midostaurin

Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM...Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era...Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.

FLT3 inhibitors may cause acute pericarditis. Early recognition and drug withdrawal are essential for recovery.

Importantly, by integrating subcellular proteomic dataset with functional metabolic assays, we uncovered a lipid-dependent vulnerability of FLT3-ITD cells: lipid restriction enhances FLT3 trafficking to the plasma membrane, and markedly reduces cell viability, restoring midostaurin sensitivity of resistant FLT3-ITD cells. Together, our findings reveal that the FLT3-ITD insertion site orchestrates a coordinated remodeling of subcellular protein organization, autophagy, and metabolism, and identify lipid-mediated control of FLT3 compartmentalization as a therapeutically actionable mechanism to overcome TKI resistance in FLT3-ITD AML.

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.