KMT2A rearrangement

We demonstrated the capability of OGT's SureSeq Myeloid Fusion Complete NGS Workflow Solution V2 to achieve 100% accurate detection for novel and canonical translocations. By allowing concurrent detection of multiple known and novel rearrangements, NGS assays offer an economical and efficient alternative to routine cytogenetic approaches.

Six weeks later, while receiving the CD20-directed immunotherapies glofitamab and obinutuzumab, another bone marrow biopsy revealed eradication of the B-ALL and new involvement by pure erythroid leukemia (PEL). This patient's B-ALL lacked an IGH::BCL2 fusion resulting from t(14; 18), suggesting it did not arise through transformation of his prior FL/DLBCL. Instead, the B-ALL was likely caused by his extensive exposure to genotoxic chemotherapy drugs – including alkylating agents – for his preceding lymphomas. The shared cytogenetic and molecular features between this patient's B-ALL and PEL imply they are clonally related.

To our knowledge, these are the first cases of LS to be reported in patients with CRLF2 rearranged acute lymphoblastic leukemia. In addition to raising awareness that this genetic mutation may associate with lineage plasticity, our cases illustrate the importance of multi-modal disease surveillance in the diagnosis of LS.

Studies indicate that KMT2A rearrangements are present in over 70% of infant leukemia cases, approximately 10% of adult AML cases, and numerous instances of secondary acute leukemias, making it a disease of critical concern to clinicians and researchers alike. The future of KMT2A-r acute leukemia research is characterized by an expanding knowledge of the disease's biology, with an emphasis on personalized therapies, immunotherapies, genomic advancements, and innovative therapeutic combinations. The overarching aim is to enhance patient outcomes, lessen the disease burden, and elevate the quality of life for those affected. Ongoing research and clinical trials in this area continue to offer promising opportunities for refining treatment strategies and improving patient prognosis.

Not achieving complete remission after induction 2 was found to be an independent prognostic factor for OS and EFS. These findings indicate that genetic abnormalities could be considered stratification factors, predict patient outcomes, and imply the application of targeted therapy.

Moreover, by incorporating the FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) allelic ratio, the pAML SCT model is refined, enhancing its ability to effectively select suitable candidates. We develop a simple and robust risk stratification model for pAML patients undergoing SCT, to aid in risk stratification and inform pretransplant decision-making at CR1 stage.

Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing.

Human KMT2A-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels...Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.

This case highlights the challenges of diagnosing KMT2A-rearranged monocytic AML and the importance of careful morphological assessment in partnership with cytogenetic and molecular diagnostics to distinguish between KMT2A-rearranged AML and JMML. Moreover, the emerging role of molecular monitoring in AML is highlighted.

Gilteritinib is the current standard of care for relapsed or refractory FLT3-mutated AML in many countries, however outcomes for patients relapsing after contemporary first-line therapies (intensive chemotherapy with midostaurin, or non-intensive chemotherapy with venetoclax) are uncertain. Twenty patients received gilteritinib as first salvage having progressed following first-line therapy with venetoclax, with CR/CRi achieved in 25% and median survival 4.5 months. Real-world results with gilteritinib mirror those seen in the clinical trials but outcomes remain suboptimal, with more effective strategies needed.

Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.

Forty patients (37.7%) received lineage-specific immunotherapy. Our findings suggest that the prevalence of KMT2A rearrangements together with the lineage-specific immunotherapy may trigger LS, which supports the thesis of the existence of leukemia stem cells that are capable of lymphoid or myeloid differentiation.

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.

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.

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.

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.

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.

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.

P3, N=160, Recruiting, Princess Maxima Center for Pediatric Oncology | 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 .

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.

We verified the prognostic impact of the subtype-specific MRD-based stratification in patients treated with the BCH-ALL2003 protocol. In conclusion, the subtype-specific MRD risk stratification may contribute to the precise treatment of childhood ALL.

P2, N=9, Terminated, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2024 --> Mar 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2024 --> Mar 2024; Low accrual

Our findings support that the efficacy of Fc-engineered CD19 antibodies may be substantially enhanced by a combination with CD47 blockade. This suggests that the combination may be a promising therapy option for BCP-ALL, especially in relapsed patients and/or patients refractory to CD19-directed therapy.

Outcome was particularly poor in Ph + trALL compared to Ph+ de novo ALL, which seemed to be mitigated by allogeneic stem cell transplantation. Our findings further define trALL as a distinct entity but highlight the need for further molecular genome sequencing of somatic and germline variants to advance our understanding of trALL.

P1/2, N=90, Recruiting, BioNova Pharmaceuticals (Shanghai) LTD. | Not yet recruiting --> Recruiting

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.

Recent phase 1/2 clinical trials confirmed the efficacy of SNDX-5613 (revumenib) and KO-539 (ziftomenib) and their acceptable tolerability. Several small molecule menin inhibitors are currently being evaluated as a combination therapy with standard of care treatments. The current paper reviews the recent progress in exploring the inhibitors of menin-KMT2A interactions and their application prospects in the treatment of acute leukemias.

In B-other patients, WT1 overexpression at diagnosis predicted an inferior prognosis. The WT1 gene may serve as a biomarker for monitoring residual disease in the B-other population, especially in children in the standard-risk group.

The prognosis of patients with KMT2A-r AML was poor, particularly those harboring AF6-related translocation; however, it is not associated with the presence of mutations. These patients can benefit from achieving CR1 MRD negative before HSCT.

The TP2 MFC-MRD level can predict the outcomes in pediatric patients with acute myeloid leukemia and help stratify post-remission treatment.

These biomarkers include: (1) diagnostic entity-defining genetic abnormalities &lsqb;e.g., B-cell acute lymphoblastic leukaemia (B-ALL) with KMT2A rearrangement]; (2) molecular alterations that guide patients' prognoses (e.g., TP53 loss frequently conferring worse prognosis); (3) mutations that serve as the targets of, and often a source of acquired resistance to, small molecular inhibitors (e.g., ABL1 tyrosine kinase inhibitors for B-ALL BCR::ABL1, hindered by ABL1 kinase domain resistance mutations); (4) the growing incorporation of molecular measurable residual disease (MRD) in the management of lymphoma patients (e.g., molecular complete response and sequencing MRD-negative criteria in multiple myeloma). Altogether, our review spans the spectrum of lymphoma types, from the genetically defined subclasses of precursor B-cell lymphomas to the highly heterogeneous categories of small and large cell mature B-cell lymphomas, Hodgkin lymphomas, plasma cell neoplasms, and T/NK-cell lymphomas, and provides an expansive summary of our current understanding of their molecular pathology.

P1, N=30, Active, not recruiting, Syndax Pharmaceuticals | Recruiting --> Active, not recruiting | N=54 --> 30

These cases demonstrate that KMT2A rearrangements can be found in primary CTCLs rather than solely acute leukemias, illustrating the importance of correlating molecular findings with clinical and histologic features in diagnosis. Additionally, this finding suggests that the subset of CTCLs driven by aberrancy of the KMT2A pathway may be responsive to therapy with hypomethylating agents or menin inhibitors, as seen in acute leukemias.

Most IALL patients were accompanied by KMT2A-R. They had poor tolerance to traditional chemotherapy, the relapse rate during treatment was high and the prognosis was poor.

P1, N=171, Recruiting, Kura Oncology, Inc. | Not yet recruiting --> Recruiting

The content of lipids (1600 cm), nucleic acids (789 cm), and haemoproteins (754, 1130, and 1315 cm), which are crucial in cell metabolism, was indicated as the main source of differentiation between subtypes. Identification of spectroscopic markers of cells with BCR-ABL1 or KMT2A-r may be useful in pharmacological studies to monitor the effectiveness of chemotherapy and further to understand differences in molecular responses between leukemia primary cells and cell lines.

A phase II study of revumenib yielded a response rate of 63% in patients with relapsed or refractory disease and KMT2A rearrangements; a phase I trial combining the drug with three chemotherapies also yielded complete remissions in patients with acute myeloid leukemia. A phase I study of a different menin inhibitor detected responses in 63% of patients with acute leukemia and certain gene alterations.

P1, N=212, Recruiting, Kura Oncology, Inc.

B-cell ALL and KMT2A rearrangement are prevalent in IALL. The therapeutic effect of IALL with standard childhood ALL protocal is similer to international infant specific protocal.

Although highly likely irreproducible, tumors with the CBX6::KMT2A::PYGO1 fusion gene were morphologically somewhat different from those containing the YAP1::KMT2A::YAP1. This suggests that KMT2A rearrangements with fusion gene partners different from YAP1 result in purely spindle-shaped cell tumors that produce collagen fibers.