KMT2A (Lysine Methyltransferase 2A)

This is a preliminary report of the results of NGS analysis of a group of pediatric patients that will allow riskstratification and will provide recommendations of diverse therapeutical approaches within the concept ofpersonalized medicine. The 198 genes panel is ample and identified mutations present in a cluster of 8 genes in the entire set of cases(46/46). We will correlate the obtained mutational profile with response to treatment and relapse considering eternalfactors as nutritional status and access to medical services and medication.

Our systematic alternative splicing analysis uncovered several subtype-specific splicing events and identifiednovel splice variants associated with pediatric ALL. A novel exon skipping alternative splicing event of the FLT3gene enabled us to provide the first validated evidence of FLT3 overexpression in iAMP21-positive B-ALL. Thisfinding may provide a rationale for using FLT3 overexpression as a novel biomarker and for applying FLT3inhibitors or FLT3 specific CAR T-cells in the clinical management of respective patients with high-risk iAMP21-positive B-ALL.

Aims: Here, we report a comprehensive analysis of baseline M-CHIP mutational landscape in pts enrolled in theFondazione Italiana Linfomi (FIL) MCL0208 phase 3 trial (NCT 02354313), evaluating lenalidomide (LEN)maintenance vs observation after chemoimmunotherapy and ASCT in untreated MCL pts ≤ 65 years... In conclusion, we provided the M-CHIP mutational landscape at baseline in younger MCL pts from aprospective clinical trial and we showed for the first time the unfavorable clinical impact of large CH clones onMCL progression. Further studies are ongoing on CH mutations detected during follow-up.

NPM1 mutations were identified in 21. 7% of 1,520 patients. Patients with NPM1mut were older and had higherWBC counts and LDH levels, and more often had a normal karyotype, but less adverse cytogenetic features,including monosomal karyotype and MR cytogenetic abnormalities at diagnosis compared to NPM1wtpatients.

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KMT2A-PTDs are complex gene rearrangements that cannot be fully ascertained using a single genomic platform. MLPA, NGS panels, and OGM are complementary technologies applied in standard-of-care testing for AML patients. MLPA and NGS panels are designed for targeted copy number analysis; however, our results showed that integration of concurrent genomic alterations is needed for accurate KMT2A-PTD identification. Unbalanced chromosomal rearrangements overlapping with KMT2A can interfere with the diagnostic sensitivity and specificity of copy-number-based KMT2A-PTD detection methodologies.

Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials...With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision-making in both intensive and low-intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on-label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

Other HOX and MEIS1 expressing leukaemias may also be sensitive to Menin inhibition. Following the encouraging results as monotherapy in refractory and relapsed AML, the combination of Menin inhibitors with chemotherapeutic agents and other targeted drugs is being investigated clinically.

It can be considered an efficient alternative to conventional karyotyping for  identifying specific SCA of interest in under-resourced laboratories. The online version contains supplementary material available at 10.1007/s12288-023-01699-2.

KMT2A mutations (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.

Complex karyotype (hazard ratio &lsqb;HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.

In summary, multilineage involvement is common in both BCR::ABL1-rearranged and KMT2A-rearranged B-ALL, which should be taken into consideration when interpreting the disease burden during the clinical course.

This report provides novel insights into the leukemogenic potential of the KMT2A::CBL rearrangement and the correlation between gene rearrangements and clinical outcomes.

P2, N=171, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Jul 2024

To date, this new class of drugs has been tested in phase I and II clinical trials, both alone and in combination with synergistic drugs showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this brief review, we summarize the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data on the treatment of acute myeloid leukemia with this promising new class of agents, particularly revumenib and ziftomenib.

EMI at diagnosis is an independent adverse prognostic risk factor for pediatric AML, and GO treatment potentially improves survival for patients with EMI at diagnosis.

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Progress in the development of molecularly targeted therapies and immunotherapy presents exciting opportunities for potential improvement. This comprehensive review synthesizes the current literature on the epidemiology, clinical presentation, molecular genetics, and therapeutic approaches specific to ALL in the infant population.

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We provide evidence to incorporate the five adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcome, and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.

In the largest cohort to date, our study describes the characteristics of infants with cutaneous involvement of myeloid neoplasms including cytomolecular findings and survival rates. Further prospective biologic and clinical studies of these infants with myeloid neoplasms will be required to individualize therapy for this rare patient population.

The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics.

This trial was registered at www.clinicaltrials.gov as no. NCT01564784.

P1, N=32, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Aug 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Aug 2025

P2, N=80, Recruiting, Children's Oncology Group | Active, not recruiting --> Recruiting

Our study reveals unique signaling networks underlying prostate cancer biology in AA and EA men, offering potential insights for clinical management strategies tailored to specific racial groups. Targeting AR and associated pathways could be particularly beneficial in addressing the disparities observed in prostate cancer outcomes in the context of AA and EA men. Further investigation into these identified pathways may lead to the development of personalized therapeutic approaches to improve outcomes for prostate cancer patients across different racial backgrounds.

Moreover, several aberrant markers, such as CD2, CD56, CD7, and CD117, were rarely expressed in the B-ALL samples, and if expressed, they were enriched in specific genetic subtypes. The results of this study indicate that immunophenotypic features are correlated with specific genetic subtypes of childhood B-ALL.

Recent work has shown that the MLL-AF4 fusion protein drives aberrant enhancer activity at key oncogenes in ALL, dependent on the continued presence of MLL-AF4 complex components. As well as providing some general insights into enhancer function, these observations may also provide an explanation for transcriptional heterogeneity observed in MLLr patients.

P3, N=160, Recruiting, Princess Maxima Center for Pediatric Oncology | Not yet recruiting --> Recruiting

P2, N=54, Recruiting, Fred Hutchinson Cancer Center | Not yet recruiting --> Recruiting

After considering transplantation, high ECM1 transcription level was not an independent risk factor, although OS was still poor (low vs. high, 71.1% vs. 56.8%, P = 0.038). Our findings suggested that ECM1 may be a potential molecular marker for diagnosis, minimal residual disease (MRD) monitoring, and prognosis prediction of B cell ALL.Trial registration Trial Registration Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry &lsqb;ChiCTR-OCH-10000940 and ChiCTR-OPC-14005546]; http://www.chictr.org.cn .

Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr-ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT.

Integrating the proteome of pre-leukemic cells with their secretome and the proteomic composition of the extracellular environment of normal progenitors highlights differential regulation of Igf2 bioavailability, as well as of VLA-4 dimer and its ligandome, upon initiation of fetal- and adult-origin leukemia, with implications for human MLLr leukemia cells' ability to communicate with their environment through granule proteins. Our study has uncovered opportunities for targeting ontogeny-specific proteomic vulnerabilities in in utero-initiated and adult-onset MLLr leukemia.

The higher the level of MRD in early induction therapy, the worse the OS. The MRD levels on day 15 is an independent prognostic factor for RFS.The MRD in early induction therapy guided accurate risk stratification and individualized treatment can improve the survival rate of pediatric ALL.

P1/2, N=150, Recruiting, Janssen Research & Development, LLC | Phase classification: P1 --> P1/2

In human serum samples, the non-reduced form of TrxR1 exists as dithiothreitol-reducible polymer/complexes, which might protect the non-reduced TrxR1 from inactivation by certain electrophilic reagents under oxidative conditions, because cleavage of these disulfides can lead to regain the activity of TrxR1. The details of the selective response of the selenenylsulfide bond to electrophilic reagents may provide new information for designing novel small-molecule inhibitors (drugs) in targeted extracellular/non-reduced TrxR1.

This is the first time that a particular group of leukemic cells has been identified in a label-free way. The identified biomarker can be used as a screening method in diagnostic laboratories or non-reference medical centers.

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The analytical performances were assessed by the limit of blanks, limit of detection, limit of quantification and linear regression. Our data demonstrated serial MRD monitoring for patients at molecular level could become "digitalized", which was deemed important to guide clinicians in treatment decision for better patient care.

P2, N=78, Recruiting, Children's Oncology Group | Active, not recruiting --> Recruiting