Role of Germline Predisposition to Therapy-Related Myeloid Neoplasms

Baranwal, Anmol; Hahn, Christopher N.; Shah, Mithun Vinod; Hiwase, Devendra

doi:10.1007/s11899-022-00676-2

Cited by 10 publications

(5 citation statements)

References 110 publications

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“…In the German I-BFM patients, we could investigate germline predisposition variants for which we used a previously published set of childhood cancer-associated genes 23 . Likely pathogenic germline mutations were found in 6/25 t-MN patients (24%), which is higher than previously published in pediatric cancer and pediatric t-MN 16 , 24 , but comparable to adult t-MN 25 . We found a germline aberration in five patients in the genes encoding BLM, WRN , and WT1 in one patient each, and FANCA in two patients.…”

Section: Resultscontrasting

confidence: 58%

Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms

Bertrums,

de Kanter,

Derks

et al. 2024

Nat Commun

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Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations in children, whereas in adults pre-existing mutant clones are selected by the exposure. However, selective pressures induced by chemotherapy early in life are less well studied. Here, we use single-cell whole genome sequencing and phylogenetic inference to show that the founding cell of t-MN in children starts expanding after cessation of platinum exposure. In patients with Li-Fraumeni syndrome, characterized by a germline TP53 mutation, we find that the t-MN already expands during treatment, suggesting that platinum-induced growth inhibition is TP53-dependent. Our results demonstrate that germline aberrations can interact with treatment exposures in inducing t-MN, which is important for the development of more targeted, patient-specific treatment regimens and follow-up.

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Section: Resultscontrasting

confidence: 58%

Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms

Bertrums,

de Kanter,

Derks

et al. 2024

Nat Commun

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“…Emerging findings indicate that the development of AML-pCT is influenced by complex factors, such as the acquisition of somatic mutations resulting from DNA-damaging cytotoxic therapy and inherited genetic cancer susceptibility [4]. Newer treatment methods, including poly (ADP-ribose) polymerase inhibitors (PARPi), were also associated with AML-pCT [4]. In a study, one in five AML-pCT patients after BC therapy was a carrier of germline mutations (most commonly in BRCA1, TP53, and BRCA1 genes).…”

Section: Discussionmentioning

confidence: 99%

“…Prior exposure to DNA-damaging agents, commonly used for the adjuvant and neoadjuvant treatment of BC, triggers the leukemogenesis and increases the risk of AML-pCT. Furthermore, the development of AML-pCT in patients previously affected by BC may also be associated with inherited cancer susceptibility [3,4]. Among patients with AML-pCT following BC, germline mutations were detected in 21%, with the highest frequency observed in the BRCA1, TP53, and BRCA2 genes [5].…”

Section: Introductionmentioning

confidence: 99%

Acute Myeloid Leukemia Post Cytotoxic Therapy in Breast Cancer Survivors—Over 23 Years of Single Center Analysis

Adamska,

Kowal-Wiśniewska,

Barańska

et al. 2024

JCM

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Background: Acute myeloid leukemia post cytotoxic therapy (AML-pCT) among breast cancer (BC) survivors represents a life-threatening complication. This study aims to assess the clinical outcomes of AML-pCT post BC. Methods: An analysis of all AML patients treated at a single hematology center (2000–2023) was performed to select patients with AML-pCT post BC. We applied the 2022 ELN criteria to define the genetic risk. Results: Among 847 AML patients, 28 were diagnosed with AML-pCT following BC. Complex karyotype (CK) occurred in 23.8% of patients. The median overall survival (OS) was 40 months. The survival outcomes were better after allogenic hematopoietic stem cell transplantation (alloHCT) treatment compared to chemotherapy alone (median OS: 47 versus 7 months, p = 0.008). Patients demonstrating CK showed lower survival compared to those without CK (2-year OS: 25.0% versus 66.2%, p = 0.0048). The multivariable Cox proportional hazards regression model indicated that treatment with alloHCT emerged as a significant factor associated with improved OS. The treatment was associated with superior OS (HR = 0.07, 95% CI = 0.01–0.86, p = 0.04). Conclusions: Patients with AML-pCT following BC were characterized with the highest frequency of adverse genetic risk profiles and demonstrated worse survival rates. AlloHCT should be performed as early as possible in such patients. The growing need for studies on inherited cancer susceptibility underscores the importance of close AML-pCT development monitoring in BC survivors.

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“…[ 10 ] However, the cumulative incidence of t-MDS/t-AML ranges from 0.8 to 6.3% at 20 years of age in children treated with standard protocols for ALL. [ 11 , 12 ] MDS, in most cases, MDS requires allo-HSCT with a more intensive conditioning regimen. Moreover, as most trials with reduced-intensity regimens have enrolled older patients and patients with comorbid conditions, [ 13 ] we may rely on the immunotherapeutic effect of donor cells for complete disease eradication.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic stem cell transplantation without preconditioning in a child with therapy-related myelodysplastic syndrome: A case report

et al. 2023

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Rationale: Infants with mixed-lineage leukemia (MLL)-rearranged leukemia are usually refractory to standard induction therapy and are not immediate candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chromosome 11q23 translocations, resulting in MLL rearrangement, have been well characterized in infant acute lymphoblastic leukemia (ALL). While t(4;11) ALL continues to have carry a bleak prognosis, patients with therapy-related myelodysplastic syndrome (t-MDS) have a shorter median overall survival than those compared with de novo MDS. Patient concerns: We describe a child with t-MDS who evolved from MLL-rearranged ALL and was successfully treated with HSCT without toxic preconditioning. Diagnoses: MDS diagnosis was based on morphological characteristics of bone marrow dysplasia in patients with clinical manifestations evidence of hematopoiesis impairments by different combinations of anemia, leukopenia, neutropenia, and thrombocytopenia. Interventions: Although the best donor for allo-HSCT is generally considered an human leukocyte antigen-matched sibling, only ~ 30% of patients have a suitable sibling. HSCT from an unrelated donor is a suitable option for patients with t-MDS who do not have matched sibling donors. Outcomes: Allo-HSCT without recipient preconditioning could be a promising treatment option for t-MDS, especially for patients with recurrent or persistent infections. Lessons: Cytogenetics, prognosis, and treatment of t-MDS are briefly discussed. Preconditioning before allo-HSCT seriously damages immune function. This work reviews our experience with a patient with t-MDS following ALL complicated by recurrent infections, and highlights our choice to omit preconditioning from allo-HSCT.

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Role of Germline Predisposition to Therapy-Related Myeloid Neoplasms

Cited by 10 publications

References 110 publications

Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms

Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms

Acute Myeloid Leukemia Post Cytotoxic Therapy in Breast Cancer Survivors—Over 23 Years of Single Center Analysis

Allogeneic stem cell transplantation without preconditioning in a child with therapy-related myelodysplastic syndrome: A case report

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