The efficacy of giritinib (segatan) combined with other drugs in the treatment of acute myeloid leukemia

Giritinib is an oral first-generation /second-generation selective FLT3 tyrosine kinase inhibitor, which is effective against patients with FLT3 mutations (especially FLT3-ITD/FLT3-TKD) relapsed /refractory (R/R) AMLhas clear activity. Monotherapy significantly improved the response rate and overall survival compared with traditional chemotherapy in the Phase III study of ADMIRAL, making it an important treatment option for FLT3 mutated R/R AML. However, the efficacy of monotherapy is still limited in terms of sustained remission and cure, which has also led to research on combining it with other drugs.

Combined low-dose chemotherapy or intensive chemotherapy: In patients who are newly diagnosed or who can tolerate intensive induction, there are multiple early-stage (Phase I/II) studies incorporating giritinib into standard induction/consolidation regimens (such as "7+3" or central chemotherapy regimens) or as consolidation/maintenance therapy. Data show that combination with chemotherapy can improve the rate of complete remission (CR/CRi) and accelerate the molecular clearance of FLT3 in newly diagnosed patients. Some studies have suggested the potential for long-term survival benefit and the overall toxicity is controllable. However, attention should be paid to the overlapping issues of myelosuppression and infection risks related to chemotherapy, which should be managed by an experienced hematology team.

CombinedBCL-2 inhibitor (Venetoclax): Basic research and early clinical data show that giritinib can be combined with BC L-2inhibitors produce a synergistic effect - in FLT3mutantAML cells, the combination of the two drugs can more effectively induce apoptosis and reduce residual lesions. Clinically, venetoclax + The combination of gilteritinib reported higher composite response rates (mCRc) and grading scores in patients with relapsed/refractory and previously treated with a FLT3 inhibitor. Sub-scientific response has become one of the currently more concerned "non-chemotherapy/targeted+targeted" combination strategies, but at the same time, we need to be alert to complications such as severe bone marrow suppression and tumor lysis syndrome, and need to adjust venetoclaxDosage and timing of administration to reduce risk.

Triple regimen: azacitidine (azacitidine)+venetoclax+gilteritinib: for those who cannot tolerate intensive chemotherapy or the elderly/ For frail patients, there are recent multi-center Phase I/II studies (as well as ongoing VICEROY and other studies) exploring azacitidine + venetoclax + geritinib triple regimen. Preliminary results show that patients with newly diagnosed FLT3 mutations have higher CR/CRi rates and molecular response rates, and some cohorts have deep FLT3 was negative (molecularly cleared), and follow-up showed encouraging survival data. However, the triple combination also increased the probability of sustained myelosuppression, requiring dose adjustment and intermittent dosing strategies to manage hematological toxicity. Relevant large-scale, multi-center randomized studies are still ongoing to verify long-term benefits.

Other joint explorations: In addition to venetoclax and HMA (azacitidine/decitabine), the academic community is also trying Combined with epigenetic drugs, immunomodulators or novel small molecules (such as iadademstat, etc.) to overcome drug resistance mechanisms (such as RAS/MAPK pathway changes, upregulation of anti-apoptotic signals, etc.) and prolong response. Early clinical or in vitro studies have reported signals from several candidate combinations, but most are still in Phase I/IB and need to be interpreted with caution.

The trade-off between efficacy and safety: Overall, the advantages of the combination regimen are to increase the remission rate, increase the chance of molecular negative conversion, and may improve event-free survival or overall survival, but the cost is usually more significant bone marrow suppression, infection, and the need for more intensive supportive care (growth factors, blood transfusions, infection prevention, and timely anti-infective treatment). In actual clinical decision-making, the most appropriate combination regimen should be selected based on the patient's age, comorbidities, previous treatment history (especially whether other FLT3 inhibitors or venetoclax have been used in the past), transplant intention and available clinical trial opportunities.

Clinical practice recommendations (key points):1) For R/R FLT3 mutationsAML, geritinib single agent has been the standard choice, but priority will be given to combination regimens proven effective in clinical trials for eligible patients; 2) If giritinib is used in combination with venetoclax or HMA, a prescription is required Strict myelosuppression monitoring and dose adjustment strategy; 3) For transplantable patients who achieve remission, hematopoietic stem cell transplantation (HSCTHSCT pan>) opportunities to strive for long-term disease-free survival; 4) All treatments should be performed under an experienced hematology-oncology team and included in clinical trials when possible to promote evidence accumulation.

Summary: Combination treatment of giritinib with other drugs (chemotherapy, venetoclax, various HMA or new small molecules)FLT3MutationAMLshows the prospect of improving response rates and molecular clearance. Some triple or double combination regimens have shown encouraging results in early/mid-term studies, but at the same time brought more significant bone marrow toxicity. The final treatment choice should be based on the latest clinical trial evidence, the patient's individual situation and risk-benefit assessment, and be implemented under the guidance of a specialist. If you need, I can organize the original documents and clinical trial numbers of each of the above-mentioned key studies (such as ADMIRAL, VICEROY, relevant JCO/ASCO/ASHabstracts) into a downloadable reference list for easy reference.

Reference materials:https://www.drugs.com/