125 research outputs found
Are there new relevant therapeutic endpoints in the modern era of the BCR::ABL1 tyrosine kinase inhibitors in chronic myeloid leukemia?
No full textA Novel NGS Assay to Detect Any KMT2A Fusion Transcript at Low Levels
No full textMeasurable residual disease (MRD) detection is associated with cancer relapse. Leukemias with rearrangement of the lysine methyltransferase 2 A gene (KMT2Ar) have an adverse prognosis with more than 80 possible fusion partner genes (FPG) identified. With the advent of effective targeted therapies for KMT2Ar leukemia such as menin inhibitors, there is an unmet need for sensitive assays to detect these various fusions. Standard next-generation sequencing (NGS) methods cannot accurately detect genetic alterations at low frequencies because of inherent technical errors and the need for high sequencing depth. Blocker Displacement Amplification (BDA) technology enables selective detection of such rare alterations with NGS. Here, we demonstrate the effective detection of KMT2Ar and its various FPG with a novel NGS assay leveraging BDA. Primers were designed to flank any known exon junction of cDNA corresponding to transcripts of the gene of interest, while non-extensible oligonucleotides (blockers) span the wildtype (WT) exon junction, therefore suppressing amplification of WT while differentially amplifying fusion junctions. We tested this assay in cell line, establishing limits of detection and input and subsequently validated our findings in clinical samples from patients with KMT2Ar leukemia. In conclusion, FusionBDA is a novel, sensitive, and specific assay for KMT2Ar acute leukemia. This assay can agnostically detect KMT2Ar with various fusions at a predicted sensitivity of at least 0.005%, therefore allowing both MRD detection and target identification
Menin inhibition with revumenib for KMT2A-rearranged relapsed or refractory acute leukemia (AUGMENT-101)
No full textPURPOSE: Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with
METHODS: AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R
RESULTS: From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% (
CONCLUSION: Revumenib led to high remission rates with a predictable safety profile in R/
The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
No full textTargeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue functio
Nucleophosmin 1 Mutations in Acute Myeloid Leukemia
No full textNucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations
Outcome of Philadelphia chromosome‐positive chronic myeloid leukemia in the United States since the introduction of imatinib therapy—The Surveillance, Epidemiology, and End Results database, 2000–2019
No full textBackground: Since the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) in 2000, the treatment of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) has improved significantly.
Methods: This study aimed to evaluate Ph-positive CML outcomes in the TKI therapy era, considering factors like age, ethnicity, and income. Using the Surveillance, Epidemiology, and End Results (SEER) database, 2857 patients with Ph-positive CML diagnosed from 2000 to 2019 were analyzed.
Results: The overall 5-year survival rates in Ph-positive CML increased to above 80%, compared with pre-TKIs historical data reporting 5-year overall survival (OS) rates of less than 50%. The 5-year OS rate was 73% for patients diagnosed in 2000-2004, 82% in 2005-2009, and 78% in 2010-2014; the 4-year OS rate was 83% in 2015-2019. The 5-year OS rate for younger patients (\u3c 60 years old) was 88% in 2000-2009 and 90% in 2010-2019 (p value .426). In older patients (60+ years old), the 5-year OS rates were 64% and 65%, respectively (p value, .303). Lower household income was associated with inferior survival across the 2000-2019. These results are inferior to European studies where TKIs are universally available and affordable, and relative OS in CML is similar to age-matched normal populations.
Conclusions: Although the outcome of Ph-positive CML has improved significantly since 2000, the SEER data still shows differences in outcomes among patient subsets, some anticipated (worse OS in older patients accounted by the relative OS), but others that suggest less than universal access and affordability of this therapy (among poorer patients) in the United States
Epigenetic modifications as key regulators of Waldenstrom's Macroglobulinemia biology
No full textAbstract Waldenstrom's Macroglobulinemia is a low-grade B-cell lymphoma characterized by the presence of lymphoplasmacytic cells in the bone marrow and a monoclonal immunoglobulin M in the circulation. Recent evidences support the hypothesis that epigenetic modifications lead to Waldesntrom cell proliferation and therefore play a crucial role in the pathogenesis of this disease. Indeed, while cytogenetic and gene expression analysis have demonstrated minimal changes; microRNA aberrations and modification in the histone acetylation status of primary Waldenstrom Macroglobulinemia tumor cells have been described. These findings provide a better understanding of the underlying molecular changes that lead to the initiation and progression of this disease.</p
Management of chronic myeloid leukemia in 2023 – common ground and common sense
No full textAbstract With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results
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