Chr del(7q)

After the survey, myelodysplastic syndromes with low blasts (ie, less than 5%) and myelodysplastic syndromes with increased blasts (ie, 5% or more) were recognised as disease entities. Our data-driven approach can efficiently harmonise current classifications of myelodysplastic syndromes and provide a reference for patient management in a real-world setting.

Novel targeted drugs may provide opportunities for patients with NUP98::PRRX1 to undergo allo-HSCT. However, since the cases of carrying the NUP98::PRRX1 are limited, more patients with this genetic change need to be investigated to elucidate the prognostic significance.

P2, N=57, Active, not recruiting, Sidney Kimmel Cancer Center at Thomas Jefferson University | Trial completion date: Dec 2023 --> Apr 2028 | Trial primary completion date: Dec 2023 --> Apr 2028

Whereas alkylator exposure modestly accelerated tumor development, the 5G2 deletion did not cooperate with KrasG12D, NrasG12D, or the MOL4070LTR retrovirus in leukemogenesis. 5G2+/del mice are a novel platform for interrogating the role of hemopoietic stem cell attrition/stress, cooperating mutations, genotoxins, and inflammation in myeloid malignancies characterized by monosomy 7/del(7q).

The complete response rates for intensive chemotherapy (IC), hypomethylating agent (HMAs)-based therapies, and azacitidine plus venetoclax were 35.7%, 22.2%, and 37.5%, respectively. In conclusion, patients with TP53-mutant AML have poor prognoses under current treatment strategies and MR gene mutations are associated with a more favorable survival. Therefore, further studies are needed to improve the survival rates in this population.

Furthermore, the combination of the BCL2 inhibitor venetoclax and the NAMPT inhibitor KPT-9274 resulted in the death of significantly more leukemic blasts in AML samples with -7/-7q compared to the NAMPT inhibitor alone. In conclusion, our findings demonstrate that AML with -7/-7q are highly sensitive to NAMPT inhibition, suggesting that NAMPT inhibitors have the potential to be an effective targeted therapy for patients with monosomy 7 or del(7q).

P2, N=78, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

The findings revealed distinct clinical, cytogenetic, and molecular characteristics distinguishing der(1;7) from -7/del(7q), indicating der(1;7) defines a unique subtype within MDS with monosomy 7q. These findings support classifying der(1;7) as a separate MDS entity in future.

The complete response rates for azacitidine monotherapy, venetoclax combined with azacitidine, decitabine monotherapy, and decitabine combined with low-dose chemotherapy were 9.1%, 41.7%, 37.5%, and 33.3%, respectively. In conclusion, TP53 abnormalities in patients with MDS were frequently accompanied by complex karyotypes, and treatments based on hypomethylating agents or venetoclax have limited efficacy. Pulmonary infections associated with immune dysfunction is associated with poor prognosis.

A karyotype on bone marrow remains mandatory at diagnosis of MDS with complementary molecular analyses now required. Analyses with FISH or other technologies providing similar information can be necessary to complete and help in case of karyotype failure, for doubtful CA, for clonality assessment, and for detection of TP53 deletion to assess TP53 biallelic alterations.

P2, N=107, Recruiting, West China Hospital of Sichuan University; West China Hospital, Sichuan University

Our study, to our knowledge, provides one of the first, if not the first, datasets from LMIC to describe characteristics of IPSS-R lower-risk MDS pts and their re-classification and corresponding survival according to the WHO 2016 and 2022 classifications. Limited availability of molecular analysis in real-life settings (e.g., TP53 mutations) highlights some of the challenges of using the 2022 WHO classification (as well as IPSS-M) LMIC. Understanding the epidemiology of MDS pts in LMIC is important especially as some of the newly approved agents for lower risk MDS are starting to be used in these countries.

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

We then conducted univariate Cox Proportional Hazards analysis to investigate the prognostic significance of clinical and molecular features on time to first treatment (TTFT; most prevalent treatments: splenectomy, n=51; rituximab, n=20) and overall survival (OS)...To conclude, we demonstrate the potential clinical utility of epiCMIT score in SMZL patients, identifying that SMZL patients with high epiCMIT harbour specific genetic characteristics, and exhibit reduced treatment-free survival. EpiCMIT could be valuable in clinical practice, helping to identify those patients destined to progress and require closer monitoring.

The prognostic influence of bone marrow blasts varied in the individual genetic subgroups, suggesting that the clinical impact of increased blasts depends on the genetic context. The molecular taxonomy derived in this study is clinically relevant and will inform future classification schemas.

Table 2 shows a provisional, hierarchical classification algorithm. Further refinement of entity labels and classification criteria is the subject of the ongoing modified Delphi Process consensus approach among icMDS experts.

Post-HCT relapse treatments included hypomethylating agents (HMA; n=13/46, 28%), HMA with donor lymphocyte infusion (DLI; n= 7/46, 15%), HMA with Venetoclax (VEN; n=7/46, 15%), chemotherapy (n=9/46, 19%), best supportive care (8/46, 17%) and second HCT (n=2/46, 4%)...The relapsed disease often shows evidence of clonal evolution in its immunophenotype and/or cytogenetic profile toward a more aggressive disease. Approaches to post-HCT relapse remain heterogenous but HMA is beneficial.

Within pts with a CKT receiving HSCT, we identified additional prognostic factors including the presence of ≥5 cytogenetic aberrations. These pts are in urgent need for novel post HSCT approaches.

For MDS/AML patients, AML-based risk classification according to ELN 2022 guidelines is not applicable as the vast majority of cases are categorized into the adverse risk group based on mutations in splicing factor genes and other secondary-type mutations. Modification of the ELN risk categories reflects the partly MDS-based biology of the disease and substantially improves the prognostic stratification. Most importantly, patients with adverse outcome potentially benefitting from inclusion into clinical trials for novel substances are identified.

Our results offer novel insights into the genomic landscape and clonal trajectory of AML with abn(7). This work unravels formerly underestimated genetic lesions (KMT2Cmut) and alterations with high prognostic impact (abnTP53 and IDH2mut) for better future risk stratification.

P1/2, N=19, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=28 --> 19 | Trial completion date: Dec 2024 --> Aug 2024 | Trial primary completion date: Dec 2023 --> Aug 2024

Contrary to the immunophenotype, the genetic profile in AML is significantly associated with a high/low number of leukocytes. The highest leukocyte counts were followed by a combination of epigenetic and driver mutations (DNMT3A/TET2/IDH1/2 plus NPM1/ FLT3/CEBPA) in both intermediate and unfavorable risk groups. We have also shown that patients' driver mutations (NPM1/FLT3/ CEBPA) are characterized by an immunologically more mature immunophenotype (CD34-) of the tumor clone.

The discriminatory power of the KPSS was higher than that of the traditional International Prognostic Scoring System. In conclusion, we identified several nutritional parameters with prognostic relevance in patients with HR-MDS and generated a prognostic model consisting of complex karyotype and serum T-cho level that enabled excellent risk stratification.

P2, N=20, Recruiting, European Institute of Oncology | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

In conclusion, this is the first comprehensive cytogenetic profile of Vietnamese patients diagnosed with de novo AML, which helps clinical doctors in prognostic classification for AML patients in Southern Vietnam.

A model incorporating CHS and age stratifies t-MN risk post CAR-T cell therapy for MM/HGBCL, with age and thrombocytopenia independently predicting t-MN risk. Clinical stratification of t-MN risk prior to CAR T-cell therapy may identify a subgroup of patients most likely to benefit from additional screening and closer surveillance. Therapy-related AML, CAR-T, MDS, Hematotoxicity

Targeted sequencing of 263 genes was performed in 604 patients enrolled in the randomized, multi-center phase 3 'ASTRAL-1' trial (NCT02348489) evaluating the second-generation hypomethylating agent guadecitabine (SGI- 110) in treatment-naïve AML pts not eligible for intensive chemotherapy in comparison to a treatment choice of decitabine, azacitidine, or low-dose cytarabine. Using different modelling algorithms, our comprehensive analysis of the so far largest study in older, treatmentnaïve AML patients identified distinct trajectories of leukemia development, provided support for AML with mutated DDX41 as a new clinico-pathologic entity and a basis for the development of a risk stratification that may be applicable for the numerous older patients receiving less intensive therapies. Tumorigenesis, Age, AML, Prognostic groups

Importantly, our comprehensive analysis suggests that timely staging and treatment, including using potential targeted therapy, should improve the care of FA patients. Beyond FA, this oncogenic sequence as highlighted in our work, i.e. clonal hematopoiesis that attenuates the p53 response, followed by additional oncogenic events leading to MDS/AML, can also be found in other “stressed hematopoiesis” conditions such as post-BMF, MDS, MPN and post-therapy leukemia, as a general canonic route leading to secondary leukemia 3,4,5.

Similarly, low expression of CUX1 in primary AML samples correlates with sensitivity to the same inhibitors, suggesting a potential therapy for malignancies with CUX1 inactivation. This work demonstrates an unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.

The findings of our study corroborate important information about T-MN patients. As well as a considerable predisposition to CPG, the clinical characteristics and somatic variant profile showed distinctive patterns. Germline variant testing should be recommended for T-MN patients. If the T-MN patients harbor pathogenic germline variants, the family members for stem cell donation should be screened for carrier status through germline variant testing to avoid donor-derived myeloid neoplasm. For the prediction of the prognosis in T-MN patients, sex, age, past treatment history, and cytogenetic findings can be considered.

Following a preparative regimen with busulfan, cyclophosphamide and melphalan (63), or other busulfan-based (19), treosulfan-based (36) or alternative conditioning regimens (28) patients were transplanted from a MSD (46), an unrelated donor (95) or an HLA-haploidentical donor (4). HSCT resulted in a 5-year DFS of 48% in this high-risk group of 145 patients with t-MDS. Cytogenetics and gene mutation profiles had the strongest impact on outcome. Characterization of the genetic profile, including the identification of germline variants, will be required for informed treatment decisions and will help elucidate the pathogenesis of t-MDS.

Pericentric inv(3)s are often subtle/cryptic by chromosomal analysis. A reflex FISH analysis for MECOM-R is recommended in myeloid neoplasms showing -7/del(7q).

P2, N=62, Completed, Sidney Kimmel Cancer Center at Thomas Jefferson University | Recruiting --> Completed | Trial completion date: Sep 2022 --> Dec 2022

In conclusion, PPM1D mutations are frequently seen in both MN-pCT and non-MN-pCT. TP53 is the most frequent co-mutation in PPM1D-mutant MN-pCT cases, while high VAF of PPM1D is observed in cases without TP53 co-mutation, suggestive of an alternative pathway in the pathogenesis of MN-pCT. A large study is warranted to investigate the impacts of PPM1D variants in patients with MN-pCT and non-MN-pCT.