MLL mutation

Key advancements include the integration of FLT3 inhibitors into intensive chemotherapy and the emergence of venetoclax...Innovations such as the liposomal formulation CPX-351 and oral formulations of CC-486 and oral decitabine/cedazuridine have further optimized treatment delivery and improved patient quality of life...Current research is actively exploring next-generation inhibitors, antibody-drug conjugates, and cellular immunotherapies such as BiTEs and CAR-T cells. This review summarizes the recent pharmacological evolution in AML and discusses how these emerging therapies bring us closer to the ultimate goal of achieving a definitive cure.

Conclusions Lenvatinib showed substantial efficacy in BRAF-mutated PTC, while TERT mutations did not predict poor outcomes. The identification of five genes associated with early treatment failure highlights the potential for genomic biomarkers to guide personalized therapy.

P1, N=30, Recruiting, Uma Borate | Trial completion date: Dec 2025 --> Feb 2027 | Trial primary completion date: Dec 2025 --> Jan 2027

Currently, most leukemias are effectively treated with immunotherapies (highly effective monoclonal antibodies targeting CD19 [blinatumomab], or CD22 [inotuzumab ozogamicin]), BCR::ABL1 tyrosine kinase inhibitors (TKIs; e.g., dasatinib, ponatinib), Bruton TKIs (e.g., ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, olutasidenib, and enasidenib), FLT3 inhibitors (e.g., midostaurin, quizartinib, and gilteritinib), menin inhibitors (revumenib, ziftomenib), and chimeric antigen receptor T-cell therapies. Herein, we provide a high-level overview of prominent clinical developments across all leukemias. In contemporary times, harnessing the benefits of novel targeted therapies and the evolving treatment landscape bolster the optimistic view that most, if not all, leukemias are curable.

Targeted therapies have improved outcomes in molecularly defined subsets of AML, with menin, IDH and FLT3 inhibitors representing major advances. However, TP53-mutated AML continues to carry a dismal prognosis, underscoring the need for more effective therapeutic strategies. Continued biomarker-driven research, novel drug combinations, and mechanistic insights will be essential to further refine AML treatment and improve long-term survival across disease subsets.

P1/2, N=66, Active, not recruiting, Institut de Recherches Internationales Servier (I.R.I.S.) | Trial completion date: Jun 2027 --> Dec 2027 | Trial primary completion date: Jun 2026 --> Dec 2026

Compared to each drug alone, co-treatment with SNDX-5613 (revumenib) and FHD-286 or OTX015 and FHD-286 significantly reduced the in vivo AML burden and improved survival of the immune depleted mice, without inducing significant toxicity, in the xenograft models of MITR and MI-resistant PD MLL1-r AML cells. These findings highlight novel, targeted, drug combinations that overcome MI resistance in AML cells with MLL1-r or mtNPM1.

P1/2, N=17, Recruiting, AstraZeneca AB

Adverse events during induction and reinduction were consistent with those reported in previous infant acute lymphoblastic leukaemia studies. Infections remain a substantial cause of morbidity and mortality in this immunocompromised patient population and extended beyond the induction and reinduction chemotherapy phases.

NGS revealed that a common progenitor cell with BCL2-IgH translocation and mutations in TP53, KMT2A, KMT2C, and KMT2D gave rise to two distinct subclones: one (CD5 + CD23+CD200+) CLL driven by mutations in TNFAIP3 and BCORL1, and the other (CD5-CD23-CD200-) driven by mutations in EP300, NOTCH1, and BCL2. This case highlights the significance of clonal heterogeneity in CLL and underscores the crucial role of MFC, flow sorting, and molecular genetics in diagnosing and understanding the complex evolution of this disease.

Ziftomenib received its first approval on 13 Nov 2025 in the USA for the treatment of adults with relapsed or refractory AML with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. This article summarises the milestones in the development of ziftomenib leading to this first approval for relapsed or refractory AML associated with an NPM1 mutation.