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Published: 28 June 2021

Last updated: 10 February 2022

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Journal articles on the topic "Gilteritinib"

Perl, Alexander E., Richard A. Larson, Nikolai Alexandrovich Podoltsev, Stephen Strickland, Eunice S. Wang, Gary J. Schiller, Giovanni Martinelli, et al. "Follow-up of patients with FLT3-mutated R/R AML in the phase 3 ADMIRAL trial." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 7013. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.7013.

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7013 Background: The phase 3 ADMIRAL trial demonstrated the superiority of gilteritinib to salvage chemotherapy (SC) in patients (pts) with FLT3-mutated ( FLT3mut+) R/R AML. Aim/Objective: A follow-up of ADMIRAL assessed long-term survivors, transplant (HSCT) outcomes. and gilteritinib safety beyond 1 year. Methods: A data cut was performed on September 20, 2020—2 years after the primary analysis. Patients who were alive without relapse, pts who underwent HSCT, and adverse events of interest (AEIs) in Years 1 (≤12 months) and 2 ( > 12 months) of gilteritinib therapy were evaluated. Results: As of September 20, 2020, 17% (n = 63/371) of pts in the intention-to-treat (ITT) population were alive (gilteritinib, n = 49; SC, n = 14); 16 pts assigned to gilteritinib remained on treatment. After a median follow-up of 37.1 months, 26 of the 49 pts in the gilteritinib arm who were alive were also without relapse; 18 of these 26 pts underwent HSCT, with 16 receiving post-HSCT gilteritinib maintenance therapy. Nineteen of the 26 pts in the gilteritinib arm without relapse continued gilteritinib beyond 1 year and remained in CR. Of the 371 ITT pts, 83 (22%) underwent HSCT during the study (gilteritinib, n = 64; SC, n = 19). Pre-HSCT CRc rates were similar across arms (gilteritinib: n = 40/64; 63%; SC: n = 11/19; 58%); 10 of 11 pts preselected for low-intensity SC achieved pre-HSCT CRc (gilteritinib, n = 9; SC, n = 1). Forty of 64 (63%) transplanted pts in the gilteritinib arm received post-HSCT gilteritinib maintenance after achieving pre-HSCT CRc; the 24-month relapse rate in pts who resumed gilteritinib after pre-HSCT CRc was 19%. Post-HSCT treatment with chemotherapy or other tyrosine kinase inhibitors was administered in 26 pts who received gilteritinib before transplantation. Cumulative 24-month relapse rates in gilteritinib-treated pts who achieved pre-HSCT CR and CRc were 20% and 45%, respectively. Median post-HSCT overall survival (landmarked to HSCT date), was similar across arms (gilteritinib, 16.1 months; SC, 15.3 months; HR = 1.076; 95% CI: 0.536, 2.160). Overall, 10.2% (n = 25/246) had ≥24 months of gilteritinib exposure. Most common AEIs during Years 1 and 2 of gilteritinib therapy were elevated ALT/AST levels. Incidences of all AEIs declined in Year 2. Cardiac AEIs in Year 2 were nonfatal cardiorespiratory arrest (n = 1) and ventricular tachycardia (n = 1). One case of differentiation syndrome and cutaneous squamous cell carcinoma occurred in Years 1 and 2, respectively. Conclusions: A high proportion of gilteritinib-treated R/R FLT3mut+ AML pts who were alive without relapse had received HSCT followed by gilteritinib maintenance. Among all transplanted pts in ADMIRAL, pre-HSCT remission rates and post-HSCT survival were similar across arms. Post-HSCT gilteritinib maintenance may relate to the low post-HSCT relapse rate in the gilteritinib arm. The safety profile of gilteritinib is stable at 2 years with no new or significant safety signals. Clinical trial information: NCT02421939.

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Perl, Alexander E., Giovanni Martinelli, Andreas Neubauer, Ellin Berman, Maria R. Baer, Richard A. Larson, Amir Tahmasb Fathi, et al. "Long-term survivors and gilteritinib safety beyond one year in FLT3-mutated R/R AML: ADMIRAL trial follow-up." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 7514. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.7514.

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7514 Background: The phase 3 ADMIRAL trial showed that gilteritinib was superior to salvage chemotherapy (SC; median overall survival [OS]: 9.3 vs 5.6 mo, respectively) in FLT3mut+ R/R AML patients (pts; Perl, et al. N Engl J Med. 2019). This follow up (FU) of the ADMIRAL trial assessed long-term (LT) survivors and gilteritinib safety beyond 1 year. Methods: A data cut was performed 1 year after the primary analysis. Response outcomes in LT survivors (OS ≥18 mo) in the gilteritinib arm, and safety during and after 12 mo of gilteritinib therapy were assessed. Results: At 1 year after the primary analysis, median FU for OS was 29.2 mo. Median OS remained longer with gilteritinib (9.3 mo) than with SC (5.6 mo; HR=0.679 [95% CI: 0.527, 0.875], nominal P=0.0026); 18-mo OS rates were 27% and 15%, respectively (Table). Of 49 censored pts in the gilteritinib arm, 20 continued treatment; 13 of these 20 pts underwent transplantation (HSCT) and received gilteritinib post-HSCT. Median gilteritinib exposure was 4.1 mo (IQR, 2.1-8.2) and median average dose was 120 mg/day (range, 43.8-192.3); 12% (n=30/246) of pts had ≥18 mo and 7% (n=17/246) had ≥24 mo of drug exposure. A total of 63 gilteritinib-treated pts had OS ≥18 mo (median exposure, 17.6 mo [IQR, 3.1-25.7 mo]). A high proportion of these LT survivors achieved remission pre-HSCT (Table); median durations of complete remission (CR) or CR with partial hematologic recovery (CRh) have not been reached. After a median of 3.5 mo, 35 of 63 (56%) LT survivors underwent HSCT; 25 of these 35 pts (71%) received post-HSCT gilteritinib therapy. Of 28 pts who did not undergo HSCT, 15 (54%) received gilteritinib for ≥18 mo. Most common grade ≥3 adverse events (AEs) during the first 12 mo of gilteritinib therapy were febrile neutropenia (45%), anemia (40%), and thrombocytopenia (23%); rates of these grade ≥3 AEs decreased to 8%, 10%, and 0, respectively, after 12 mo of treatment. Most common fatal AEs during the first 12 mo of gilteritinib therapy were AML (11%), infections (11%), and cardiac disorders (3%); after 12 mo of treatment, rates of these fatal AEs were 6%, 8%, and 2%, respectively. Conclusions: Results from this ADMIRAL trial FU suggest LT survival in pts receiving gilteritinib is related to ongoing remission, subsequent HSCT, or post-HSCT gilteritinib therapy. The safety profile of gilteritinib beyond 1 year was stable. Clinical trial information: NCT02421939 . [Table: see text]

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Ueno, Yoko, Masamichi Mori, Yoshiteru Kamiyama, Naoki Kaneko, Eriko Isshiki, and Masahiro Takeuchi. "Gilteritinib (ASP2215), a Novel FLT3/AXL Inhibitor: Preclinical Evaluation in Combination with Azacitidine in Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 2830. http://dx.doi.org/10.1182/blood.v128.22.2830.2830.

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Abstract Background FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML). Activating mutations in FLT3 such as internal tandem duplications (ITD) at the juxtamembrane domain are present in approximately 25-30% of newly diagnosed AML cases. Patients with AML harboring the FLT3-ITD mutation have poorer prognosis following the current induction chemotherapy treatment of cytarabine (AraC) and an anthracycline (daunorubicin [DNR] or idarubicin [IDR]). Azacitidine (Aza) is a treatment option for AML patients who are not eligible for intensive chemotherapy. Gilteritinib, a novel, small molecule inhibitor of the tyrosine kinases FLT3/AXL, is in Phase 3 development for treatment of FLT3 mutation-positive AML, including patients with FLT3-ITD mutations. In previous preclinical studies, gilteritinib has demonstrated superior antitumor effects when given in combination with AraC and either DNR or IDR compared with combination chemotherapy. Here, we report preclinical antileukemic activity of gilteritinib in combination with Aza against FLT3-ITD mutation-positive AML. Methods: The antitumor effects of gilteritinib alone and in combination with Aza were investigated in MV4-11 cells harboring the FLT3-ITD mutation. Apoptosis was detected using annexin V staining via flow cytometry; PARP cleavage was evaluated via Western blot analysis. Anti-apoptotic protein expression was evaluated by Western blot. Furthermore, the combination antitumor effects were evaluated in MV4-11-xenografted nude mice administered once-daily, oral gilteritinib at 3 mg/kg for 21 days alone and concomitantly with once-daily intravenous Aza at 3 mg/kg for 5 days. Pharmacokinetic parameters were also investigated in MV4-11 xenografted nude mice. Statistical differences in antitumor effects of combination therapy versus gilteritinib alone and combination therapy versus Aza alone were assessed on Day 21 using the Student's t-test. Results: Gilteritinib treatment for 48h resulted in an induction of apoptosis in MV4-11 cells as determined by an increase in annexin V-positive cells. When used in combination, gilteritinib augmented the Aza-induced increase in annexin V-positive cells. Gilteritinib also decreased the expression of anti-apoptotic proteins such as MCL-1, BCL2L10, and survivin, which are reported to be important in chemotherapy sensitivity, following 24h treatment. In combination with annexin results, an increase in PARP cleavage was also observed in MV4-11 cells following gilteritinib treatment; cells co-treated with gilteritinib and Aza showed a further increase in PARP cleavage. In mice xenografted with MV4-11 cells, oral gilteritinib (3 mg/kg/day) inhibited the tumor growth by 71%; Aza alone did not suppress tumor growth. The tumor volume in the doublet combination group (94% growth inhibition) was significantly smaller than in each single treatment group on Day 21 (Figure). No obvious influences on body weight, behavior, or diarrhea were noted in the combination group. Plasma concentrations for either gilteritinib or Aza were not considerably increased by their use in combination therapy when compared with the concentrations observed with single treatment. Conclusions: Gilteritinib treatment augmented Aza-induced apoptosis in part by reductions of anti-apoptotic protein expressions in vitro. In the non-clinical models used, gilteritinib, in combination with Aza, showed superior antitumor efficacy compared with each single agent alone. These findings support the development of gilteritinib in combination with Aza as a potential treatment of FLT3-ITD mutation-positive AML. Figure Antitumor Effect of Gilteritinib in Combination with Azacitidine in Mice Xenografted with MV4-11 Cells ***P<.001 vs gilteritinib alone; +++P<.001 vs azacitidine alone (Student's t-test). Figure. Antitumor Effect of Gilteritinib in Combination with Azacitidine in Mice Xenografted with MV4-11 Cells. / ***P<.001 vs gilteritinib alone; +++ P<.001 vs azacitidine alone (Student's t-test). Disclosures Ueno: Astellas Pharma Inc: Employment. Mori:Astellas Pharma Inc: Employment. Kamiyama:Astellas Pharma Inc: Employment. Kaneko:Astellas Pharma Inc: Employment. Isshiki:Astellas Pharma Inc: Employment. Takeuchi:Astellas Pharma Inc: Employment.

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Diller, Elizabeth, and Janelle E. Mann. "Gilteritinib (Xospata®)." Oncology Times 41, no. 4 (February 2019): 14. http://dx.doi.org/10.1097/01.cot.0000553980.60791.5c.

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Cortes, Jorge E., Jessica Altman, Ellen K. Ritchie, Richard A. Larson, David Claxton, Mark D. Minden, Alec Goldenberg, et al. "A phase II/III, multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS7068. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps7068.

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TPS7068 Background: Gilteritinib, a highly selective, potent FLT3/AXL inhibitor, showed antileukemic activity with favorable tolerability in a Phase 1/2 trial of FLT3 mutation-positive (FLT3mut+) relapsed/refractory AML. In FLT3mut+ AML cell lines, gilteritinib plus azacitidine (AZA) inhibited growth, and induced apoptosis and differentiation. This ongoing Phase 2/3 trial will examine the efficacy, safety, and tolerability of gilteritinib alone, gilteritinib plus AZA or AZA alone in newly diagnosed FLT3mut+AML patients ineligible for intensive induction chemotherapy. Methods: This open-label, 3-arm, 2-stage randomized trial (NCT02752035) will enroll ~540 newly diagnosed adults with FLT3mut+ (FLT3-ITD or -TKD) AML; those with APL, BCR-ABL+, or active CNS leukemia will be excluded. Before initiation, the safety and tolerability of gilteritinib plus AZA will be assessed in a Safety Cohort to establish the appropriate gilteritinib dose for combination therapy. Subjects will then be randomized 1:1:1 to receive oral gilteritinib alone (120 mg daily; Days 1–28), AZA alone (75 mg/m2 by subcutaneous injection or intravenous infusion on Days 1–7), or AZA (75 mg/m2; Days 1–7) plus oral gilteritinib (daily on Days 1–28 at the dose determined from the Safety Cohort), and stratified by age ( < 75 vs ≥75 years). Subjects will continue treatment until a discontinuation event occurs. The primary endpoint is overall survival of subjects receiving gilteritinib or gilteritinib plus AZA versus AZA alone; the key secondary endpoint is event-free survival. Additional secondary endpoints: complete remission rate, leukemia-free survival, remission duration, composite remission rate, tolerability, and fatigue. Dose changes and interruptions are allowed in all treatment arms. A formal interim futility analysis by an Independent Data Monitoring Committee is planned when ~50 subjects in each treatment arm have either discontinued therapy or completed 2 treatment cycles. Enrollment began on November 21, 2016; as of January 31, 2017, the Safety Cohort is ongoing. Clinical trial information: NCT02752035.

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Tarver, Theodore C., Jason E. Hill, Leena Rahmat, Alexander E. Perl, Erkut Bahceci, Kenichi Mori, and Catherine C. Smith. "Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations." Blood Advances 4, no. 3 (February 10, 2020): 514–24. http://dx.doi.org/10.1182/bloodadvances.2019000919.

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Abstract Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at <200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.

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Knight, Tristan, Xinan Qiao, Jun Ma, Holly Edwards, Lisa Polin, Juiwanna Kushner, Sijana H. Dzinic, et al. "The Combination of CUDC-907 and Gilteritinib Shows Promising Antileukemic Activity in Vitro and In Vivo in Preclinical Models of FLT3-ITD AML." Blood 134, Supplement_1 (November 13, 2019): 1262. http://dx.doi.org/10.1182/blood-2019-123793.

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Introduction FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are found in approximately one quarter of acute myeloid leukemia (AML) cases. Its presence results in constitutive activation of the FLT3 receptor tyrosine kinase and its downstream growth/pro-survival pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT, and confers a poor prognosis. Gilteritinib is a selective inhibitor of FLT3 recently approved by the Food and Drug Administration for treatment of patients with relapsed/refractory AML and a FLT3 mutation. However, gilteritinib exposure induces upregulation of FLT3 - a mechanism of resistance. Previously, we showed that CUDC-907, a dual PI3K/histone deacetylase inhibitor, downregulates FLT3 expression (Li X, et al. Haematologica. 2019; epub ahead of print). We therefore hypothesized that combining CUDC-907 with gilteritinib would abrogate FLT3 upregulation and expression, resulting in synergistic antileukemic activities against FLT3-mutated AML. Methods FLT3-ITD AML cell lines and primary patient samples were treated with gilteritinib or CUDC-907, alone or in combination at clinically achievable concentrations, and subjected to annexin V/propidium iodide staining and flow cytometry analysis to quantify apoptosis. Protein levels of FLT3, Bcl-2 family proteins, and key components of the MAPK/ERK, PI3K/AKT, and JAK/STAT pathways were examined using western blotting. The impact of the observed alterations upon apoptosis were confirmed via overexpression, knockdown, and targeted inhibitor experiments. Real-time RT-PCR was used to determine FLT3 transcript levels. The FLT3-ITD AML cell line MV4-11 was used to generate a xenograft mouse model to assess in vivo efficacy of the two agents. Results CUDC-907 and gilteritinib demonstrated potent synergistic antileukemic effects in FLT3-ITD AML cell lines in vitro and patient samples ex vivo, with combined therapy. CUDC-907 abolished gilteritinib-induced expression of FLT3 in both cell lines and primary patient samples. Gilteritinib treatment reduced p-AKT, p-S6, and p-STAT5 and increased p-ERK, while CUDC-907 reduced p-AKT and p-ERK, and upregulated p-STAT5. The combination of gilteritinib and CUDC-907 decreased not only p-AKT and p-S6, but also p-ERK and p-STAT5. Targeted inhibition of ERK and JAK2/STAT5 signaling by SCH772984 and AZD1480, respectively, confirmed their roles in resistance to gilteritinib and CUDC-907 monotherapies, respectively. Combined gilteritinib and CUDC-907 treatment reduced expression of the anti-apoptotic BCL-2 family member Mcl-1 and increased expression of the pro-apoptotic protein Bim. MCL-1 overexpression and BIM knockdown partially rescued FLT3-ITD AML cells upon drug treatment, confirming their role in the antileukemic activity of combined gilteritinib and CUDC-907. To determine in vivo efficacy of the two agents, NSGS mice were injected with MV4-11 cells. Three days later, the mice were randomized into vehicle control (n=5), 40 mg/kg gilteritinib (oral gavage; n=5), 100 mg/kg CUDC-907 (oral gavage; n=5) or combination (40 mg/kg gilteritinib + 100 mg/kg CUDC-907; n=6) groups. CUDC-907 was given daily for 5 days on, 2 days off, for a total of 4 cycles. Gilteritinib was administered daily for 28 days. Both agents were well tolerated; maximal weight loss was 5.5%, 0.9%, and 6.7% in the CUDC-907, gilteritinib, and combination groups, respectively. Median survival of mice in the vehicle control group was 43 days. Median survival in the CUDC-907 monotherapy and gilteritinib monotherapy arm was 40.5 days and 104 days, respectively. One mouse in the combination therapy arm died on day 138, while the remaining 5 mice in the combination therapy arm continue to survive, as of time of writing (day 168), and are asymptomatic (Figure 1). Conclusion We confirmed that the combination of CUDC-907 plus gilteritinib synergistically induces apoptosis in both FLT3-ITD AML cell lines and primary patient samples, and that gilteritinib-induced FLT3 expression is abolished by CUDC-907. Cooperative inhibition of the PI3K-AKT, JAK-STAT, and RAS-RAF pathways, as well as upregulation of Bim/downregulation of Mcl-1 all appear to contribute to this observed antileukemic synergy. Our cell line-derived xenograft mouse model provides strong evidence of in vivo efficacy and robust grounds for clinical translation of this therapeutic combination. Disclosures No relevant conflicts of interest to declare.

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Izumi, Shintaro, Yosuke Minami, Shinichi Masuda, Yoshikazu Utsu, Emiko Sakaida, and Nobuyuki Aotsuka. "Emergence of Natural Killer Cell Large Granular Lymphocytes during Gilteritinib Treatment in Acute Myeloid Leukemia with FLT3-ITD Mutation." Reports—Medical Cases, Images, and Videos 3, no. 3 (September 17, 2020): 25. http://dx.doi.org/10.3390/reports3030025.

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As the potent, selective Fms-Like Tyrosine Kinase 3 (FLT3) inhibitor gilteritinib has only been approved for use for a few years, its efficacy and complications remain incompletely understood. We herein report an elderly patient with FLT3 internal tandem duplications (FLT3-ITD) mutated acute myeloid leukemia (AML) who developed natural killer cell large granular lymphocytes (NK-LGL) in the bone marrow and peripheral blood during gilteritinib treatment. Case: A 79-year-old Japanese female had been diagnosed with FLT3-ITD-mutated AML. The patient received hydroxycarbamide 2000 mg daily for induction chemotherapy but did not achieve remission at day 28 postinduction. The treatment was then changed to gilteritinib 120 mg daily. Although the reduction of blasts in peripheral blood occurred immediately, it was revealed abnormal lymphocytes with large granules developed in bone marrow and peripheral blood. These lymphocytes were analyzed by flow cytometry, which revealed that these cells were NK-LGL because they expressed CD2, CD7, CD16, and CD56 and did not express CD3, CD19, and CD20. The patient achieved partial remission (PR) in a month with gilteritinib treatment. Leukemia eventually could not be controlled, but PR persisted for about 4 months and leukemia was controlled for 4 months after progression disease (PD) with gilteritinib treatment alone. Conclusion: Gilteritinib may induce the NK-LGL. The exact mechanism and effect of LGL in patients with FLT3 mutated AML treated with gilteritinib warrants further investigation.

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Zhu, Ruiqi, Li Li, Bao Nguyen, Amy S. Duffield, and Donald Small. "Gilteritinib and Venetoclax Synergize to Eliminate FLT3/ITD+ Leukemia Cells through BIM." Blood 134, Supplement_1 (November 13, 2019): 2564. http://dx.doi.org/10.1182/blood-2019-131635.

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Gilteritinib and Venetoclax synergize to eliminate FLT3/ITD+ leukemia cells through BIM Abstract Acute myeloid leukemia (AML) is characterized by a clonal proliferation of immature myeloid cells in the bone marrow or other tissues. The most commonly mutated gene in AML is FMS-like tyrosine kinase (FLT3). FLT3 downstream signaling pathways include PI3K/AKT, STAT5 and MAPK, which affect apoptosis, differentiation and cell proliferation. An internal tandem duplication mutation in FLT3 (FLT3/ITD) is identified in approximately 25% of patients with AML, and this mutation is associated with a particularly poor prognosis. A subset of AML also has a point mutation in the tyrosine kinase domain of FLT3 (FLT3/TKD); however, this mutation does not have the same pronounced impact on prognosis as the FLT3/ITD mutation. Since tyrosine kinases are an attractive drug target, tyrosine kinase inhibitors (TKIs) that target FLT3 have been developed, including recent agents that show enhanced specificity, such as Gilteritinib. Despite these advances, TKI monotherapy continues to show limited success, indicating that combination therapy is likely necessary for the effective treatment of FLT3/ITD AML. As FLT3 signaling pathway activity is known to be anti-apoptotic, in this study we investigated the combinatorial effect of a FLT3-selective TKI and the BCL-2 inhibitor Venetoclax. The BCL-2 protein plays a key role in apoptosis, with anti-apoptotic/prosurvival effects. Venetoclax is a selective BCL-2 inhibitor, and is used clinically in the treatment of chronic lymphocytic leukemia and relapsed/refractory AML. We first investigated the combinatorial effect of treatment with Gilteritinb and Venetoclax in a FLT3/ITD+ leukemia cell line (Molm14). Combined treatment with Gilteritinib (20nM) and Venetoclax (80nM) reduced cell proliferation by 83.7%, as compared to Gilteritinib (62.2%, P<0.05) or Venetoclax (37.3%, P<0.05) alone. The drug combination demonstrated synergy (CI=0.42). Combined treatment shows that these agents act synergistically to enhance apoptosis (88.2%), as compared with Gilteritinib (52.1%, P<0.05) or Venetoclax (12.1%, P<0.05) alone. Moreover, the combined treatment also significantly reduced cell proliferation in patient samples with FLT3/ITD+ and FLT3/TKD mutations. Further experiments with cell line (Molm14 cells resistant to 60nM CEP-701) showed that Venetoclax can re-sensitize FLT3 TKI-resistant cell lines to TKI treatment. Western blot analysis indicates that this effect is mediated by inhibiting MAKP pathway-whose reactivation is an important reason for TKI resistance in FLT3/ITD+ patients. These data demonstrate that combined treatment with Gilteritinb and Venetoclax reduces cell proliferation and enhances apoptosis in a FLT3/ITD leukemia cell line. We next investigated the mechanism of action of this drug combination. BCL-2 and other antiapoptotic proteins in this subfamily (i.e. MCL-1, BCL-XL) exert their pro-survival effects by sequestering BIM. BIM is a proapoptotic protein, that, when released by BCL-2, can activate cell death mediators. These cell death mediators include BAX and BAK, which perforate the mitochondrial membrane, resulting in apoptosis. Venetoclax acts by binding to BCL-2 and displacing BIM, freeing BIM to associate with and activate cell death mediators, resulting in apoptosis. We found that in Molm14 cells, Venetoclax not only dissociates BIM from BCL2, but also decreases expression of BIM and enhances the binding of BIM and MCL-1. In contrast, we found that Gilteritinib increases expression of BIM, reduces the binding of BIM with MCL-1 via a reduction of MCL1 expression, and shows enhanced binding of BIM with BCL2. Cells treated with both Venetoclax and Gilteritinib show dissociation of BIM from both BCL2 and MCL-1, though the interaction between BIM and BCL-XL is not affected. Combination treatment also showed increased binding between BIM and the cell death mediator BAX, leading to increased apoptosis. These studies provide evidence that the addition of Venetoclax may enhance TKI therapy in the treatment of FLT3/ITD leukemia. Additionally, these findings suggest that enhanced cell death in FLT3/ITD AML cells treated with combination therapy occurs because Venetoclax mitigates unintentded pro-survival effects of the TKI, including an increase in BIM expression and increased association between BIM and BCL-2. Disclosures Duffield: MedImmune: Consultancy; Boston Biomedical/Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Small:Pharos I, B & T: Consultancy, Research Funding; InSilico Medicine: Membership on an entity's Board of Directors or advisory committees.

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Knight, Tristan, Xinan Qiao, Holly Edwards, Hai Lin, Jeffrey W. Taub, and Yubin Ge. "Novel Therapy for FLT3-ITD Acute Myeloid Leukemia Utilizing the Combination of CUDC-907 and Gilteritinib." Blood 132, Supplement 1 (November 29, 2018): 1427. http://dx.doi.org/10.1182/blood-2018-99-111177.

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Abstract Introduction: FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase, and is mutated in approximately one third of acute myeloid leukemia (AML) patients; this mutation confers a poor prognosis. Two FLT3 mutations are commonly seen in AML: internal tandem duplications (ITD) in the juxtamembrane domain (~25% of AML), and point mutations in the receptor tyrosine kinase at codon 835 (D835) (~7% of AML). Both mutations result in constitutive FLT3 activation, causing downstream activation of multiple pathways, in particular, those involved in cell survival including the RAS-RAF-MEK-ERK, JAK-STAT5, and PI3K/AKT pathways. PI3K-AKT may also be activated by AXL, also a tyrosine kinase, via its targets PLC, Grb2, and PI3K. Logically, then, inhibition of FLT3 is a promising pharmacological approach for treating this subtype of AML. Gilteritinib (ASP-2215) is a novel dual inhibitor of FLT3 and AXL, exposure to which results in upregulation of FLT3 as a resistance mechanism. Previously, we found that the novel dual PI3K/histone deacetylase (HDAC) inhibitor CUDC-907 downregulates FLT3 expression in AML cells (Figure 1A). Additionally, inhibition of FLT3 and AXL by gilteritinib may not result in robust inactivation of both the PI3K-Akt and MEK/ERK pathways due to crosstalk between the two pathways. Thus, our hypothesis was that CUDC-907 would sensitize AML cells to gilteritinib, resulting in concurrent inhibition of all the downstream signaling pathways of FLT3 and AXL, leading to synergistic antileukemic activities again FLT3-mutated AML (Figure 1B). Methods: FLT3-ITD AML cell lines (MV4-11 and MOLM-13) and primary patient samples were treated with CUDC-907, gilteritinib, both, or neither for 24 hours, at clinically achievable concentrations. Annexin V/Propidium Iodide (PI) staining and flow cytometry analyses was performed, and combination indexes (CI) calculated; CI<1, CI=1, and CI>1 indicating synergistic, additive, or antagonistic effects, respectively. Western blots were performed after treatment for 0-24 hours to determine protein expression of relevant targets. Results: CUDC-907 and gilteritinib demonstrated potent synergistic antileukemic effects in FLT3-ITD AML cell lines and FLT3-ITD patient samples (AML#171, AML#180), the combination exceeding either in isolation (Figure 1C). These findings were confirmed via western blot, which showed accentuated upregulation of cleaved caspase3 with combination therapy, in both cell lines and one patient sample, demonstrating drug-induced apoptosis. We confirmed that CUDC-907 abolishes gilteritinib-induced expression of FLT3 in a time-dependent fashion in cell lines MV4-11 and MOLM-13 (Figure 1D). Gilteritinib treatment decreased p-AKT, p-S6, and p-STAT5, while inhibition of the ERK pathway, as assessed by p-ERK expression, varied amongst the samples (Figure 1E). CUDC-907 treatment decreased both p-AKT and p-ERK. MOLM-13 cells showed increased p-ERK following gilteritinib treatment and increased p-STAT5 after CUDC-907 treatment. In all samples, combination of gilteritinib with CUDC-907 resulted in decrease of p-STAT5 and p-S6, similar to gilteritinib treatment alone, and further reduction of p-AKT and p-ERK compared to single drug treatments. Gilteritinib treatment also reduced expression of anti-apoptotic protein Mcl-1, which was further decreased in combination treated cells. Subsequently, time-course analysis was performed in both cell lines; findings were consistent with prior observations, and confirmed that protein expression changed over time, in relation to gilteritinib/CUDC-907/combined treatment exposure. Conclusion: We confirmed that CUDC-907 and Gilteritinib synergistically induce apoptosis in both cell lines and primary patient samples derived from patients with FLT3-ITD AML, and that CUDC-907 abolishes Gilteritinib-induced FLT3 expression. Additionally, the combination cooperatively inhibits the PI3K-AKT, JAK-STAT, and RAS-RAF pathways, while preventing escape via alternative pathways. Our results provide a strong foundation for subsequent in vivo murine studies, and eventual clinical evaluation of the combination of gilteritinib and CUDC-907 for the treatment of AML. Figure 1. Figure 1. Disclosures Ge: MEI Pharma: Research Funding.

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Dissertations / Theses on the topic "Gilteritinib"

Novotná, Kateřina. "Interakce gilteritinibu s transportéry OCT1 a OCT2; vztah ke konvenční terapii akutní myeloidní leukémie." Master's thesis, 2021. http://www.nusl.cz/ntk/nusl-446641.

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Univerzita Karlova Farmaceutická fakulta v Hradci Králové Katedra Farmakologie a toxikologie Student: Kateřina Novotná Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Interaction of gilteritinib with OCT1 and OCT2 transporters; relation to conventional therapy of acute myeloid leukemia. Gilteritinib is one of the recently approved drugs which is primarily used in the treatment of relapsed/refractory acute myeloid leukemia (AML) with mutated FMS-like tyrosine kinase 3 (FLT3) receptor. In this project, gilteritinib was investigated in terms of its ability to interact with solute carrier (SLC) membrane transporters, namely with OCT1 and OCT2. These membrane proteins play a role in uptake of endogenous compounds and also drugs into the cells of main elimination organs (liver, kidney), but also to cancer cells. In particular, we wanted to examine potential interaction with daunorubicin and mitoxantrone, drugs traditionally used in AML therapy. First, we performed accumulation study and evaluated, whether gilteritinib is potential inhibitor of OCT1 and OCT2 studying differential uptake of daunorubicin and mitoxantrone into MDCKII-OCT1 and MDCKII-OCT2 cells based on OCT1 and OCT2 inhibition by gilteritinib. Secondly, the study evaluating the transfer of gilteritinib across the...

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Conference papers on the topic "Gilteritinib"

Joshi, Sunil K., Tamilla Nechiporuk, Daniel Bottomly, Paul Piehowski, Julie A. Reisz, Janét Pittsenbarger, Andy Kaempf, et al. "Abstract LT022: The AML microenvironment catalyzes a step-wise evolution to gilteritinib resistance." In Abstracts: AACR Virtual Special Conference: The Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; January 11-12, 2021. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.tme21-lt022.

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Chen, Xiaoyue, Sean Caenepeel, Brian Belmontes, Patricia L. McElroy, Karen Rex, Tao Osgood, and Paul Hughes. "Abstract 1050: Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1050.

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Joshi, Sunil K., Stephen Christy, Renata Scopim Ribeiro, Shannon McWeeney, Jeffrey W. Tyner, Cristina E. Tognon, Brian J. Druker, and Elie Traer. "Abstract 926: Extrinsic and intrinsic activation of RAS/MAPK signaling enables resistance to FLT3 inhibitor, gilteritinib, in acute myeloid leukemia." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-926.

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Viswanadha, Srikant, Satyanarayana Eleswarapu, Kumar V. Penmetsa, and Swaroop Vakkalanka. "Abstract C044: RP7214, a small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), potentiates activity of Gilteritinib and Cytarabine in preclinical models of AML." In Abstracts: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1535-7163.targ-19-c044.

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Li, Na, Vivek Mahajan, Lindsay Butler, Elizabeth Rainbolt, Shasta Kidder, Kay Meshaw, Diana Gietl, et al. "Abstract 2933: Inhibition of FLT3 and AXL by gilteritinib controls systemic tumor growth in luciferase-transduced MV-4-11 acute myeloid leukemia." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-2933.

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Viswanadha, Srikant, Satyanarayana Eleswarapu, Kumar V. Penmetsa, and Swaroop Vakkalanka. "Abstract C045: RP4010, a small molecule inhibitor of Store-Operated Calcium Entry (SOCE), potentiates activity of Gilteritinib and Cytarabine in preclinical models of AML." In Abstracts: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1535-7163.targ-19-c045.

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Perl, Alexander E., Giovanni Martinelli, Jorge E. Cortes, Andreas Neubauer, Ellin Berman, Stefania Paolini, Pau Montesinos, et al. "Abstract CT184: Gilteritinib significantly prolongs overall survival in patients withFLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-ct184.

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