ANZCHOG

ABL2 rearrangements represent a subtype of acute lymphoblastic leukaemia (ALL) associated with poor prognosis and survival. This study reports a high-risk T-cell ALL (T-ALL) case with a novel TPR::ABL2 gene fusion resulting from a chromosomal deletion. Overexpression of TPR::ABL2 in Ba/F3 cells promoted cytokine-independent growth, demonstrating its oncogenic nature. Both primary patient and Ba/F3 cells carrying TPR::ABL2 exhibited kinase activation and sensitivity to tyrosine kinase inhibitors (TKIs). This study expands the repertoire of ABL2 fusions identified in ALL and supports the incorporation of TKIs into T-ALL treatment regimens to improve outcomes for this subtype.

Abstract ABL-rearranged (ABLr) acute lymphoblastic leukaemia (ALL) is associated with high rates of treatment failure and relapse and novel treatments are required. We investigated activity of the STAMP inhibitor asciminib in non-BCR::ABL1 ABLr ALL. The most common fusion inABLr ALL isNUP214::ABL1, which is associated with aggressive disease. For the first time we establish asciminib activity in three pre-clinical patient derived xenograft models ofNUP214::ABL1ALL. Treatment with asciminib reducedNUP214::ABL1leukaemic burden, splenomegaly and ABL1 kinase activation. We observed significantly increased survival outcomes in asciminib-treated versus control mice. Additionally, site directed mutagenesis,in vitrocell death assays andin silicostructural modeling defined a region of the ABL1 SH3 domain critical for asciminib efficacy and necessary for mediation of allosteric inhibition. Our findings establish asciminib as a potential treatment forNUP214::ABL1ALL, significantly expanding the number of ALL patients who may benefit from asciminib therapy which has an excellent safety and tolerability profile.

KMT2A-rearranged leukemias are a highly aggressive subset of acute leukemia, characterized by poor prognosis and frequent relapses despite intensive treatment. Menin inhibitors, which target the critical KMT2A-menin interaction driving leukemogenesis, have shown promise in early clinical trials. However, resistance to these inhibitors, often driven by menin mutations or alternative oncogenic pathways, remains a significant challenge. This review explores combination therapies aimed at overcoming resistance and improving patient outcomes. Potential strategies include inhibiting DOT1L, a histone methyltransferase essential for KMT2A-driven transcription, and BRD4, a regulator of transcriptional super-enhancers. Additionally, targeting MYC, a key oncogene frequently upregulated in KMT2A-rearranged leukemia, offers another approach. Direct inhibition of KMT2A-fusion proteins and c-MYB, a transcription factor critical for leukemic stem cell maintenance, is also explored. By integrating these diverse strategies, we propose a comprehensive therapeutic paradigm that targets multiple points of the leukemic transcriptional and epigenetic network. These combination approaches aim to disrupt key oncogenic pathways, reduce resistance, and enhance treatment efficacy, ultimately providing more durable remissions and improved survival for patients with KMT2A-rearranged leukemias.

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.

BackgroundZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma (ZFTAfus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTAfus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTAfus ST-EPN patients treated in multiple institutions.MethodsWe conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTAfus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches.ResultsA total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort.ConclusionThis is the largest study to date of contemporaneously treated molecularly confirmed ZFTAfus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma.

BACKGROUNDPanobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens.METHODSFollowing cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2.RESULTSSix patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC.CONCLUSIONSTreatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.

The Access to Innovative Molecular Profiling for Paediatric Brain Cancers (AIM BRAIN) project is a trial testing the feasibility of clinical implementation of diagnostic methylation and molecular profiling for central nervous system (CNS) tumours in Australia and New Zealand. AIM BRAIN builds on an existing study, MNP2.0, and allows cross-validation of results derived from identical samples in separate laboratories in Melbourne, Australia, and DKFZ, Heidelberg, Germany. Parallel methylation profiling (Illumina 850K EPIC array) from co-enrolled cases has revealed excellent concordance between laboratories with 50/51 cases (98%) yielding identical classification using the DKFZ Molecular Neuropathology 2.0 Classifier v11b4. 77/91 (85%) of AIM BRAIN cases classified concordantly by methylation array when compared to their diagnostic histopathology. Of these 77 cases, 16 had classifications below a threshold of 0.90, however still classified correctly. In 14 discordant cases either the histopathology was not well defined, not represented on the classifier, or a very low classification score was obtained. Molecular profiling through MNP2.0 identified 49/167 (29.3%) tumours with gene fusions including BRAF-KIAA1549 (n=29), RELA-C1lorf95 (n=5) and 15 rare or novel fusions. BRAF-KIAA1549 was almost exclusively associated with pilocytic astrocytoma (28/29) and RELA-C1lorf95 with ependymoma. Six pathogenic germline mutations were identified in TP53 (n=2), BRCA1, NF1, LZTR1 and ATM. The incidence of germline predisposition was low (4%) and sex biased towards females (5F:1M), (p<0.08). Our findings confirm methylation profiling as a robust platform for classifying CNS tumours with potential to reveal new CNS tumour entities when combined with molecular profiling.