Xospata (gilteritinib) / Astellas - LARVOL DELTA

Successful Allogeneic Hematopoietic Stem Cell Transplantation for AML with Pulmonary Mucormycosis under Isavuconazole. (PubMed, J Infect Chemother) - "Although liposomal amphotericin B (≥ 5 mg/kg) administration following complete surgical resection is recommended, many cases remain incurable. A 70-year-old man with FLT3-ITD mutated acute myeloid leukemia achieved complete remission after the second induction therapy with gilteritinib...To the best of our knowledge, this is the first reported case of ISCZ treatment in an allo-HCT patient with unresectable IPM. ISCZ could be a safe and effective anti-Mucorales therapy in the allo-HCT setting."

Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • Transplantation • FLT3

Venetoclax plus gilteritinib is effective in preclinical models of FLT3-mutant BCL11B-a lineage-ambiguous leukemia. (PubMed, Blood) - "Longitudinal single cell RNA-seq analysis identified mitochondrial pathways and a pro-lymphoid gene expression signature as potential drivers of rare cell survival on VenGilt therapy. These data support clinical evaluation of venetoclax in combination with gilteritinib in BCL11B-a lineage ambiguous leukemias."

IO biomarker • Journal • Preclinical • Hematological Malignancies • Leukemia • Oncology • BCL11B • BCL2 • FLT3

Rational combination of homoharringtonine to selectively target FLT3-ITD acute myeloid leukemia through synthetic lethality. (PubMed, Phytomedicine) - "FLT3-ITD AML cells represent a responsive subgroup to HHT treatment in vitro and in vivo. The combination of HHT and quizartinib demonstrates optimal efficacy and selectivity against FLT3-ITD AML cells in xenografts, with no observed toxicity."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BAX • FLT3 • MCL1

A Case of Acute Myeloid Leukemia with an FMS-like Tyrosine Kinase 3-tyrosine Kinase Domain Mutation Developing Gilteritinib-induced Differentiation Syndrome. (PubMed, Intern Med) - "We herein report a case of FLT3-tyrosine kinase domain-mutated AML treated with idarubicin and cytarabine, followed by a single dose of gilteritinib. Initial steroid therapy was ineffective; however, steroid pulse therapy and additional idarubicin resolved the DS. This case shows that gilteritinib-induced DS can occur early and severely and requires prompt and aggressive management."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Multi-selective RAS(ON) Inhibition Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 and BCL2 Inhibitors in Acute Myeloid Leukemia. (PubMed, bioRxiv) - "In murine patient-derived xenograft models of RAS-mutant AML, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination with gilteritinib or venetoclax. Our findings strongly support clinical investigation of broad-spectrum RAS(ON) inhibition in AML to treat and potentially prevent drug resistance due to activated RAS signaling."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

RNA activation of CEBPA improves leukemia treatment. (PubMed, Mol Ther Nucleic Acids) - "Importantly, MTL-CEBPA enhances the efficacy of commonly prescribed FLT3 inhibitor, gilteritinib, both in vitro and in vivo. All together, these findings support RNAa of CEBPA as a potential adjuvant therapy for FLT3-mutated AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CEBPA • FLT3

Sitravatinib combined with venetoclax exerts effective synergy to eliminate acute myeloid leukemia cells with FLT3-ITD mutations. (PubMed, Transl Oncol) - "The combination of venetoclax and FLT3 inhibitors gilteritinib and quizartinib has shown promising results in reducing leukemia burden and improving survival in pre-clinical studies and clinical trials of AML with FLT3 mutation. Finally, we tested the potential application of sitravatinib plus venetoclax in vivo using patient-derived xenografts, and found that the combined therapy was significantly more effective in inhibiting leukemia cell expansion, reducing infiltration in the spleen, and prolonging survival time compared to a single administration. Our study demonstrates the potential use of sitravatinib plus venetoclax as an alternative therapeutic strategy to treat AML patients with FLT3-ITD mutation."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • FLT3 • MCL1

Impact of transplant conditioning, NPM1 mutations, and measurable residual disease in FLT3-ITD acute myeloid leukemia. (PubMed, Blood Adv) - P3 | "We conducted a post-hoc analysis of data from BMT CTN 1506 (MORPHO), a randomized trial of gilteritinib versus placebo as post-transplantation maintenance for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), focusing the interactions between conditioning regimen intensity, measurable residual disease (MRD), and NPM1 co-mutation status reported from diagnosis...Our findings suggest that only a subset of patients with FLT3-ITD AML undergoing HCT may benefit from myeloablative conditioning, and that, much like AML therapy prior to HCT, the intensity of the HCT regimen should be adapted according to the molecular features of the disease. (NCT02997202)."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • FLT3 • NPM1

Discovery of degrader for FLT3, GSPT1 and IKZF1/3 proteins merging PROTAC and molecular glue targeting FLT3-ITD mutant acute myeloid leukemia. (PubMed, Eur J Med Chem) - "Importantly, A2 exhibited significantly enhanced antiproliferative activity against drug-resistant AML cells compared to Gilteritinib (MV-4-11: IC50 = 1.67 ± 0.14 nM vs IC50 = 6.52 ± 1.20 nM). Furthermore, A2 with the rigid linker demonstrated improved some pharmacokinetic properties such as half-life (T1/2), which were achieved through rational design. Overall, A2 achieves concurrent degradation of these proteins by functioning as both PROTAC and molecular glue."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CRBN • FLT3 • GSPT1 • IKZF1

Autophagy-dependent hepatocyte apoptosis mediates gilteritinib-induced hepatotoxicity. (PubMed, Toxicol Lett) - "Pharmacological inhibition of autophagy with autophagy inhibitor 3-methyladenine (3-MA, 5mM) or gene silence of Atg7 attenuated apoptosis, mitochondrial membrane potential loss, and ROS overproduction, while autophagy induction by Torin1 (100nM) exacerbated hepatocyte death. Targeting autophagy pathways, represents a potential therapeutic strategy to alleviate gilteritinib-induced hepatotoxicity, enabling safer clinical use of this vital AML therapy. This study elucidates a critical autophagy-apoptosis axis in drug-induced liver injury and provides actionable insights for managing adverse effects of targeted cancer therapies."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Hepatology • Leukemia • Liver Failure • Oncology • ANXA5 • ATG7 • CASP3 • FLT3

TARGETING FLT3 IN B-ALL: FROM GENOMIC INSIGHTS TO THERAPEUTIC APPLICATIONS (EHA 2025) - "In vitro studies using 6 FLT3i [Gilteritinib (Gil), Midostaurin, Crenolanib, Sorafenib, Quizartibin and Ponatinib (Pon)] and Venetoclax (Ven) were conducted on pt primary cells and on 11 B-ALL wt and 4 AML cell lines (OCI-AML3 wt; MV-4-11, MOLM-13, MONO-MAC6 FLT3-mut).Data analyses highlight the heterogeneity in FLT3i sensitivity across pediatric ALL cell lines with midostaurin, Pon and quizartinib were among the top scoring drugs for most cell lines (Fig. FLT3 alterations identify a novel subgroup of TN B-ALL with therapeutic potential also in combination regimens."

Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • ABL1 • FLT3 • IKZF1 • KMT2A • NUP214 • ZNF384

EFFICACY AND SAFETY OF GILTERITINIB IN R/R FLT3 ACUTE MYELOID LEUKEMIA: A REAL-WORLD STUDY (EHA 2025) - "As initial previous treatment, 77.27% had received intensive chemotherapy and 59.09% midostaurin.Median time of follow up was 9,09 months. The most frequent side effects have been fever, elevated liver enzymes and gastrointestinal symptoms.Significant haematological toxicity has been observed.Our Composite Complete Remission rates (CR + CRi) are similar to the Admiral trial. OS is slightly lower in our series but our sample has more patients with relapse than primary refractoriness, more previous exposure to FLT3 inhibitors and more intensive chemotherapy."

Clinical • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Musculoskeletal Pain • Neutropenia • Thrombocytopenia • FLT3

A NOVEL CONDITIONING REGIMEN WITH ALKYLATING AGENTS, VENETOCLAX, CYTARABINE, CLADRIBINE, AND DECITABINE (ADVANCED) FOR UPFRONT ALLOGENEIC STEM CELL TRANSPLANTATION IN ADVERSE-RISK ACUTE MYELOID LEUKEMIA PATIENTS (EHA 2025) - "Alkylating agents were administered on days -3 and -2 individually (busulfan 3.2 mg/kg (days -3 and/or -2) or thiotepa 5 mg/kg (day -3) + busulfan 3.2 mg/kg (day -2), or melphalan 100 mg/m2 (day -2) based on age, general status, and prior treatment (Figure 1)...GVHD prophylaxis consisted of cyclophosphamide 40 mg/kg (days +3 and +4), a calcineurin inhibitor (from day -1 up to day +60 - +90), and mycophenolate mofetil (from day 0 up to day +35) (Figure 1).We collected patients' and AML characteristics...The ELN 2022 adverse risk aberrations were MECOM rearrangement (1), MECOM rearrangement + TP53 mutation (1), BCR-ABL1 (1), and MDS-related mutations (6).Ponatinib and Gilteritinib were added in two cases with BCR-ABL1 and FLT3 mutations, respectively... The upfront alloSCT with ADVANCED conditioning demonstrates promissing early efficacy for newly diagnosed or R/R adverse-risk AML patients with active disease. The toxicity profile was manageable without unexpected..."

Clinical • Metastases • Acute Myelogenous Leukemia • Febrile Neutropenia • Graft versus Host Disease • Immunology • Infectious Disease • Neutropenia • Transplantation • ABL1 • BCR • FLT3 • MECOM • TP53

THE MOLECULAR BACKGROUND DETERMINES THE EXTENT BY WHICH LSD1 INHIBITORS SENSITIZE AML CELLS TO KINASE AND RAS INHIBITORS (EHA 2025) - "These cells present FLT3, NRAS and JAK2 activating mutations, respectively.Independently of FLT3 and RAS mutations, Iadademstat, sensitized 10, 8, 8 and 7 AML cell lines to gilteritinib, trametinib, pictilisib and RMC-7977, respectively...These included the phosphorylations of pNIBAN2(Ser692) and pNFIL3(Ser287)...Remarkably, gilteritinib reduced STAT5A/B phosphorylation, and iadademstat sensitised HEL cells to the JAK inhibitor ruxolitinib. In summary, the heterogeneity by which LSD1 inhibition sensitizes AML cells to FLT3, PI3K, RAS and MEK inhibitors can be rationalised by differences in how LSD1 regulates the wirings of kinase signalling networks irrespective of FLT3 and RAS mutations."

Acute Myelogenous Leukemia • FLT3 • NRAS • STAT5

HIGH-RISK CLINICAL FEATURES AND POOR OUTCOMES IN PEDIATRIC PAX5R B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA: FLT3 TARGETING AS A POTENTIAL NOVEL TREATMENT STRATEGY (EHA 2025) - "Apoptosis experiments using AnnexinV/7AAD staining, were conducted with PAX5r PDX blasts in co-colture with human bone marrow stromal cell, to test the ex vivo efficacy of gilteritinib (GILT).Overall, 58 PAX5r BCP-ALL pts were included...A tendency for slow treatment response was observed, with 20% showing poor prednisone response and 25% FCM-MRD>10% on day +15... This national retrospective study suggests that pediatric PAX5r BCP-ALL is associated with high-risk clinical features and poor outcomes. FLT3 is highly expressed in PAX5r ALL as well as in the PAX5r PDX model we generated. Ex vivo treatment with GILT showed promising single-agent efficacy and synergistic/additive effect with chemotherapy."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ANXA5 • FLT3 • KMT2A • PAX5 • ZNF384

COVALENT FLT3 INHIBITOR BMF-500 IN RELAPSED OR REFRACTORY (R/R) ACUTE LEUKEMIA (AL): PRELIMINARY PHASE 1 DATA FROM THE COVALENT-103 STUDY (NCT05918692) (EHA 2025) - P1 | "Background: R/R FLT3m AL post-failure with gilteritinib (gilt) has a poor prognosis...Baseline features: 8 (33.3%) females, 5 (20.8%) non-whites, mean 57 yrs (23,80), median therapies 4 (1,10), HSCT 10 (41.7%), 24 (100%) with prior venetoclax (ven)...Nine (81.8%) pts showed clinical activity: decreased BM blasts (77.8%; 1 normalized blasts, 1 >50% reduction, 5 50% reduction), 4 decreased hydroxyurea use, 4 decreased transfusions... BMF-500 was well-tolerated. The majority of efficacy-evaluable pts showed reduced BM blasts, with 1 pt achieving CRi. mOS of the efficacy-evaluable FLT3m pts has not yet been reached."

P1 data • Bone Marrow Transplantation • Dermatology • Endocrine Disorders • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Hypotension • Leukemia • Neutropenia • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • FLT3

LONG-TERM FOLLOW-UP OF PREDOMINANTLY ASIAN PATIENTS WITH RELAPSED/REFRACTORY FLT3-MUTATED ACUTE MYELOID LEUKEMIA TREATED WITH GILTERITINIB VERSUS SALVAGE CHEMOTHERAPY IN THE PHASE 3 COMMODORE TRIAL (EHA 2025) - P3 | "In this phase III, open-label, multicenter study, patients with R/R FLT3mut+ AML from 48 sites in China, Malaysia, Thailand, Singapore and Russia, were randomized 1:1 to gilteritinib (120 mg/day) or SC (low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine; or fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor). With a median follow-up of over 3 years, gilteritinib improved clinical outcomes compared with SC and was well-tolerated in a predominantly Asian population with R/R FLT3mut+ AML, consistent with the results from the primary analysis, further supporting its long-term use."

Clinical • P3 data • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Bone Marrow Transplantation • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3

VENETOCLAX IN COMBINATION WITH CYTARABINE AND ACTINOMYCIN D (ACTIVE) FOR RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA (EHA 2025) - "Venetoclax exposure was confirmed in 13% (14/107) of cases, and 25 % (26/107) had relapsed after a previous alloSCT.Gilteritinib, trametinib, ivosidenib, ponatinib, and dasatinib were added to ACTIVE in 22 % (23/107), 4 % (4/107), 2 % (2/107), 1 % (1/107), and 1 % (1/107), respectively.The ORR was 78 % (82/105), and the CRc rate was 62 % (65/105) with 45 % (29/65) achieving MRD negativity. ACTIVE-based salvage treatment demonstrates promissing antileukemic efficacy with a high bridge-to-alloSCT rate in R/R AML."

Combination therapy • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Oncology

PHASE I/II STUDY OF DECITABINE, VENETOCLAX, AND QUIZARTINIB TRIPLET COMBINATION IN FLT3-ITD MUTATED AML (EHA 2025) - "Background: Patients (pts) newly diagnosed with FLT3-ITD mutated (m) acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy (IC) experience poor outcomes with a median overall survival (OS) of 9.9 months with azacitidine+venetoclax (VEN) (Konopleva et al...With a median follow-up of 17 months, the median OS was not reached.(Figure 1).The 47 R/R AML pts were heavily pretreated (median 3 [range 1-5] prior AML therapies); 85% (40/47) had received ≥1 prior FLT3 inhibitors (FLT3i's), with 78% having prior exposure to gilteritinib and 38% having undergone prior ASCT... The combination of decitabine, venetoclax, and quizartinib demonstrated significant results in the frontline setting; 92% of pts achieved CRc with median platelet and ANC recovery of 36 and 37 days, and median OS not reached. The study continues to accrue, and updated results will be reported at the meeting."

P1/2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Febrile Neutropenia • Infectious Disease • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock • FLT3

A META-ANALYSIS ON GILTERITINIB USING REAL-WORLD AND RANDOMIZED TRIAL DATA IN PATIENTS WITH FLT3-MUTATED REFRACTORY/RELAPSED ACUTE MYELOID LEUKEMIA. (EHA 2025) - "Our meta-analysis, which includes patients who had not been previously exposed to FLT3 inhibitors, such as those enrolled in phase 3 clinical trials, as well as patients who had received induction therapies incorporating these agents in real-world studies, suggests a general improvement in OS. The 1-year OS rate remained consistent at 36%, with no significant heterogeneity across the studies. Access to BMT enhanced by gilteritinib in about one-quarter of r/r AML patients highlighting its potential as a curative strategy whatever the care setting."

Real-world • Real-world evidence • Retrospective data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • FLT3

RGT-61159, A POTENT AND SELECTIVE SMALL MOLECULE MYB RNA INHIBITOR, SHOWED SIGNIFICANT ANTI-TUMOR ACTIVITY AS MONOTHERAPY OR IN COMBINATION WITH STANDARDS OF CARE IN SEVERAL LEUKEMIA DISEASE MODELS HARBORING AML MOST COMMON GENETIC LESIONS (EHA 2025) - P1 | "Significant synergistic cell killing activity was observed when RGT-61159 was combined with Flt3 inhibitors (e.g. gilteritinib and midostaurin) in MOLM-13 and MV4.11 cell lines harboring Flt3 ITD mutation, and with menin inhibitors (e.g. KO-539, revemenib) in AML cell lines with NPM1 mutation or MLL-fusion. Finally, RGT-61159 in combination with a Bcl2 inhibitor (venetoclax) resulted in synergistic cell killing activity in AML cell lines carrying NPM1 mutations or AML-1-ETO fusion protein... In summary, MYB oncogene represents a therapeutic target of relevance to AML and other hematological malignancies. RGT-61159 is a potent and selective oral small molecule inhibitor of MYB RNA and protein and an attractive therapeutic avenue to treat cancers overexpressing the oncogenic MYB protein as single agent or in combination with SoC. A phase 1 study of RGT-61159 in AML / high risk MDS is planned in addition to the ongoing phase 1 study in adults with relapsed/​refractory..."

Combination therapy • IO biomarker • Monotherapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • ABL1 • BCR • FLT3 • IDH1 • NPM1

OUTCOMES OF RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA AFTER MENIN INHIBITION (EHA 2025) - "Prior to MENINi, 84% (n=43) of patients had received intensive chemotherapy (IC) and 73% (n=37) had received venetoclax (VEN)-based therapy...The most used MENINi was revumenib (n=40, 78%), followed by ziftomenib (n=9, 18%)...Of these 4 responders, 3 received AZA (azacitidine)/VEN, 1 received FLAG-IDA/VEN, and all 4 were VEN-naïve...No patients with FLT3-ITD after MENINi responded to further therapy, including 8 treated with gilteritinib (GILT), despite 4 of them being GILT-naïve... MENINi are promising in AML, but outcomes after failure are poor. Responses to post-MENINi therapy can be seen with VEN-based regimens in VEN-naïve patients. Studies focused on sequencing as well as preventing and overcoming MENINi resistance are needed."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • KMT2A • MEN1 • NPM1 • NUP98 • WT1

Olutasidenib Combined With Co-targeted Therapy in Relapsed or Refractory IDH1-mutated Myeloid Malignancies Harboring Activated Signaling Pathway Mutations (clinicaltrials.gov) - P2 | N=68 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P2 trial • Oncology

FLT3 INHIBITORS MIDOSTAURIN AND GILTERITINIB ENHANCE CYTARABINE ACCUMULATION BY AFFECTING OCTN1 AND ENT1 TRANSPORTERS IN AML CELLS (EHA 2025) - "Our findings suggest that FLT3 inhibitors significantly enhance intracellular cytarabine accumulation, most likely by affecting the intracellular trafficking of OCTN1 and ENT1 transporters in AML cells. Gaining a deeper understanding of how FLT3 inhibitors regulate these transporters could pave the way for novel therapeutic strategies, ultimately improving treatment outcomes for this AML subtype."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • SLC29A1

MULTIDRUG RESISTANCE AND METABOLIC REPROGRAMMING IN FLT3 MUTANT AML FOLLOWING PROLONGED FLT3 INHIBITOR TREATMENT (EHA 2025) - "MV4-11QR cells also showed cross-resistance to other FLT3i, including midostaurin (IC50 wt: 38.1 nM vs. QR: not reached [NR]) and gilteritinib (IC50 wt: 2.8 nM vs. QR: 65.6 nM). Given their broad resistance profile, we further investigated resistance to other AML therapies, such as venetoclax (VEN) and cytarabine (AraC)... Our findings provide evidence of cellular reprogramming following prolonged AC220 exposure. Investigating the mechanisms underlying FLT3i resistance may guide the development of combination therapies to overcome this challenge."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ACOX1 • FLT3 • PTPN1 • SOD2 • TP53