CEBPA mutation

CN-AML patients with CEBPA mutation have specific concomitant gene profile, and the concomitant mutations of different functional genes have a certain impact on the clinical characteristics and prognosis of the patients.

In conclusion, CSF3R mutations were found at a higher frequency in aCML patients than in previous studies, which might reflect ethnic differences. Additional studies are needed to confirm these findings and the relationship between CSF3R and CEBPA mutations.

Not available.

AML cases defined by differentiation (WHO2022) and AML not otherwise specified (ICC) are categorized as lacking specific defining genetic abnormalities, WHO2022 labels this as a myeloid neoplasm post cytotoxic therapy (MN-pCT), described as an appendix after specific diagnosis. Similarly, in ICC, it can be described as "therapy-related", without a separate AML category.

No abstract available

P2, N=107, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting

This meta-analysis sheds light on the prevalence of genetic mutations in AML patients with MS, providing insights into the unique characteristics of the mutations and their frequencies. These discoveries are crucial in informing therapeutic and prognostic decisions for individuals with myeloid sarcoma.

Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.

P2, N=153, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

In the intermediate-risk group, the high median VAF of GATA2 (≥38.51%) had no significant effect in OS and RFS compared with the low median VAF (<38.51%). This study offers new insights on the prognosis of GATA2mut in the favorable-risk group, where VAF can be used as a guide.

The genetic and molecular abnormalities of primary MS can be detected by FISH and NGS techniques. FLT3-ITD, RUNX1, ASXL1 or TP53 mutation indicates a worse prognosis, but further clinical studies are needed to confirm it.

In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.

Among these, CEBPA double mutations displayed a significant association, with ABO antigen weakness being observed in 20 out of the 25 individuals (80.0%) possessing these mutations. From this study, new factors associated with ABO antigen weakness have been identified.

In summary, HLA loss detection is essential for patients with recurrence after transplantation, especially for those with more HLA mismatched loci and non-sibling donor. Furthermore, the detection of HLA loss has a guiding role in choosing subsequent therapy when relapsed, as secondary transplantation is more suitable than DLI for those with HLA loss.

Together, we demonstrate that CD74 is expressed on a subset of pediatric AMLs at increased levels compared to normal hematopoietic cells and is a promising target for therapy in expressing patients. Given that nearly half of patients expressing CD74 at high levels experience an adverse event within 5 years, and the availability of CD74 targeting drugs, this represents a promising line of therapy worthy of additional investigation.

However, ITDpos/NUP98::NSD1 patients continued to have poor outcomes with intensified therapy, including sorafenib. Co-occurring mutational profile in ITDpos AML has significant prognostic impacts is critical to determining risk stratification and therapeutic allocation for ITDpos patients.

Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and ATP5IF1) were overexpressed and were associated with poorer survival, and the results were independently validated in the TARGET AML cohort. In conclusion, concurrent WT1 or DNMT3A mutations and a dysregulated immune and metabolic state were correlated with poor survival in patients with CEBPA, and upfront allogeneic transplantation may be indicated for better long-term disease control.

Moreover, co-mutations in bZIP patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIP).

P1/2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.

Isolated TP53 mutation was seen in association with smoking, high-grade cytomorphologic features, adverse prognosis, and recurrent CEBPA deletions. These tumors tend to have strong PD-L1 expression and high TMB, suggesting potential benefit from immune checkpoint inhibitors. Hence, the recognition of this molecular group has prognostic and therapeutic implications.

The ELN-2022 risk stratification system may not be appropriate for patients unable to receive intensive therapy or FLT3 inhibitor; more real-world data is needed to straify patients with worse ECOG PS and inferior intensive therapy.

NRAS mutations were associated with poor outcome in trisomy AML, whereas DNMT3A and FLT3-ITD mutations had neutral effect. Trisomy AML appeared biologically distinct from CN-AML.

The study presents the largest molecular profiling to our knowledge of this population. The study emphasises the need for integration of NGS to enhance risk stratification and precision, enable better characterisation of high-risk patients, and improve the potential for targeted treatments.

Our findings reveal a novel therapeutic strategy using CEBPA mRNA LNP applicable to inherited or acquired disorders of CEBPA. This approach of restoration of normal mRNA could have potential for therapy of many pre-malignant and malignant disorders.

Background: The IA regimen (combination of idarubicin and cytarabine) is used as the most common induction of remission therapy for acute myeloid leukemia, with the complete response (CR) rates of up to 70%. As induction and consolidation therapy whose adverse reactions were tolerable, the low-dose IA with Venetoclax regimen produces deep remission for the patients with newly diagnosed primary AML.

Introduction Azacitidine and venetoclax combination therapy (Aza/Ven) is a novel strategy for acute myeloid leukemia (AML). Our mathematical model, involving gene mutations and WT1, could efficiently predict the response of Aza/Ven, which may support the selection of 1 st line treatment. In conclusion, our study revealed the genetic landscape of real-world Aza/Ven therapy and provided a potential prognostic model.

Nevertheless, the presence of mutations in ASXL1 and JAK2 genes, age >65 years and the presence of fibrosis were associated with reduced OS (p<0.05, Kaplan-Meier), whereas NPM1-mutated gene characterized patients with better outcome. Overall, a typical mutational pattern and distinct morphological features defined patients affected by myeloid neoplasms with concomitant mutations in SRSF2 and IDH1/2.

A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics.

Our study indicates that in-frame bZIP CEBPA mutations are the critical molecular aberrations associated with favorable outcomes in AML patients treated with curative intent chemotherapy. Compared to WHO-HAEM5, the ICC identifies a more homogenous group of CEBPA-mutated AML patients with favorable outcomes.

Conclusion Allogeneic HCT exerts a greater benefit on RFS in AML pts with mutations in the chromatin modifier, spliceosome, and myeloid TF pathways. Further study is warranted to replicate this finding.

These data suggest that somatic mutations in CMML have unique patterns of clustering that define disease phenotype and influence disease outcomes.

Conclusions HMA-F MDS is characterized by increased genomic complexity by acquisition of new somatic mutations (NGS) and SVs (OGM), highlighting their complementary role in MDS progression. OGM further highlighted cataclysmic genomic changes by chromoanagenesis in a subset of MDS pts at HMA-F.

Background: The 2017 European LeukemiaNet (ELN-2017) risk classification system updated AML guidelines in 2022, adjusted FLT3-ITD mutated patients without core binding factor (CBF) or adverse risk markers to intermediate risk groups, according to the clinical trial results of midostaurin on patients with FLT3-ITD not NPM1 mutation and MRD in treatment decisions...323 (89.0%) patients received induction therapy: 271 (74.6%) patients received cytarabine-based chemotherapy, 52 (14.3%) patients unfit for intensive chemotherapy received hypomethylating agents (HMA)-based therapy, while 36 (9.9%) patients only received best supportive care, mainly due to early death during hydroxyurea treatment or did not want any therapy due to potential treatment costs...Among these patients, only 9 received FLT3 inhibitors (gilteritinib or sorafenib) due to late approval of FLT3 inhibitors in China; the remaining 52 patients received chemotherapy alone: 40 have FLT3-ITD allelic ratio <50%, 12 have allelic ratio ≥50%... our real-world clinical data show that the ELN-2022 risk classification system is not superior to the ELN-2017 version in classifying patients in our center. For patients with FLT3-ITD mutation but unable to receive FLT3 inhibitor, their risk classification and treatment therapy should be considered as adverse risk group.

RUNX1 was not an independent prognostic factor for survival. Overall, our findings agree with the updated WHO classification system for AML that AML-RUNX1mut should not be recognized as a distinct AML entity.

Background Results from the phase 3 QuANTUM-First study (NCT02668653) showed that in patients (pts) with newly diagnosed (nd) acute myeloid leukemia (AML) and positive for FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD+), the addition of the oral, highly potent, and selective, type 2 FLT3 inhibitor quizartinib (Quiz) to standard chemotherapy ± allogeneic hematopoietic cell transplantation (allo-HCT), followed by continuation monotherapy for up to 3 years, decreased the relative risk of death by 22.4% vs placebo (PBO) (PMID: 37116523)...Pts who achieved CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine combined with Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 years (36 cycles) of continuation therapy with Quiz (30-60 mg/d) or PBO...Conclusions These analyses demonstrated that in QuANTUM-First: 1) a substantial fraction of the estimated effect of Quiz on OS was mediated through its effect on achieving a durable CR and 2) more pts in the Quiz arm vs the PBO arm achieved CR after day 42 of the last induction cycle, suggesting that there was a delay in CR achievement with Quiz. Longer EFS was observed in Quiz over PBO based on the EFS definition including CRs between day 42 and end of induction.

Our findings suggest Latino children are more likely to have a favorable cytogenetic subtype than NLW children, which suggests disparities in outcomes are not primarily due to underlying differences in prognostic subtypes. Additional analyses of pediatric AML as it relates to cytogenetic subtypes and race/ethnicity is ongoing, including the incorporation of disease response and treatment outcomes, to understand how these factors may impact disparities in outcomes.

Supported by National Institute of Cancer Research No. LX22NPO5102 funded by the European Union–Next Generation EU, and AZV grant NU20-07-00322.