midostaurin

Microclones and macroclones (low and high AR) were independently associated with increased relapse risk (sHR 1.50 [95% CI 1.18-1.91], 1.98 [1.50-2.62], and 2.33 [1.69-3.22], respectively) after adjustment for age, white blood cell count, other gene mutations, midostaurin treatment, and allogeneic hematopoietic stem cell transplantation...These findings challenge current risk stratification models and support the integration of NGS-based FLT3-ITD detection into the diagnostic and prognostic workflow for AML. Prospective trials addressing the management of patients with FLT3-ITD microclones are warranted, as is their consideration in future ELN guidelines.

Five prognostic LRGs were determined for CRC, and a new risk model was developed and validated, revealing the critical role of LRGs in CRC and improving our understanding of clinical interventions for this cancer type.

P1/2, N=41, Not yet recruiting, Centre Hospitalier Universitaire De Bordeaux

Midostaurin clearance was delayed during co-administration. Midostaurin therapeutic drug monitoring may serve for decision-making when DDI with CYP3A4 inhibitors is suspected.

The patient was initially treated with a hybrid induction regimen of FLAG-IDA (fludarabine, arabinofuranosyl cytidine, granulocyte colony-stimulating factor (G-CSF)-idarubicin) plus vincristine and prednisone, followed by reinduction with decitabine and venetoclax due to persistent disease. In this case, the delayed introduction of midostaurin was favored to minimize toxicity during induction. Ongoing studies are needed to determine the best treatment strategies and timing for targeted therapies in this rare leukemia subtype.

Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.

First-generation inhibitors, such as midostaurin, provided the foundation for targeted therapy, while recently developed agents such as gilteritinib and quizartinib have shown more selectivity and demonstrated superior clinical efficiency and improved tolerability. This review discusses the significance of FLT-3 mutations, the evolution of targeted therapies, current treatment guidelines, and ongoing challenges such as resistance and high relapse rates. We also discuss the emerging combinations of therapies and novel agents currently in clinical trials that aim to overcome resistance and improve long-term outcomes for patients with FLT-3-mutated AML.

P3, N=214, Completed, Arog Pharmaceuticals, Inc. | Recruiting --> Completed | N=510 --> 214 | Trial completion date: Nov 2024 --> Apr 2026 | Trial primary completion date: Nov 2022 --> Apr 2026

GPR182+ PSCs could also predict the responses of colorectal cancer patients to certain drug treatments, such as rapamycin and midostaurin. Our findings map the epithelial heterogeneity in FAP and reveal that GPR182+ PSCs are crucial in driving heterogeneity and immune evasion. GPR182+ PSCs represent promising biomarkers for prognosis and drug responses, providing novel insights into FAP pathology and therapeutic development.

DPP4 expression was assessed by qPCR in 22Rv1 and C4-2 cells treated with dasatinib or midostaurin at IC50 concentrations. On the contrary, DPP4 expression in both 22Rv1 and C4-2 was reduced after treatment with midostarin (p < 0.05). Our study establishes DPP4 as a multifaceted pan-cancer biomarker with prognostic significance and immunotherapeutic implications, particularly in prostate cancer.

In this first real-world analysis of post-alloHCT FLT3-TKI maintenance in older adults, utilization was low and adherence was modest, although not impaired by age alone. Gilteritinib demonstrated the highest adherence and appeared to have favorable tolerability. Strategies to improve adherence and prospective data in older adults are needed to maximize the benefits of FLT3-TKI maintenance in this population.

Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them.