Gilteritinib combination therapies in pediatric patients with FLT3-mutated acute myeloid leukemia.
Ontology highlight
ABSTRACT:
SUBMITTER: McCall D
PROVIDER: S-EPMC9153013 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
Publications
Gilteritinib combination therapies in pediatric patients with FLT3-mutated acute myeloid leukemia.
McCall David D Roth Michael M Mahadeo Kris M KM Toepfer Laurie L Nunez Cesar C Short Nicholas J NJ Daver Naval N Kadia Tapan M TM DiNardo Courtney C Yi Joanna S JS Cuglievan Branko B
Blood advances 20211201 23
Similar Datasets
Project description:PurposeThe FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but seldom reduces FLT3mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3mut AML.MethodsThis phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria.ResultsSixty-one patients were enrolled (n = 56 FLT3mut); 64% (n = 36 of 56) of FLT3mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3mut patients was 10.0 months.ConclusionThe combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.
| S-EPMC9746764 | biostudies-literature
Project description: Not available
| S-EPMC6538870 | biostudies-literature
Project description:Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the activation of FLT3 and has been implicated in the pathogenesis of AML. The studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, gilteritinib, to block mutated FLT3 in cellular and animal models of AML. Initial kinase studies showed that gilteritinib, a type I tyrosine kinase inhibitor, was highly selective for both FLT3 and AXL while having weak activity against c-KIT. Gilteritinib demonstrated potent inhibitory activity against the internal tandem duplication (FLT3-ITD) and FLT3-D835Y point mutations in cellular assays using MV4-11 and MOLM-13 cells as well as Ba/F3 cells expressing mutated FLT3. Gilteritinib also inhibited FLT3-F691 mutations, although to a lesser degree, in these assays. Furthermore, gilteritinib decreased the phosphorylation levels of FLT3 and its downstream targets in both cellular and animal models. In vivo, gilteritinib was distributed at high levels in xenografted tumors after oral administration. The decreased FLT3 activity and high intratumor distribution of gilteritinib translated to tumor regression and improved survival in xenograft and intra-bone marrow transplantation models of FLT3-driven AML. No overt toxicity was seen in mouse models treated with gilteritinib. These results indicate that gilteritinib may be an important next-generation FLT3 inhibitor for use in the treatment of FLT3 mutation-positive AML.
| S-EPMC5613053 | biostudies-literature
Project description:Patients with relapsed or refractory acute myeloid leukemia (RR-AML) with mutations of FMS-like tyrosine kinase 3 (FLT3) have a poor prognosis even after allogeneic hematopoietic cell transplantation (allo-HCT). Multiple FLT3 inhibitors, including gilteritinib, have been developed and serve as treatment options for RR-AML. Here, we describe three cases of FLT3 mutated RR-AML that were successfully treated with gilteritinib administration before and after allo-HCT. Gilteritinib treatment before HCT was helpful in achieving remission. However, HCT often resulted in mild liver damage, and careful introduction of gilteritinib after HCT at a lower dose may be helpful for its safe usage. The three cases discussed had a successful clinical outcome in terms of disease control as well as the management of side effects associated with gilteritinib treatment.
| S-EPMC10749211 | biostudies-literature
Project description:The phase 3 COMMODORE trial evaluated gilteritinib versus salvage chemotherapy (SC) in a predominantly Asian relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) patient population. The primary endpoint was overall survival (OS); secondary endpoints included event-free survival (EFS) and complete remission (CR) rate. As of June 30, 2020 (interim analysis: 32.2 months after study initiation), 234 patients were randomized (gilteritinib, n = 116; SC, n = 118). Median OS was significantly longer with gilteritinib versus SC (9.6 vs. 5.0 months; HR 0.566 [95% CI: 0.392, 0.818]; p = 0.00211) with a median follow-up of 10.3 months. Median EFS was also significantly longer with gilteritinib (2.8 vs. 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; p = 0.00004). CR rates with gilteritinib and SC were 16.4% and 10.2%, respectively; composite CR rates were 50.0% and 20.3%, respectively. Exposure-adjusted grade ≥3 adverse event (AE) rates were lower with gilteritinib (58.38 events/patient-year [E/PY]) versus SC (168.30 E/PY). Common AEs with gilteritinib were anemia (77.9%) and thrombocytopenia (45.1%). Gilteritinib plasma concentration peaked ~4 h postdose; ~3-fold accumulation occurred with multiple dosing. The COMMODORE trial demonstrated that gilteritinib significantly improved OS and EFS in predominantly Asian patients, validating the outcomes of gilteritinib from the ADMIRAL trial in R/R FLT3mut+ AML.
| S-EPMC11518977 | biostudies-literature
Project description:The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.
| S-EPMC9151663 | biostudies-literature
Project description:Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i's in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i's remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.
| S-EPMC8159924 | biostudies-literature
Project description:BackgroundGilteritinib is the only drug approved as monotherapy for acute myeloid leukemia (AML) patients harboring FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation throughout the world. However, drug resistance inevitably develops in clinical. Sitravatinib is a multi-kinase inhibitor under evaluation in clinical trials of various solid tumors. In this study, we explored the antitumor activity of sitravatinib against FLT3-ITD and clinically-relevant drug resistance in FLT3 mutant AML.MethodsGrowth inhibitory assays were performed in AML cell lines and BaF3 cells expressing various FLT3 mutants to evaluate the antitumor activity of sitravatinib in vitro. Immunoblotting was used to examine the activity of FLT3 and its downstream pathways. Molecular docking was performed to predict the binding sites of FLT3 to sitravatinib. The survival benefit of sitravatinib in vivo was assessed in MOLM13 xenograft mouse models and mouse models of transformed BaF3 cells harboring different FLT3 mutants. Primary patient samples and a patient-derived xenograft (PDX) model were also used to determine the efficacy of sitravatinib.ResultsSitravatinib inhibited cell proliferation, induced cell cycle arrest and apoptosis in FLT3-ITD AML cell lines. In vivo studies showed that sitravatinib exhibited a better therapeutic effect than gilteritinib in MOLM13 xenograft model and BaF3-FLT3-ITD model. Unlike gilteritinib, the predicted binding sites of sitravatinib to FLT3 did not include F691 residue. Sitravatinib displayed a potent inhibitory effect on FLT3-ITD-F691L mutation which conferred resistance to gilteritinib and all other FLT3 inhibitors available, both in vitro and in vivo. Compared with gilteritinib, sitravatinib retained effective activity against FLT3 mutation in the presence of cytokines through the more potent and steady inhibition of p-ERK and p-AKT. Furthermore, patient blasts harboring FLT3-ITD were more sensitive to sitravatinib than to gilteritinib in vitro and in the PDX model.ConclusionsOur study reveals the potential therapeutic role of sitravatinib in FLT3 mutant AML and provides an alternative inhibitor for the treatment of AML patients who are resistant to current FLT3 inhibitors.
| S-EPMC9872318 | biostudies-literature
Project description: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.
| S-EPMC6493465 | biostudies-literature
Project description:PurposeTo investigate the efficacy of the combination of the FLT3 inhibitors midostaurin or gilteritinib with the Bcl-2 inhibitor venetoclax in FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) and the underlying molecular mechanism.Experimental designUsing both FLT3-ITD cell lines and primary patient samples, Annexin V-FITC/propidium iodide staining and flow cytometry analysis were used to quantify cell death induced by midostaurin or gilteritinib, alone or in combination with venetoclax. Western blot analysis was performed to assess changes in protein expression levels of members of the JAK/STAT, MAPK/ERK, and PI3K/AKT pathways, and members of the Bcl-2 family of proteins. The MV4-11-derived xenograft mouse model was used to assess in vivo efficacy of the combination of gilteritinib and venetoclax. Lentiviral overexpression of Mcl-1 was used to confirm its role in cell death induced by midostaurin or gilteritinib with venetoclax. Changes of Mcl-1 transcript levels were assessed by RT-PCR.ResultsThe combination of midostaurin or gilteritinib with venetoclax potently and synergistically induces apoptosis in FLT3-ITD AML cell lines and primary patient samples. The FLT3 inhibitors induced downregulation of Mcl-1, enhancing venetoclax activity. Phosphorylated-ERK expression is induced by venetoclax but abolished by the combination of venetoclax with midostaurin or gilteritinib. Simultaneous downregulation of Mcl-1 by midostaurin or gilteritinib and inhibition of Bcl-2 by venetoclax results in "free" Bim, leading to synergistic induction of apoptosis. In vivo results show that gilteritinib in combination with venetoclax has therapeutic potential.ConclusionsInhibition of Bcl-2 via venetoclax synergistically enhances the efficacy of midostaurin and gilteritinib in FLT3-mutated AML.See related commentary by Perl, p. 6567.
| S-EPMC6858954 | biostudies-literature