkylating regimen of trastuzumab, carboplatin, docetaxel, and pertuzumab (TCHP), who developed therapy-related acute myeloid leukemia (t-AML) within 30 months of the completion of treatment. Both patients had marked cytogenetic abnormalities, including deletions of chromosomes 5 and 7, and highly aggressive disease that resulted in a poor prognosis. While platinum and taxane-based chemotherapy regimens have been previously linked to the development of t-AML or therapy-related myelodysplastic syndrome (t-MDS) following treatment for ovarian cancer, they have not yet been shown to increase the risk of t-AML/t-MDS after their use for breast cancer therapy. As TCHP is widely used for the treatment of HER2/neu overexpressed breast cancer, these cases highlight the need to further evaluate the link between taxane and platinum-based chemotherapeutics for breast cancer and the development of t-AML/t-MDS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Gill et al.)

Prospective evidence for management of therapy-related acute myeloid leukemia (t-AML) is limited, with evidence extrapolated from major AML trials. Optimal treatment is challenging and needs consideration of patient-specific, disease-specific, and therapy-specific factors. Clinical trials are recommended, especially for unfit patients or those with unfavorable cytogenetics or mutations. CPX-351 as an upfront intensive chemotherapy is preferred for fit patients; venetoclax with decitabine or azacitidine is an option for patients unfit for intensive chemotherapy. Hematopoietic cell transplant, the only curative option, should be offered to eligible patients with intermediate or unfavorable t-AML or patients with good-risk AML with minimal residual disease. Ongoing clinical trials focusing on treatment of t-AML, including targeted agents and immunotherapy, bode well for the future., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Highlights from the article: We retrospectively reviewed all AML patients treated at City of Hope between June 2016 and April 2019, and identified 8 patients with t-AML and active advanced non-hematological malignancies who received VEN-HMA. All patients were treated with VEN-HMA for newly diagnosed AML except for one who was treated with the combination for r/r AML after failing 2 prior AML therapies. Five patients received concurrent treatment for the underlying non-hematological malignancies, including hormonal therapies, immunotherapy, tyrosine kinase inhibitor and chemotherapy (Table 1). 4 S. Kayser, K. Döhner, J. Krauter, The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML, Blood., 117, 2011, 2137-2145Kayser S, Döhner K, Krauter J, et al.

Therapy-related myeloid neoplasm (t-MN) is a rare but devastating consequence of chemotherapy and/or radiotherapy used for the treatment of solid cancers and various hematologic malignancies. Our current understanding of the etiology is that hematopoietic clones that are contemporaneous with the primary cancer and resistant to the cytotoxic exposure have the potential to undergo selective expansion and transformation to t-MN. Consequently, a large proportion of cases are associated with adverse risk factors, resulting in limited effective treatment options. Despite the emergence of some therapies with promising activity in t-MN, most effects are short-lived and allogeneic stem cell transplantation remains the only curative option for eligible patients. This review summarizes the current literature on t-AML and t-MDS, with the aim of providing practical recommendations on the clinical evaluation and management of these conditions., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn 2+ /Mg 2+ -dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. VIDEO ABSTRACT., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)