ADMIRAL Trial Research Articles

Phase 3 study of gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia

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.

FLT3 Inhibitors in Combination with FLAG-IDA in Relapsed or Refractory Acute Myeloid Leukemia

1. Introduction The addition of a FLT3 inhibitor improves overall survival in combination with front-line intensive chemotherapy in acute myeloid leukemia (AML). In the ADMIRAL trial, gilteritinib - a second-generation, type I FLT3 inhibitor - improved survival in relapsed or refractory AML compared to intensive chemotherapy. However, it is unknown whether the combination of a FLT3 inhibitor and intensive chemotherapy improves survival in the relapsed or refractory setting compared with intensive chemotherapy alone or intensive chemotherapy with venetoclax in FLT3 mut AML. 2. Methods We analyzed 27 patients with FLT3 mut AML treated with FLAG-IDA for relapsed or refractory disease from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. Baseline disease characteristics were obtained, including molecular profiling either through PCR, NGS, or both, alongside cytogenetic risk, doses of induction regimens, response, and survival. We separated patients that underwent treatment with FLAG-IDA and a FLT3 inhibitor (gilteritinib, midostaurin, or sorafenib), venetoclax, or FLAG-IDA alone. Measurable residual disease (MRD) assays were PCR-based when available; otherwise, MRD was assessed through multiparameter flow cytometry. We used the D'Agostino & Pearson method for normality testing and the Kruskal-Wallis test for between-group comparisons. We applied the Bonferroni correction if multiple comparisons were made. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results All 27 patients treated with FLAG-IDA harbored mutations in FLT3-ITD (70.3%) or FLT3-TKD (29.6%). Twelve (44.4%) patients received FLT3 inhibitors with FLAG-IDA: eight (66.7%) with midostaurin, three (25.0%) with gilteritinib, and one (8.3%) with sorafenib. Five (41.6%) patients received a FLT3 inhibitor (FLT3i) for previously untreated disease, then subsequently received a FLT3i at disease progression. Ten (37.0%) patients received FLAG-IDA without a FLT3i, and five (18.5%) received FLAG-IDA and venetoclax. The median FLT3 variant allele frequency was 33.96% (95% CI, 5.1-63.9) in the FLT3i cohort, 18.0% (95% CI, 8.0-27.0) in the FLAG-IDA cohort, and 5.0% (95% CI, 3.0-29.0) in the venetoclax cohort. The median prior lines of therapy were as follows: three for the FLT3i cohort, two for the FLAG-IDA cohort, and three for the venetoclax cohort (p = 0.137). There was no difference in the achievement of CRc between the FLT3i and FLAG-IDA groups (27.3% vs 33.3%, p > 0.999) or between the FLT3i and venetoclax groups (27.3% vs 50.0%, p = 0.560). The proportion of responders that achieved MRD negativity was nonsignificantly higher in the FLT3i cohort (75.0% vs 20.0%, p = 0.206). The median overall survival nonsignificantly favored the FLT3i cohort compared to the FLAG-IDA cohort (7.7 months vs 4.1 months, p = 0.992) and the venetoclax cohort (7.7 months vs 6.3 months, p = 0.902). 4. Discussion The addition of a FLT3 inhibitor resulted in nonsignificantly higher rates of MRD negativity and prolonged overall survival when compared to FLAG-IDA alone or FLAG-IDA and venetoclax. The optimal combination regimen for relapsed or refractory FLT3 mut AML is unknown, but likely should include a FLT3 inhibitor. The limitations of our study include its retrospective nature; subsequent FLT3 inhibitor combinations or maintenance strategies may have provided a survival benefit the FLT3i cohort. Therefore, prospective clinical trial designs are needed to further confirm these findings.

Iadademstat and Gilteritinib for the Treatment of FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia: The Frida Study

Background: Frontline and relapsed /refractory (R/R) acute myeloid leukemia (AML) patients carrying fms-related tyrosine kinase 3 [FLT3]-mutations (FLT3 mut+) benefit from FLT3 inhibitors (FLT3i) that have emerged as active therapeutic agents for this subset of AML encompassing up to 30-40% of all AML cases. The FLT3i gilteritinib, as monotherapy for R/R AML pts, has improved outcomes but the duration of remission achieved is transient and often brief. The Phase 3 randomized ADMIRAL trial of gilteritinib demonstrated a 20% CR rate and 2.8 months event-free-survival (EFS) (Perl, et al., NEJM 2019). The development of new targeted agents which synergize with FLT3 inhibitors, and ideally also inhibit the emergence of resistance, is therefore a major medical need in AML. Iadademstat (iada/ORY-1001) is a specific, oral, potent, covalent inhibitor of the epigenetic Lysine-Specific Demethylase 1 (LSD1/KDMA1) enzyme. Epigenetic dysregulation is a hallmark of AML. Up to 70% of recurring mutations in AML patients target epigenetic regulators of gene expression, resulting in myeloid differentiation blockade and enhanced leukemic stem cell renewal, underscoring the potential of epigenetic therapies to change the natural history of the disease. Preclinically, iada produces striking synergy with FLT3is, particularly gilteritinib in FLT3 wild-type and FLT3 mut+ AML cells and in derived cell lines resistant to venetoclax, azacitidine and other FLT3is (Sacilotto et al., 2022 Eur J. of Cancer 174S1). The novel MOAs generating this synergy in combinations include activation of a pro-differentiating epigenetic transcriptional program with simultaneous suppression of MYC-driven target genes (Yashar, et al. 2023, Mol. Cancer Res). The recently completed Phase 2 study of iada in combination with azacitidine (ALICE) produced a high rate of composite remission, including complete remission (CR) and CR with incomplete count recovery (CRi) (mostly MRD negative), as well as durable responses, in treatment naïve, unfit AML patients (pts), without exacerbating the toxicity profile of azacitidine (Salamero et al., 2022, Blood S1). The FRIDA study (NCT05546580) aims to establish the safety, tolerability, and the recommended phase 2 dose (RP2D) of the combination of iada plus gilteritinib in FLT3 mut+ R/R AML. Methods: Adult pts with body weight ≥50 Kg and ECOG 0-2, with FLT3 mut+ R/R AML, after no more than 2 prior lines of therapy, are enrolling. Certain patients with prior exposure to FLT3is including gilteritinib may be eligible. Up to 18 pts, in a 3+3 escalation phase, will receive iada at doses of 75 to 150 ug, orally, in 5 days ON - 2 days OFF schedule, with continuous gilteritinib, at 120 mg/day orally. In the expansion phase, up to 14 pts at the selected safe and pharmacologically active dose/s (determined based on all available data from escalation pts including PK, target engagement (TE), safety, tolerability, and emerging activity) will be enrolled. Primary endpoints of the study are safety and RP2D determination, based on the same 5 criteria outlined above. Bayesian posterior probability efficacy monitoring will be performed periodically for each dose cohort in the expansion phase. Bayesian efficacy futility and early stopping boundary will be applied during the monitoring. Posterior probability criterion (Prob (CR>0.3) ≥ 0.60) at the end of the study will warrant additional development. The safety of the combination treatment will also be continuously evaluated during expansion following a Bayesian design stopping rule.Secondary endpoints include overall survival, EFS, CR, CR/CR with partial hematologic recovery (CRh), overall response rates, time to response, duration of response, and transfusion rate. Exploratory endpoints include measurable residual disease and gene mutational analysis. At the time of the submission, FRIDA is enrolling a second dose level cohort in escalation phase and plans to have the 15 sites open to accrual in the US by the end of 2023. Additional sites will be added for a subsequent randomized controlled double-blinded FRIDA 2 study to assess the efficacy of the iada and gilteritinib combination in R/R FLT3 mut+ AML.

Gilteritinib and the risk of intracranial hemorrhage: a case series of a possible, under-reported side effect

Gilteritinib is currently approved for patients with relapsed/refractory AML with FLT3 mutations, based on the positive results of the pivotal ADMIRAL study. In ADMIRAL trial, no increased risk of bleeding was reported, but in the previous dose finding study, a single event of intracranial hemorrhage (ICH) was registered after exposure to subtherapeutic doses of gilteritinib. Here, we report the first case series on five ICHs diagnosed in patients with FLT3-mutated AML, occurred within the first month of exposure to gilteritinib. Our cohort included 24 patients treated in three Italian centers. Most of these ICH cases were non-severe and self-limiting, while one was fatal. This link with ICHs remains in any case uncertain for the presence of active AML. We further reported that an analysis of the post-marketing surveillance data (EudraVigilance) retrieved other 11 cases of ICHs present in the database after gilteritinib treatment. A causality assessment was performed according to the Dx3 method to evaluate the possibility that ICHs might be an actual side effect of gilteritinib. In conclusion, further research is needed to elucidate the potential role of gilteritinib in the pathogenesis of ICHs.

Gilteritinib: The Story of a Proceeding Success into Hard-to-Treat FLT3-Mutated AML Patients.

The traditionally dismal outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations has been mitigated by the recent introduction of tyrosine kinase inhibitors (TKI) into clinics, such as midostaurin and gilteritinib. The present work summarizes the clinical data that led to the use of gilteritinib in clinical practice. Gilteritinib is a second-generation TKI with deeper single-agent activity than first-generation drugs against both FLT3-ITD and TKD mutations in human studies. Moreover, the phase I/II dose-escalation, dose-expansion Chrysalis trial showed an acceptable safety profile of gilteritinib (diarrhea, elevated aspartate aminotransferase, febrile neutropenia, anemia, thrombocytopenia, sepsis, and pneumonia) and a 49% overall response rate (ORR) in 191 FLT3-mutated relapsed/refractory (R/R) AML patients. In 2019, the pivotal ADMIRAL trial showed that the median overall survival was significantly longer in patients treated with gilteritinib than among those receiving chemotherapy (9.3 vs. 5.6 months, respectively) and the ORR to gilteritinib was 67.6%, outperforming the 25.8% for chemotherapy arm and leading to the license for its clinical use by the US Food and Drug Administration. Since then, several real-world experiences have confirmed the positive results in the R/R AML setting. Finally, gilteritinib-based combinations currently under investigation, with several compounds (venetoclax, azacitidine, conventional chemotherapy, etc.) and some practical tips (maintenance after allogeneic transplantation, interaction with antifungal drugs, extramedullary disease, and onset of resistance), will be analyzed in detail in this review.

Gilteritinib (XOSPATA®) in Turkey: Early Access Program Results.

Gilteritinib (XOSPATA®, Astellas) is a type I oral FLT3 inhibitor, a tyrosine kinase AXL inhibitor, involved in both c-Kit and FMS-like tyrosine kinase 3 (FLT3) resistance. In the phase 3 ADMIRAL trial, gilteritinib was compared with the standard of care in (R/R) acute myeloid leukemia (AML) patients who harbored any FLT3 mutation and showed superior efficacy with regard to response and survival. This research aimed to investigate the real-life efficacy and safety of gilteritinib in FLT3-positive R/R AML patients who were treated as a part of an early access program held in Turkey in April 2020 (NCT03409081). The research included 17 R/R AML patients who had received gilteritinib from seven centers. The overall response rate was 100%. The most common adverse events were anemia and hypokalemia (7 patients, 41.2%). Grade 4 thrombocytopenia was observed in one patient only (5.9%), leading to permanent treatment discontinuation. Patients with peripheral edema had a 10.47 (95% CI: 1.64-66.82) times higher risk of death than those without peripheral edema (p<0.05). This research showed that patients with febrile neutropenia and peripheral edema were at a high risk of death when compared to patients without febrile neutropenia and peripheral edema.

Patient-reported outcomes from the phase 3 ADMIRAL trial in patients with FLT3-mutated relapsed/refractory AML

Patient-reported outcomes (PROs) can inform treatment selection and assess treatment value in acute myeloid leukemia (AML). We evaluated PROs from the ADMIRAL trial (NCT02421939) in patients with FLT3-mutated relapsed/refractory (R/R) AML. PRO instruments consisted of Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), Functional Assessment of Chronic Illness Therapy-Dyspnea Short Form (FACIT-Dys SF), EuroQoL 5-Dimension 5-Level (EQ-5D-5L), and leukemia treatment-specific symptom questionnaires. Clinically significant effects on fatigue were observed with gilteritinib during the first two treatment cycles. Shorter survival was associated with clinically significant worsening of BFI, FACT-Leu, FACIT-Dys SF, and EQ-5D-5L measures. Transplantation and transfusion independence in gilteritinib-arm patients were also associated with maintenance or improvement in PROs. Health-related quality of life remained stable in the gilteritinib arm. Hospitalization had a small but significant effect on patient-reported fatigue. Gilteritinib was associated with a favorable effect on fatigue and other PROs in patients with FLT3-mutated R/R AML.

FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile

FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML). Approximately 30% of the adult cases harbor an internal tandem duplication (FLT3-ITD) and 5-10% a tyrosine kinase domain (TKD) amino acid substitution (FLT3-TKD). The treatment paradigm of AML patients harboring FLT3 mutations (30%) has been modified by the discovery of tyrosine kinase inhibitors. First- and second-generation inhibitors classify FLT3 inhibitors according to FLT3 specificity: first-generation FLT3 inhibitors include sorafenib and midostaurin and second-generation inhibitors are represented by quizartinib, gilteritinib and crenolanib, among others. Activity of these inhibitors depends on their mechanism of receptor binding (active vs inactive conformation) and efficacy against the FLT3-ITD and -TKD mutations (type 1 inhibitors are active both on FLT3-ITD and TKD, whereas type 2 inhibitors are active only on FLT3-ITD). The FLT3 inhibitors sorafenib, midostaurin, quizartinib and gilteritinib have been tested in monotherapy in several settings including refractory or relapsed AML (R/R AML), post-transplant maintenance as well as in combination with intensive chemotherapy (ICT) or non-intensity regimens. The results of published randomized studies support the use of sorafenib in a post-transplant setting (SORMAIN trial), midostaurin in combination with ICT based (RATIFY trial) and gilteritinib for R/R AML (ADMIRAL trial). Gilteritinib in combination with hypomethylating agent as well as quizartinib are not supported by solid randomized trial results for their use in FLT3-mutated AML patients.

Outcomes in Patients with FLT3-Mutated Relapsed/ Refractory Acute Myelogenous Leukemia Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib versus Salvage Chemotherapy

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (45%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients.

Gilteritinib Activity in Refractory or Relapsed FLT3-Mutated Acute Myeloid Leukemia Patients Previously Treated By Intensive Chemotherapy and Midostaurin: A Study from the French AML Intergroup ALFA/Filo

Background The recent phase 3 ADMIRAL trial has shown that outcomes of relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients were improved by the single-agent FLT3 tyrosine kinase inhibitor gilteritinib as compared with salvage chemotherapy. In this trial, overall survival (OS) was significantly improved in the gilteritinib arm and complete remission (CR/CRi), after excluding those obtained after allogenic hematopoietic stem cell transplantation (Allo-HSCT) were 26.3% in the gilteritinib group. Methods Here, the real-world efficacy and safety of gilteritinib was assessed in an ambispective study that included 167 R/R FLT3-mutated AML patients (Cohort A) from the French early access program ELEGANCE between March 1st, 2019, and March 1st, 2021. Gilteritinib was administered to 27 patients in association with other treatments, while 140 received it as single agent (Cohort B), including 67 previously treated by intensive chemotherapy and midostaurin (Cohort C). Results Characteristics of the three cohorts at gilteritinib initiation are described in Table 1. Briefly, in the whole cohort A, there were 141 (84.4%) cases of de novo AML, FLT3 mutation was ITD in 104 (62.3%) and TKD in 33 (19.8%), whereas 36 (21.6%) patients were FLT3 wild-type at diagnosis, acquired mutation later in disease evolution and were FLT3 mutated at gilteritinib initiation. Finally, 6 (3.6%) patients had both FLT3-ITD and TKD mutations. The median FLT3-ITD/wt ratio was 0.50 (IQR, 0.12-0.70 and range 0.01-1.90), and the median size of ITD was 48 bp (IQR, 30-75, range 3-408). Most patients (136, 81.4%) had an intermediate cytogenetic risk, and 84 (50.3%) had an NPM1 co-mutation. The main differences in patient characteristics in this study, compared to ADMIRAL, were ECOG ≥ 2 (83.6% vs 16.6%), FLT3-TKD mutations (21.0% vs 8.5%), primary induction failure (15.0% vs 40.0%) and previous lines of treatment (beyond 2nd in 37.1% vs 0.0%). The rates of response to gilteritinib are described in Table 1. Moreover, CRc (CR + CR without hematological recovery + CR with incomplete platelet recovery) to gilteritinib as single agent in subgroups defined as per AML phase at gilteritinib initiation were 4.5% (N=22) for patients refractory after front-line, 37.5% (N=32) for those relapsing less than 6 months from CR/CRi, 26.7% (N=30) when relapse occurred after 6 months and 16.1% (N=56) for patients refractory after 1st relapse and beyond. Finally, 32 (19.2%), 25 (17.9%) and 15 (22.4%) patients received an Allo-HSCT after gilteritinib, in CRc for 21 (65.6%), 17 (68.0%) and 11 (73.3%) patients in cohorts A, B and C, respectively. In terms of safety, in the subgroup of patients treated with gilteritinib as single agent (Cohort B), 39 (28.3%) experienced a serious adverse event (SAE) during gilteritinib treatment: infection in 22 (56.4%), hemorrhage in 1 (2.6%), cardiovascular in 4 (10.3%), hepatic in 4 (10.3%), differentiation syndrome in 2 (5.2%) and other SAE in 6 (15.4%). In terms of health care resource consumption, the median duration of hospitalization during the first 6 months of treatment was 9.0 days (IQR 0-29, range 0-117) with a median of 7 RBC units (IQR 0-14, range 0-54) and of 5 platelet units (IQR 0-13.5, range 0-56) transfusions. After a median follow-up of 14.5 months, median OS and 12-month OS were 6.4 months (IQR, 3.2-14.7) and 31.4% (95%CI 22.4-39.7) in the 140 patients who received gilteritinib as single agent, and 7.8 months (IQR, 3.2-20.8) and 38.3% (95%CI 26.0-50.4) in the subgroup of 67 patients previously treated by intensive chemotherapy and midostaurin (Figure 1). Multivariate analyses disclosed female gender (HR 1.61, 95%CI 1.07-2.42, p=0.02), adverse cytogenetic risk (HR 2.52, 95%CI 1.24-5.13, p=0.01) and allo-HSCT after gilteritinib (HR 0.13, 95%CI 0.05-0.37, p<0.0001) as factors significantly and independently associated with OS. Conclusion Although patients in this study were more heavily pretreated, these real-world data reproduce ADMIRAL results and provide new insights in the outcome of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Frida Study: An Option for Mutated FLT3 Relapsed/Refractory Acute Myeloid Leukemia Patients with a Novel Iadademstat and Gilteritinib Combination Therapy

Background: Epigenetic dysregulation is a hallmark of acute myeloid leukemia (AML) and is caused by recurrent translocations and/or mutations in chromatin regulators and transcription factors, resulting in myeloid differentiation blockade and leukemic stem cell renewal. Accordingly, about 70% of recurring mutations in AML patients target regulators of gene expression, underscoring the potential of epigenetic therapies to change the natural history of the disease. Iadademstat (iada/ORY-1001) is a specific, oral, potent, covalent inhibitor of the epigenetic Lysine-Specific Demethylase 1 (LSD1/KDMA1) enzyme. Preclinical models demonstrate that exposure to iada decreases leukemic stem cell survival and preclinical and clinical studies shows iada's effect on inducing macrophage/monocytic differentiation of blast cells. Furthermore, a Phase 2 ongoing study of iada in combination with azacitidine (ALICE) shows high complete remission (CR)/ CR with incomplete count recovery (CRi) and durable responses in treatment naïve, unfit AML patients (pts) without exacerbating the toxicity profile of azacitidine (Salamero et al., Abstract P586 EHA 2022). Despite improvements in AML therapy, relapses remain a common challenge, contributing to the death of more than 50% of pts, particularly in those subpopulations with higher risk genetics, the largest of which (up to 30-40% of AML pts) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. Use of the FLT3 inhibitor (FLT3i) gilteritinib as monotherapy for relapsed/refractory (R/R) pts has resulted in improved outcomes but the duration of remission achieved is transient and often brief. The Phase 3 randomized ADMIRAL trial of gilteritinib revealed a CR rate of 20%; and an event-free-survival (EFS) of 2.8 months (Perl, et al., NEJM 2019). Preclinically, iada produces marked synergy with FLT3i, including gilteritinib, in FLT3 wild-type and mutated (FLT3 mut+) AML cells and in derived cell lines resistant to venetoclax, azacitidine and other FLT3is. The novel MOAs generating this synergy of the combination include activation of a pro-differentiative epigenetic and transcriptional program with simultaneous suppression of the activity of MYC target genes (Yashar, et al. 2022, https://doi.org/10.1101/2022.01.17.476469). The FRIDA clinical trial is designed to establish the safety, tolerability of the combination of iada plus gilteritinib and to identify the recommended phase 2 dose (RP2D) in FLT3 mut+ R/R AML specifically according to FDA's Project Optimus. Methods: Adult pts with body weight ≥50 Kg and ECOG 0-2, with FLT3 mut+ R/R AML, after 1 or 2 prior lines of therapy, will be enrolled. Up to 18 pts, in a 3+3 escalation phase, will receive iada at doses of 75 to 150 ug, orally, in 5 days ON - 2 days OFF schedule, with continuous gilteritinib, at 120 mg/day orally. In the expansion phase, up to 14 pts at the selected safe and pharmacologically active dose/s (determined based on all available data from escalation pts including PK, target engagement (TE), safety, tolerability, and emerging activity) will be enrolled. TE will be assessed with a proprietary validated chemo-probe assay for LSD1 occupancy in PBMCs. Primary endpoints of the study are safety and RP2D determination, based on the same 5 criteria outlined above. Bayesian posterior probability efficacy monitoring will be performed periodically for each dose cohort starting from the first 6 additional pts in the expansion phase (total of 12). Bayesian efficacy futility and early stopping boundary will be applied during the monitoring. Posterior probability criterion (Prob (θ>0.3) ≥ 0.60) at the end of the study will warrant additional development. The safety of the combination treatment will be also continuously evaluated during expansion following a Bayesian design stopping rule. Secondary endpoints include overall survival, EFS, CR, CR/CR with partial hematologic recovery (CRh), overall response rates, time to response, duration of response, and transfusion rate. Exploratory endpoints include measurable residual disease and gene mutational analysis. Pts who achieve a response can undergo hematopoietic stem cell transplant. The study plans to have 15 sites enrolling in the US. Additional sites will be added for a subsequent randomized controlled double-blinded FRIDA 2 study to assess the efficacy of the iada and gilteritinib combination in R/R FLT3 mut+ AML.

Gilteritinib activity in refractory or relapsed FLT3-mutated acute myeloid leukemia patients previously treated by intensive chemotherapy and midostaurin: a study from the French AML Intergroup ALFA/FILO.

The real-world efficacy and safety of gilteritinib was assessed in an ambispective study that included 167 R/R FLT3-mutated AML patients. Among them, 140 received gilteritinib as single agent (cohort B), including 67 previously treated by intensive chemotherapy and midostaurin (cohort C). The main differences in patient characteristics in this study compared to the ADMIRAL trial were ECOG ≥ 2 (83.6% vs. 16.6%), FLT3-TKD mutation (21.0% vs. 8.5%), primary induction failure (15.0% vs. 40.0%) and line of treatment (beyond 2nd in 37.1% vs. 0.0%). The rates of composite complete remission, excluding those that occurred after hematopoietic stem cell transplantation (HSCT), were similar at respectively 25.4% and 27.5% in cohorts B and C. Median overall survival (OS) for these two groups was also similar at respectively 6.4 and 7.8 months. Multivariate analyses for prognostic factors associated with OS identified female gender (HR 1.61), adverse cytogenetic risk (HR 2.52), and allogenic HSCT after gilteritinib (HR 0.13). Although these patients were more heavily pretreated, these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting.

Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib

AbstractThe phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, and treatment-emergent mutations were analyzed in patients in the ADMIRAL trial. Baseline comutations were grouped according to gene subgroups (DNA methylation/hydroxymethylation, transcription, chromatin–spliceosome, receptor tyrosine kinase-Ras signaling, TP53-aneuploidy, NPM1, DNMT3A, DNMT3A/NPM1, WT-1, and IDH1/IDH2). Across all but 1 gene subgroup (TP53-aneuploidy), higher pretransplant response rates and a trend toward longer overall survival were observed with gilteritinib vs SC. Patients with DNMT3A/NPM1 comutations who received gilteritinib had the most favorable outcomes of any molecular subgroup analyzed. Survival outcomes with gilteritinib were not adversely affected by FLT3-ITD allelic ratio, FLT3-ITD length, or multiple FLT3-ITD mutations. Among patients who relapsed on gilteritinib, Ras/mitogen-activated protein kinase (MAPK) pathway and FLT3 F691L gene mutations were the most common mutational events associated with treatment resistance. However, the occurrence of Ras/MAPK pathway gene mutations at baseline did not preclude a clinical benefit from gilteritinib. Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Follow-up of patients with R/R FLT3-mutation–positive AML treated with gilteritinib in the phase 3 ADMIRAL trial

AbstractThe phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation–positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Gilteritinib Versus Salvage Chemotherapy for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: A Phase 3, Randomized, Multicenter, Open-Label Trial in Asia

▪Background: Due to poor prognosis, treatment options for patients with FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) who are refractory to therapy or have relapsed (R/R) are needed globally. Gilteritinib is approved in multiple countries, including Japan, and has recently received conditional approval in China for the treatment of R/R FLT3mut+ AML; in the phase 3 ADMIRAL trial, superior survival benefit and a favorable safety profile were shown for patients receiving gilteritinib compared to those receiving salvage chemotherapy (SC) (HR 0.64 [95% CI: 0.49, 0.83]; P<0.001) in the R/R FLT3mut+ AML setting. While data from the Asian subpopulation of ADMIRAL have been evaluated, larger randomized, controlled trials of outcomes for treatments in a predominantly Asian population are lacking.Aim/Objective: To evaluate the efficacy and safety/tolerability of gilteritinib compared with SC in Asian patients with R/R FLT3mut+ AML after first-line therapy.Methods: In this phase 3, open-label, multicenter COMMODORE (NCT03182244) trial, adult patients in China, Russia, Singapore, Thailand, and Malaysia with R/R FLT3mut+ AML were randomized 1:1 to gilteritinib 120 mg orally per day or SC (low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine; or fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor) over continuous 28-day cycles. Patients must have had an ECOG performance status score ≤2; those with acute promyelocytic leukemia, BCR-ABL-positive leukemia, clinically active central nervous system disease, or secondary AML were excluded. The primary endpoint was overall survival (OS), and key secondary efficacy endpoints were event-free survival (EFS) and complete remission (CR). Additional secondary endpoints included duration of remission, composite CR (CRc), and safety/tolerability. OS and EFS were analyzed with stratified Cox proportional hazard models, and response rates were analyzed with the Cochran-Mantel-Haenszel test. Results of the interim analysis are presented here.Results: As of June 30, 2020, a total of 234 patients were randomized (gilteritinib, n=116; SC, n=118). Median age was 51.5 and 49.5 years in the gilteritinib and SC groups, respectively; most patients had not previously received FLT3 inhibitors (87.9% and 93.2%, respectively). Baseline FLT3 mutations in the gilteritinib vs SC groups were: FLT3-ITD (91.4% vs 83.1%), FLT3-TKD (6.0% vs 11.9%), and both FLT3-ITD and FLT3-TKD (2.6% vs 5.1%). Median follow-up duration for OS was 11.1 months for gilteritinib and 6.9 months for SC. Median OS was significantly longer in the gilteritinib group (9.0 months) compared with the SC group (4.7 months; HR 0.549 [95% CI: 0.379, 0.795]; P=0.00126; Figure); 1-year survival rates were 33.3% and 23.2%, respectively. Patients on gilteritinib had significantly longer EFS than those receiving SC (median EFS 2.8 vs 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; P=0.00004). A higher proportion of patients achieved CR on gilteritinib (16.4%) compared with SC (10.2%; P=0.17690); CRc rates were 50.0% and 20.3% (P<0.00001). Grade ≥3 adverse events (AEs) in the gilteritinib (97.3%) vs SC (94.2%) groups were comparable; rates for serious AEs were higher for gilteritinib (73.5%) vs SC (61.5%). When adjusted for treatment exposure, AE rates were lower with gilteritinib (grade ≥3, 55.56 events/patient-year [E/PY]; serious, 6.19 E/PY) than with SC (grade ≥3, 164.00 E/PY; serious, 12.40 E/PY). The most common AEs occurring in the gilteritinib group were anemia (76.1%), thrombocytopenia (46.9%), pyrexia (41.6%), and increased blood lactate dehydrogenase (41.6%); for SC, the most common AEs were anemia (64.4%), decreased white blood cell count (41.3%), and thrombocytopenia (38.5%). AEs leading to death occurred in 22 (19.5%) and 15 (14.4%) of patients receiving gilteritinib or SC, respectively.Conclusions: Gilteritinib significantly prolonged OS and EFS compared with SC in patients with R/R FLT3mut+ AML in Asia. When adjusted for treatment exposure, safety/tolerability was favorable for gilteritinib compared with SC. The results of the COMMODORE trial further validate and affirm the clinical efficacy and safety data from the ADMIRAL trial, reinforcing the significant benefit of gilteritinib in R/R FLT3mut+ AML. [Display omitted] DisclosuresWang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Li: Astellas Pharma, Inc.: Research Funding. Liu: Astellas Pharma, Inc.: Research Funding. Du: Astellas Pharma, Inc.: Research Funding. Jiang: Astellas Pharma, Inc.: Research Funding. Hu: Astellas Pharma, Inc.: Research Funding. Yuan: Astellas Pharma, Inc.: Current Employment. Sakatani: Astellas Pharma, Inc.: Current Employment, Current equity holder in publicly-traded company. Kadokura: Astellas Pharma, Inc.: Current Employment. Takeuchi: Astellas Pharma, Inc.: Current Employment. Izuka: Astellas Pharma, Inc.: Current Employment. Girshova: Astellas Pharma, Inc.: Research Funding. Tan: Astellas Pharma, Inc.: Research Funding. Wong: Astellas Pharma, INc.: Research Funding. Khuhapinant: Astellas Pharma, Inc.: Research Funding. Martynova: Astellas Pharma, Inc.: Research Funding. Hasabou: Astellas Pharma, Inc.: Current Employment. Tiu: Astellas Pharma, Inc.: Current Employment.

Phase 3, Open-Label, Randomized Study of Gilteritinib and Azacitidine Vs Azacitidine for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia in Patients Ineligible for Intensive Induction Chemotherapy

Phase 3, Open-Label, Randomized Study of Gilteritinib and Azacitidine Vs Azacitidine for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia in Patients Ineligible for Intensive Induction Chemotherapy

Gilteritinib (GILT) Monotherapy with Addition of Decitabine (DEC) in Non-Responders in Older Newly Diagnosed (ND) FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Having High and Low Variant Allele Frequency (VAF): A Phase 2/1b Sub-Study of the Beat AML Master Trial

Gilteritinib (GILT) Monotherapy with Addition of Decitabine (DEC) in Non-Responders in Older Newly Diagnosed (ND) FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Having High and Low Variant Allele Frequency (VAF): A Phase 2/1b Sub-Study of the Beat AML Master Trial

Cost-effectiveness of gilteritinib for relapsed/refractory FLT3mut+ acute myeloid leukemia.

BACKGROUND: Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and confirmed feline McDonough sarcoma (FMS)-like tyrosine kinase 3 gene mutations (FLT3mut+) have a poor prognosis and limited effective treatment options. Gilteritinib is the first targeted therapy approved in the United States and Europe for R/R FLT3mut+ AML with significantly improved efficacy compared with existing treatments. OBJECTIVE: To evaluate gilteritinib against salvage chemotherapy (SC) and best supportive care (BSC) over a lifetime horizon among adult patients with R/R FLT3mut+ AML from a US third-party payer's perspective. METHODS: The model structure of this cost-effectiveness analysis included a decision tree to stratify patients based on their hematopoietic stem cell transplantation (HSCT) status, followed by 2 separate 3-state partitioned survival models to predict the long-term health status conditional on HSCT status. The ADMIRAL trial data and literature were used to predict probabilities of patients being in different health states until a conservative cure point at year 3. Afterwards, living patients followed the survival outcomes of long-term survivors with AML. Model inputs for utilities, medical resource use, and costs were based on the ADMIRAL trial, published literature, and public sources. All costs were inflated to 2019 US dollars (USD). Total incremental costs (in 2019 USD), life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Deterministic sensitivity analyses and probabilistic sensitivity analyses were performed. RESULTS: Over a lifetime horizon with a 3.0% annual discount rate, the base-case model estimated that gilteritinib led to an increase of 1.29 discounted QALYs at an additional cost of $148,106 vs SC, corresponding to an ICER of $115,192 per QALY; for BSC, results were an increase of 2.32 discounted QALYs, $249,674, and $107,435, respectively. The base-case findings were robust in sensitivity analyses. The estimated probabilities of gilteritinib being cost-effective vs SC and BSC were 90.5% and 99.8%, respectively, in the probabilistic sensitivity analyses, based on a willingness-to-pay threshold of $150,000 per QALY. CONCLUSIONS: Gilteritinib is a cost-effective novel treatment for patients with R/R FLT3mut+ AML in the United States. DISCLOSURES: This work was supported by Astellas Pharma, Inc., which was involved in all stages of the research and manuscript development. Garnham, Pandya, and Shah are employees of Astellas and hold stock/stock options. Zeidan consulted and received personal fees/honoraria and research funding from Astellas. Zeidan also has received research funding from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff Oncology, Incyte, Takeda, Novartis, Amgen, Aprea, and ADC Therapeutics; has participated in advisory boards; has consulted with and/or received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Daiichi Sankyo, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Syndax, Gilead, Kura, Aprea, Lox Oncology, Genentech, Servier, Jasper, Tyme, and Epizyme; has served on clinical trial committees for Novartis, Abbvie, Geron, Gilead, Kura, Lox Oncology, BioCryst, and Celgene/BMS; and has received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. Qi and Yang are employees of Analysis Group, Inc., which received consulting fees from Astellas for work on this study. Part of this material was presented at the American Society of Hematology (ASH) Annual Meeting; December 7-10, 2019; Orlando, FL.

AML-091: Clinical Outcomes in Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated with Gilteritinib Who Received Prior Midostaurin or Sorafenib

<h3>Context:</h3> Findings from the phase 1/2 CHRYSALIS trial and the phase 3 ADMIRAL trial demonstrated the safety and efficacy of the <i>FLT3</i> inhibitor gilteritinib in patients with FLT3-mutated (<i>FLT3^Mut</i>⁺) relapsed/refractory (R/R) AML. The efficacy of gilteritinib after prior tyrosine kinase inhibitor (TKI) therapy in these patients is unclear. <h3>Objective:</h3> Determine whether prior TKI therapy affected response and survival in <i>FLT3^Mut</i>⁺ R/R AML patients treated with gilteritinib. <h3>Design:</h3> A retrospective analysis of the CHRYSALIS and ADMIRAL trials. <h3>Patients:</h3> We retrospectively analyzed outcomes in patients with R/R AML previously treated with TKIs (midostaurin/sorafenib), before receiving 120 or 200 mg gilteritinib. <h3>Main Outcomes Measures:</h3> Treatment response and overall survival (OS) in patients who previously received or did not receive treatment with TKIs. <h3>Results:</h3> Of the 145 FLT3-mutation-enriched patients who received 120- or 200-mg gilteritinib in the CHRYSALIS trial, 33 (23%; 120 mg, n=15; 200 mg, n=18) had received a prior TKI (all sorafenib). Rates of composite complete remission (CRc) in patients who received prior TKIs (42%) and those who did not (43%) were similar. Among patients who received prior TKIs, rates of CRc were 53% in the 120 mg group and 33% in the 200 mg group; rates of CRc in patients without prior TKIs were similar across dose groups (44% and 42%, respectively). In the ADMIRAL trial, 31 of 247 (13%) R/R <i>FLT3^Mut</i>⁺ AML patients in the gilteritinib arm and 14 of 124 (11%) patients in the salvage chemotherapy (SC) arm had received prior TKIs. In the gilteritinib arm, CRc rates were comparable in patients who received (48%) and did not receive prior TKIs (55%); lower CRc rates were observed in the SC arm in both TKI and non-TKI pretreated groups (21% and 22%, respectively). Median OS in patients treated with prior TKIs was 6.5 months with gilteritinib and 4.7 months with SC (HR=0.671 [95% CI: 0.328, 1.376]); in patients without prior TKIs, median OS was 9.6 and 6.0 months, respectively (HR=0.625 [95% CI: 0.474, 0.824]). <h3>Conclusion:</h3> High response rates with gilteritinib were observed in patients with <i>FLT3^Mut</i>⁺ R/R AML who received prior TKIs.

AML-162: Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia: Updated Analyses of a Phase 1b Study

<h3>Background/Objective:</h3> To provide updated results from a Phase 1b trial (NCT03625505) of BCL-2 inhibitor venetoclax and FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Ven+Gilt) in patients with relapsed/refractory (R/R) FLT3-mutated (<i>FLT3^Mut</i>⁺) acute myeloid leukemia (AML). <h3>Methods:</h3> Patients with R/R AML <i>FLT3^Mut</i>⁺ received up to Ven 400mg daily with Gilt (80 or 120 mg) daily in 28-day cycles, following Ven ramp-up. Primary endpoint was modified composite complete remission (mCRc) to align with Phase 3 ADMIRAL trial CRc responses. Secondary endpoint was mCRc duration of response (DOR); overall survival (OS), and changes in <i>FLT3</i> allelic burden were exploratory. Adverse events (AEs) were monitored. <h3>Results:</h3> At data cutoff (November 30, 2020), 43 patients (median age 63 yrs) with <i>FLT3^Mut</i>⁺ were enrolled. <i>FLT3</i> internal tandem duplications (ITD) were identified in 86% patients, and 14% had only tyrosine kinase domain (TKD) mutations. Baseline cytogenetic risk was favorable in 5%, 55% intermediate, 31% poor, and 12% had no mitoses/missing data. Median (range) prior lines of therapy were 2 (1–5), and 77% patients had 2 or more prior lines of therapy: 65% received at least one prior FLT3 inhibitor, and 7% received prior Ven; 33% had prior transplant. Grade 3/4 AEs were reported in 98% of patients; grade ≥3 cytopenias occurred in 79% and were predominantly managed by Ven/Gilt dose interruptions. The only grade 3/4 nonhematologic AEs reported in >20% of patients was pneumonia (n=9; 21%) and 1 instance of clinical tumor lysis syndrome. Serious AEs were reported in 74% of patients. Overall, 30- and 60-day mortality rates were 0% and 12%, respectively. AEs led to either Ven or Gilt interruptions in 56% patients, reductions in 7%, and discontinuations in 14%. mCRc was achieved by 86% of <i>FLT3^Mut</i>⁺ efficacy population (36/42) with median time to first response of 1.0 mo (range: 0.7–4.6) and 86% with prior FLT3 tyrosine kinase inhibitor (TKI) exposure (24/28). FLT3 molecular clearance (<10^–2) was observed in 69% of mCRc patients with PCR analyzed at baseline and at least 1 follow-up timepoint (18/26). <h3>Conclusions:</h3> Updated analyses show Ven+Gilt achieved high rates of mCRc in patients with heavily pre-treated and prior TKI-exposed R/R <i>FLT3^Mut</i>⁺AML with encouraging molecular clearance rates. Using similar criteria to previous <i>FLT3^Mut</i>⁺ studies, high mCRc rate with Ven+Gilt suggests strong anti-leukemic activity. Cytopenias were prominent but manageable.