Prognostic impact of <i>DNMT3A</i> mutation in acute myeloid leukemia with mutated <i>NPM1</i>

Oñate, Guadalupe; Bataller, Àlex; Garrido, Ana; Hoyos, Montserrat; Arnán, Montserrat; Vives, Susana; Coll, Rosa; Tormo, Mar; Sampol, Antònia; Escoda, Lourdes; Salamero, Olga; Garcia, Antoni; Bargay, Joan; Aljarilla, Alba; Nomdedeu, Josep; Esteve, Jordi; Sierra, Jorge; Pratcorona, Marta

doi:10.1182/bloodadvances.2020004136

Cited by 24 publications

(17 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Then further analysis revealed that there was no difference regarding EFS and OS between patients with first-class mutation and patients without first-class mutation. As known, the firstclass mutations included prognostic genes such as CEBPA, FLT3, DNMT3A, NPM1, and RNF213; they are previously observed to correlate with prognosis of AML [28][29][30]. However, our study indicated that the mutated genes might not be correlated with survival in patients with relapsed AML after allo-HSCT, which might result from the reduced small sample size in our study; this presumption needed more validation by future studies.…”

Section: Discussionmentioning

confidence: 60%

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Zhao

et al. 2021

Ann Hematol

View full text Add to dashboard Cite

This study aimed to evaluate the efficacy and safety of venetoclax plus azacitidine and donor lymphocyte infusion (DLI) in treating patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-six AML patients who relapsed after allo-HSCT were enrolled and treated with venetoclax plus azacitidine and DLI. Complete remission with incomplete recovery (CRi), partial remission (PR), and objective remission rate (ORR) were assessed, and then event-free survival (EFS) and overall survival (OS) were evaluated. Besides, adverse events were documented. Additionally, whole exome sequencing was performed in bone marrow samples. The CRi, PR, and ORR rates were 26.9%, 34.6%, and 61.5%, respectively. The median time of EFS and OS was 120 (95% CI: 71–610) days and 284.5 (95% CI: 81–610) days, respectively. The most common adverse events were hematologic system adverse events including agranulocytosis, anemia, and thrombocytopenia, while the adverse events of other systems were relatively less and milder. In addition, no serious adverse events existed. Of note, there were 6 (23.1%) patients who developed GVHD. As for gene mutation, 49 mutated genes were found, which were categorized as first-, second-, and third-class mutations, and then further analysis revealed that the first-class mutations were not correlated with EFS or OS. Additionally, the most frequent mutated genes were FLT3, CEBPA, DNMT3A, KIT, KRAS, and NRAS. Venetoclax plus azacitidine and DLI is efficient and tolerant in treating patients with relapsed AML after allo-HSCT, implying this combined therapy as a potential treatment option in the studied patients.

show abstract

Section: Discussionmentioning

confidence: 60%

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Zhao

et al. 2021

Ann Hematol

View full text Add to dashboard Cite

show abstract

“…In addition, this category includes patients with cytogenetic abnormalities not classified as favorable or adverse, as well as patients without NPM1 mutation and adverse-risk genetic lesions, which are biologically heterogeneous 29,40 . In this context, further knowledge on the prognostic impact of additional markers and gene mutation interactions, such as the deleterious effect associated with BCOR, SETBP1, ZRSR2 or DNMT3A co-mutations might contribute to redefine the current classification in future updates, as suggested by Eisfeld et al from the CALGB network 20,41 .…”

Section: Discussionmentioning

confidence: 99%

“…29,40 In this context, further knowledge on the prognostic impact of additional markers and gene mutation interactions, such as the deleterious effect associated with BCOR , SETBP1, ZRSR2 , or DNMT3A comutations might contribute to redefine the current classification in future updates, as suggested by Eisfeld et al 20 from the CALGB network. 41 …”

Section: Discussionmentioning

confidence: 99%

European LeukemiaNet 2017 risk stratification for acute myeloid leukemia: validation in a risk-adapted protocol

et al. 2022

Self Cite

View full text Add to dashboard Cite

The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and post-remission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the CETLAM-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, while it recommends allogeneic stem cell transplantation as a post-remission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%) and 245 (36%) patients allocated to the favorable, intermediate and adverse risk group, respectively. The 2 and 5 year-overall survival (OS) were 77 and 70% for favorable risk patients, 52 and 46% for intermediate risk patients, and 33 and 23% for adverse risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype and/or TP53 mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol, based on alloSCT after remission for non-favorable ELN subgroups, and identifies a genetic subset with a very poor outcome which warrants investigation of novel strategies.

show abstract

“…In de novo adult AML, NPM1 is most frequently mutated with DNMT3A, 39 and the majority of DNMT3A mutations are found in R882, replicated by the murine R878 model used in our study. Recent analysis aimed to elucidate the prognostic impact of cooccurring DNMT3A and NPM1 mutations in AML has found that DNMT3A mutation status does not have an overall prognostic impact 40 ; however, DNMT3A mut was associated with significantly higher measurable residual disease (MRD) compared with DNMT3A wt , and DNMT3A mut patients exhibited a trend toward a greater risk of molecular relapse. Based on our results, we speculate that the cell of origin incurring and sustaining the NPM1 cooperating mutation will have an impact on disease prognosis and may be a relevant consideration when evaluating MRD.…”

Section: Discussionmentioning

confidence: 99%

Cell origin–dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy

et al. 2022

View full text Add to dashboard Cite

In adult acute myeloid leukemia (AML), acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced expression of cytokine and pro-inflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA in cooperation with Dnmt3aR878H acutely increased accessibility of a distinct set of promoters in HSCs compared to MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between pre-existing Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention into transformation from CH to AML.

show abstract

Prognostic impact of DNMT3A mutation in acute myeloid leukemia with mutated NPM1

Cited by 24 publications

References 49 publications

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

Venetoclax plus azacitidine and donor lymphocyte infusion in treating acute myeloid leukemia patients who relapse after allogeneic hematopoietic stem cell transplantation

European LeukemiaNet 2017 risk stratification for acute myeloid leukemia: validation in a risk-adapted protocol

Cell origin–dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy

Contact Info

Product

Resources

About