Flt3 inhibition alleviates chronic kidney disease by suppressing CD103+ dendritic cell-mediated T cell activation.

BACKGROUND: Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs. METHODS: To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN. RESULTS: Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103- DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice. CONCLUSION: Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD.

The potential of triplet combination therapies for patients with FLT3-ITD -mutated acute myeloid leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) encompasses a heterogeneous group of aggressive myeloid malignancies, where FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent, accounting for approximately 25-30% of adult patients. The presence of this mutation is related to a dismal prognosis and high relapse rates. In the lasts years many FLT3 inhibitors have been developed. AREAS COVERED: This review provides a comprehensive overview of FLT3mut AML, summarizing the state of art of current treatment and available data about combination strategies including an FLT3 inhibitor. EXPERT OPINION: In addition, the review discusses the emergence of drug resistance and the need for a nuanced approaches in treating patients who are ineligible for or resistant to intensive chemotherapy. Specifically, it explores the historical context of FLT3 inhibitors (FLT3Is) and their impact on treatment outcomes, emphasizing the pivotal role of midostaurin, as well as gilteritinib and quizartinib, and providing detailed insights into ongoing trials exploring the safety and efficacy of novel triplet combinations involving FLT3Is in different AML settings.

Which novel agents will have a clinically meaningful impact in AML at diagnosis?

New drug approvals now afford AML physicians a wider choice of initial treatment options than ever before. Although chemotherapy for AML is by no means ready to be replaced entirely by novel agents, the role of traditional cytotoxics in AML therapy is rapidly changing. In particular, biologically targeted agents such as the BCL2 inhibitor venetoclax and inhibitors of FLT3 and IDH mutations stand out as drugs likely to take AML therapy in important new directions. Maximum response and survival benefits likely require combinations of novel agents and chemotherapy or multiple novel agents together. The recently-published phase 3 VIALE-A study demonstrates a very successful example of a new combination approach, which led to venetoclax plus azacitidine establishing itself as the new standard of care for patients unfit for intensive chemotherapy. One could reasonably expect other subsets of AML to benefit from this regimen or other applications of venetoclax combinations. Building on this experience, venetoclax-based regimens also have the potential to replace standard intensive cytarabine/anthracycline "7&3" induction approach for some if not many patients who are fit for induction. This review will describe novel agents with the greatest potential for impactful frontline applications that will change the AML treatment paradigm.

Mutations within the Activation Loop Domain of FLT3 in Two Pediatric Patients with Refractory Infant Acute Myeloid Leukemia.

Approximately 24% of all pediatric acute myeloid leukemia (AML) cases have mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor gene. FLT3-TKD point mutations are rare in pediatrics and often occur in younger patients and in combination with 11q23 abnormalities. There is a paucity of data related to their prognostic implications in children. We describe 2 pediatric patients with FLT3-activating mutations as a feature of their AML. Both were diagnosed in infancy. The first experienced induction failure and had refractory disease without expression of FLT3-TKD mutation on subsequent bone marrow evaluations. His disease also harbored a KMT2A-PICALM gene rearrangement. He died of invasive fungal disease nine months after diagnosis. The second had a post-induction remission but developed swelling of the left calcaneus shown on biopsy to be a myeloid sarcoma positive for a new BRAF V600E mutation in addition to his known KMT2A rearrangement but without FLT3-TKD mutation. Despite multiple courses of therapy including BRAF/MEK-inhibition, he died of progressive disease nine months after diagnosis. FLT3 inhibition was not utilized in either patient as studies have largely focused on its role in internal tandem duplication (ITD) mutations and because the mutation was no longer detectable in either patient on subsequent evaluation. However, these cases add to the suggestion that these mutations confer a worse prognosis in pediatric AML patients.

Evaluation of gilteritinib in combination with chemotherapy in preclinical models of FLT3-ITD+ acute myeloid leukemia.

Activating internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations in Fms-like tyrosine kinase 3 (FLT3) occur in approximately 30% of patients with acute myeloid leukemia (AML), and confer a poor prognosis with standard cytarabine/anthracycline or azacitidine-based chemotherapy regimens. Gilteritinib is a highly-specific, potent FLT3/AXL inhibitor with demonstrated activity against FLT3-ITD and FLT3-TKD mutations. Compared with salvage chemotherapy, treatment with once-daily oral gilteritinib demonstrated a clinical benefit in patients with FLT3-mutated relapsed/refractory AML, which led to its recent approval in Japan and the United States. We investigated the effects of gilteritinib combined with cytarabine plus daunorubicin/idarubicin, or combined with azacitidine in human FLT3-ITD-positive (FLT3-ITD +) AML cell lines and xenografted mouse models. Gilteritinib induced G1 arrest and apoptosis in a dose-dependent manner. The addition of cytarabine, daunorubicin, idarubicin, or azacitidine potentiated apoptosis. Gilteritinib alone or combined with cytarabine, daunorubicin, idarubicin, or azacitidine, inhibited anti-apoptotic protein expression in MV4-11 cells. In xenografted mice, administration of cytarabine, idarubicin, or azacitidine in combination with gilteritinib had little impact on plasma or intratumor PK profiles of gilteritinib, cytarabine, idarubicin, or azacitidine. Gilteritinib combined with chemotherapy reduced tumor volume to a greater extent than either gilteritinib or chemotherapy alone. Of note, the addition of cytarabine plus daunorubicin/idarubicin led to tumor regression in mice, with complete regression observed in six out of eight mice in both triple combination groups. These findings support the investigation of gilteritinib combined with chemotherapy in patients with FLT3-ITD + AML, including those who are ineligible for intensive chemotherapy.