ADMIRAL Trial Research Articles

Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia

BackgroundUntil recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001).MethodsWe evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC.ResultsMedian OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%).ConclusionFindings in Japanese patients are consistent with those of the overall ADMIRAL study population.

Abstract NG14: Reduction in mitochondrial priming drives resistance to targeted therapy in acute myeloid leukemia

Abstract Relapse is the leading cause of treatment failure in acute myeloid leukemia (AML) patients. FDA approval of 8 targeted therapies in the past two years has drastically altered the landscape of AML treatment. Despite this success, the duration of clinical response is limited by the frequent development of acquired drug resistance to targeted therapy. To identify mechanism of resistance and to search for therapies that overcome resistance, we adopted broadly applicable functional approach to precision medicine called “dynamic BH3 profiling” (DBP) and coupled it with RNA-seq and targeted exome sequencing technology. DBP measures drug induced early death signaling using BH3 peptides that mimic pro-apoptotic BH3 proteins. To first validate the utility of DBP as precision medicine tool we created landscapes of pharmacologic sensitivity of 17 patient-derived xenograft (PDX) AML models to a panel of 40 clinically relevant agents, together with genomic and transcriptomic profiles. Aggregated across the panel, unsupervised clustering of drug-induced apoptotic signaling using DBP by itself could segregated PDXs according to prior treatment status (PDXs from treatment naïve patients clustered distinctly from R/R PDXs). While genomic mutations and transcriptomic signature profiles between R/R and treatment naïve PDXs did not show significantly distinct clustering patterns. Next we show that DBP could predict in vivo responses of drugs of widely varying mechanism of action, including a FLT-3 inhibitor, BCL-2 and MCL-1 inhibitors (BH3 mimetics), SMAC mimetic, and BRD4 inhibitor, in 6 AML PDX models (AUC of ROC 0.8731, p&amp;lt;0.005). Next, we created resistant PDX models to single agents including, quizartinib, birinapant, venetoclax, S63845 and JQ-1. After selecting for in vivo acquired resistance to drugs with distinct mechanism, a common mechanism of resistance was identified for all - a reduction in mitochondrial apoptotic priming. Apart from PDX models, paired pretreatment and post relapse myeloblasts of patients who had complete response followed by a relapse on venetoclax plus azacytidine therapy (NCT02203773) also showed selection for decreased mitochondrial apoptotic priming in relapsed myeloblasts using promiscuously interacting BIM (P=0.0075) and PUMA peptides (P=0.0078). Using targeted exome sequencing for recurrently mutated leukemia genes, we found that although there was acquisition of new mutations between paired clinical samples, there was no consistent molecular signature defining relapsed phenotype. We report that loss in apoptotic priming in BH3 mimetics resistant PDXs can be explained by alterations in BCL-2 family proteins levels and interaction patterns at outer mitochondrial membrane that vary among cases. However, there was absence of gene signature depicting reduction in pro-apoptotic genes and upregulation in anti-apoptotic genes, measured by unbiased RNA-seq (Bhatt et al. Cancer cell, In press). Enrichment for pro-survival pathways, including JAK-STAT, MAPK, and PI3K-AKT was observed using RNA-seq of resistant PDXs compared to matched parental counterpart in BH3-mimetics and FLT-3 inhibitor resistant models but not SMAC-mimetics and BRD-4 resistant models. To identify the agents that are effective in the resistant settings, we compared DBP profiles of 40 targeted agents in myeloblasts of pre and post resistant models. We found that reduction in overall priming led to broad chemoresistance even to mechanistically distinct agents in resistant myeloblasts, yet there was maintenance of persistent sensitivity to selected agents. For instance, in venetoclax and S63845 resistant PDXs, mitochondrial priming measured by DBP on resistant myeloblasts identified in vivo activity of FLT-3 inhibitors and SMAC mimetics while in quizartinib resistant settings, SMAC mimetics, BH3 mimetics and MAPK inhibitors showed anti-leukemic effects. This suggested that while common modes of mechanism do exist, drugs that enhance mitochondrial apoptotic sensitivity can overcome resistance to a particular agents. Finally we applied this approach to humans, showing that the pretreatment mitochondrial apoptotic priming determined by DBP identifies responders to single agent FLT-3 inhibitor gilteritinib in ADMIRAL trial and responders to lenalidomide (LEN) and MEC combination therapy in LEN-MEC Phase I trial (NCT01442714) R/R AML (Garcia* and Bhatt* et al. American Journal of hematology, 2020). In summary, our results suggest that acquired resistance to targeted therapy in AML is accompanied by common mechanism of reduction in mitochondrial priming along with drug-specific resistance mechanisms. Hence measurements of apoptotic priming using dynamic BH3 profiling may serve as a broadly applicable precision medicine tool in guiding therapy for relapsed leukemia. Citation Format: Shruti Bhatt, Marissa S. Piosos, Elyse A. Olesinski, Binyam G. Yilma, Jeremy A. Ryan, Thelma Mashaka, Buon Leutz, Sophia Adamia, David M. Weinstock, Jacqueline S. Garcia, Anthony Letai. Reduction in mitochondrial priming drives resistance to targeted therapy in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG14.

Follow-up of patients with FLT3-mutated R/R AML in the phase 3 ADMIRAL trial.

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 ( &gt; 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.

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

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

Comparison of Gilteritinib and Salvage Chemotherapy in FLT3-Mutated Acute Myeloid Leukemia on the Number Needed to Treat for Various Clinical Outcomes: A Secondary Analysis of the Admiral Trial

Introduction/background: FMS-like receptor tyrosine kinase-3 (FLT3) mutations are common in acute myeloid leukemia (AML) and are associated with poor prognosis. Historically, patients with relapsed/refractory (R/R) FLT3 mutation-positive (FLT3mut+) AML experienced dismal survival outcomes. Gilteritinib, a highly potent and selective FLT3 inhibitor, was recently approved as the first targeted therapy for patients with R/R FLT3mut+ AML, and has the potential to bring significant clinical benefits to these patients. The randomized, phase 3 ADMIRAL trial (NCT02421939; Perl, et al. 2019) was the first head-to-head study that evaluated 120-mg/day gilteritinib versus salvage chemotherapy in R/R FLT3mut+ AML patients. The ADMIRAL trial demonstrated that gilteritinib was superior to salvage chemotherapy based on significantly longer median overall survival (OS) and higher response rates, including complete remission/complete remission with partial hematological recovery (CR/CRh), composite CR (CRc), and hematopoietic stem cell transplantation (HSCT) rate. Based on these results, the current study estimated the number needed to treat (NNT) with gilteritinib, compared with salvage chemotherapy, in order to evaluate its clinical benefit with CR/CRh, CRc, 1-year OS, and HSCT rates. Methods: NNT is an established and easily interpretable measure to assess the effectiveness of healthcare interventions. The clinical event estimates (ie, CR/CRh rate, CRc rate, 1-year OS, and HSCT rate) of gilteritinib and salvage chemotherapy among R/R FLT3mut+ AML patients were obtained from the ADMIRAL trial. CR/CRh was defined as the combined rate of CR and CRh. CRc was defined as the combination of CR, CR with incomplete hematologic recovery, and CR with incomplete platelet recovery. OS was defined as time from randomization to death due to any cause. The NNT is calculated as the inverse of the absolute rate difference between the event rates of gilteritinib and salvage chemotherapy. Positive NNT values represent treatment benefit, with lower values indicating greater benefit of gilteritinib over salvage chemotherapy. The 95% confidence interval (CI) of the NNT was derived from the 95% CI of the event rate difference. Results: In the ADMIRAL trial, patients assigned to gilteritinib had significantly higher CR/CRh rates (34.0% vs 15.3%) and CRc rates (54.3% vs 21.8%) than patients assigned to salvage chemotherapy. The NNT for CR/CRh and CRc was 5.35 (95% CI: 3.66, 9.98) and 3.08 (95% CI: 2.38, 4.36), suggesting that treating five and three patients with gilteritinib instead of salvage chemotherapy would result in one additional patient achieving CR/CRh and CRc, respectively. With respect to the survival outcome, patients randomized to gilteritinib had significantly prolonged OS compared to those randomized to salvage chemotherapy (median OS: 9.3 vs 5.6 months; hazard ratio: 0.64); rates of 1-year survival were 37.1% versus 16.7%, respectively. The NNT comparing gilteritinib with salvage chemotherapy was 4.90 (95% CI: 3.29, 9.64) for 1-year OS, which suggests that treating approximately five patients with gilteritinib instead of salvage chemotherapy would lead to one additional survivor at the end of the first year. Lastly, more patients underwent HSCT in the gilteritinib arm versus the salvage chemotherapy arm (25.5% vs 15.3%); the corresponding NNT was estimated at 9.82 (95% CI: 5.40, 54.59) for gilteritinib versus salvage chemotherapy. Conclusion: The results demonstrated that treatment with gilteritinib compared with salvage chemotherapy leads to more R/R FLT3mut+ AML patients achieving CR/CRh, CRc, and proceeding to HSCT, as well as more patients remaining alive at 1 year. This NNT analysis supports the superior clinical benefit of gilteritinib versus salvage chemotherapy in R/R FLT3mut+ AML patients. Disclosures Pandya: Astellas Pharma, Inc.: Current Employment. Qi:BMS: Other: Employee of Analysis Group Inc., which received consulting fees; Astellas Pharma, Inc.: Research Funding. Yang:Analysis Group Inc.: Current Employment; Takeda Pharmaceutical Company Ltd: Research Funding. Garnham:Astellas Pharma, Inc.: Current Employment. Shah:Astellas: Current Employment. Zeidan:Taiho: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Cardinal Health: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; CCITLA: Other; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria; Aprea: Research Funding; MedImmune/Astrazeneca: Research Funding; Astex: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; BeyondSpring: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other.

Clinical Outcomes Following Treatment with Gilteritinib or Quizartinib in Patients with Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia &amp; Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly &amp; Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly &amp; Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.

Real-World Use of FLT3-TKIs in R/R FLT3-Mutated AML in the United States

Background: Targeted inhibition of the FLT3 tyrosine kinase is a treatment strategy for patients with relapsed or refractory, FLT3 mutation-positive acute myeloid leukemia (R/R FLT3mut+ AML). While the multikinase inhibitors, sorafenib and midostaurin, were not approved specifically for R/R AML, they are used off-label as treatment. Since FDA approval on 11/28/2018, gilteritinib has become the first globally approved targeted therapy for the treatment of R/R FLT3mut+ AML in adults. This study aims to understand the treatment landscape for R/R FLT3mut+ AML patients following the introduction of a new therapeutic agent. Aim/Objective: To describe the characteristics and treatment patterns of patients initiating FLT3 tyrosine kinase inhibitors (TKIs) for R/R FLT3mut+ AML in the real-world setting. Methods: This US-based retrospective cohort study was conducted using two separate closed-claims databases (MarketScan, 1/1/2007-2/29/2020; IQVIA, 1/1/2006-4/30/2020) and a specialty-pharmacy claims database (ProMetrics, 12/6/2018-3/12/2020). Patients ≥18 years of age, with an AML diagnosis and newly initiated FLT3-TKI (ie, gilteritinib, midostaurin, or sorafenib) therapy for R/R diagnosis or episode ("R/R AML") on or after gilteritinib market availability were eligible for inclusion. Patients were indexed on the first newly initiated FLT3-TKI for R/R AML observed on or after 12/1/2018. Patients' baseline clinical and demographic characteristics, AML-related treatments preceding FLT3-TKI initiation for R/R AML, and concomitant therapies (defined as any AML-related treatment overlapping with FLT3-TKI use after R/R AML) were identified. Because individual patients could have received more than one FLT3-TKI during the study period, treatment sequencing was analyzed by FLT3-TKI-containing regimens. Given the larger sample size available within the ProMetrics Specialty Pharmacy database, gilteritinib dose patterns and treatment duration were analyzed using de-identified dispensed prescription data from a separate gilteritinib-only cohort for greater precision. Descriptive statistics were used to evaluate all study outcomes, except for treatment duration, which was estimated using Kaplan-Meier life table analysis. Results: A total of 52 and 51 patients initiating FLT3-TKIs for R/R AML were identified in the MarketScan and IQVIA databases, respectively. The mean age of patients was 53.1 (MarketScan) and 52.3 years (IQVIA); patients had a mean ± SD Quan-Charlson Comorbidity Index of 3.6 ± 2.4 (MarketScan) and 3.7 ± 2.2 (IQVIA). Most patients treated with FLT3-TKIs for R/R AML during the study period were first initiated on gilteritinib (MarketScan: n=35 [67.3%], IQVIA: n=36 [70.6%]); sorafenib was the second most common FLT3-TKI (MarketScan: n=9 [17.3%], IQVIA: n=8 [15.7%]), followed by midostaurin (MarketScan: n=8 [15.4%], IQVIA: n=7 [13.7%]). During the study period, 61 and 55 FLT3-TKI-containing regimens among 52 and 51 R/R AML patients were identified across the MarketScan and IQVIA databases, respectively. Most FLT3-TKI-containing regimens for R/R AML included gilteritinib (MarketScan: n=43 [70.5%], IQVIA: n=38 [69.1%]). Prior exposure to other FLT3-TKIs for new onset and/or R/R AML indications was observed in up to 63% of gilteritinib-, 56% of sorafenib-, and 13% of midostaurin-containing regimens (Table). Following onset of R/R AML, gilteritinib was given without concomitant chemotherapy in 47% (Marketscan: 20/43) to 55% (IQVIA: 21/38) of gilteritinib regimens; in a smaller sample of sorafenib regimens, sorafenib was given without concomitant chemotherapy in up to 56% (IQVIA: 5/9) of regimens. Of 748 patients identified in the ProMetrics database with gilteritinib claims, 714 (95%) patients were initiated on a 120-mg daily dose, with less than 5% (n=34) incurring a downward dosage titration. The median treatment duration was 150 days (95% CI: 129-172 days). Conclusions: Among FLT3-TKI-containing regimens initiated for R/R AML after gilteritinib market approval, close to 70% included gilteritinib, an agent approved for R/R FLT3mut+ AML. Sample sizes for midostaurin- and sorafenib-containing regimens limited characterization of treatment patterns. Gilteritinib was given without concomitant chemotherapy in approximately 50% of regimens prescribed; the dose and treatment durations were similar to those previously reported by the ADMIRAL trial. Disclosures Grinblatt: Astellas: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau. Pandya:Astellas Pharma, Inc.: Current Employment. Sullivan:Astellas Pharma: Current Employment. Feng:Astellas: Current Employment. Hedlund:Astellas: Current Employment.

Evolution of Gilteritinib Resistance from Residual Disease to Relapse

Evolution of Gilteritinib Resistance from Residual Disease to Relapse

Pain and Opioid Use in Patients with FLT3 Mutation-Positive Relapsed/Refractory AML: A Subanalysis of Patient-Reported Outcomes from the Admiral Trial

Pain and Opioid Use in Patients with FLT3 Mutation-Positive Relapsed/Refractory AML: A Subanalysis of Patient-Reported Outcomes from the Admiral Trial

Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study

Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study

Gilteritinib Remains Clinically Active in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors

Gilteritinib Remains Clinically Active in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors

Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia.

Gilteritinib (Xospata®), a next-generation tyrosine kinase inhibitor (TKI), is approved in several countries/regions worldwide for the treatment of relapsed or refractory acute myeloid leukaemia (AML) in adults with FMS-like tyrosine kinase 3 (FLT3) mutations. In this patient population, oral gilteritinib significantly improved overall survival (OS) and the response rate for complete remission with full or partial haematological recovery compared with salvage chemotherapy in the phase III ADMIRAL trial. In an integrated safety analysis of patients with relapsed or refractory AML, the most commonly reported grade ≥ 3 treatment-related adverse events (AEs) in gilteritinib recipients included anaemia, febrile neutropenia and thrombocytopenia. Clinically relevant AEs of special interest (AESIs) with gilteritinib therapy included differentiation syndrome, posterior reversible encephalopathy syndrome, QT interval prolongation and pancreatitis. AEs, including AESIs, were generally manageable with dose reduction, interruption or discontinuation. All patients of reproductive potential should use contraception during gilteritinib treatment due to the risk of embryo-foetal toxicity. Given its convenient oral regimen, along with the poor prognosis and paucity of treatment options for adults with relapsed or refractory FLT3-mutated AML, gilteritinib represents a valuable first-line targeted monotherapy in these patients.

Long-term survivors and gilteritinib safety beyond one year in FLT3-mutated R/R AML: ADMIRAL trial follow-up.

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]

Gilteritinib: An FMS-like tyrosine kinase 3/AXL tyrosine kinase inhibitor for the treatment of relapsed or refractory acute myeloid leukemia patients.

Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with FLT3 mutation.

Outcome of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia Before Second-Generation FLT3 Tyrosine Kinase Inhibitors: A Toulouse-Bordeaux DATAML Registry Study.

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse–Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%; relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0–32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27–45), 24.7% (95%CI: 1–33) and 19.7% (95%CI: 1–28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.

Cost-Effectiveness Analysis of Gilteritinib Versus Salvage Chemotherapy (SC) for the Treatment of Relapsed or Refractory (R/R) FLT3-Mutated (FLT3mut+) Acute Myeloid Leukemia (AML)

Introduction: FLT3 is a frequently mutated gene in approximately one-third of AML cases and is associated with a poor prognosis. Few effective therapeutic options exist for patients with R/R FLT3mut+ AML. In 2018, gilteritinib was approved in the US as the first targeted therapy indicated for R/R FLT3mut+ AML. The efficacy of gilteritinib was established in the ADMIRAL trial, a phase 3 randomized trial, in comparison with SC (i.e., low-dose cyctarbine [LDAC], azacitidine, mitoxantrone + etoposide + cytarabine [MEC], and fludarabine + cytarabine + granulocyte colony stimulating factor + idarubicin [FLAG-IDA]). The results from the trial indicated that gilteritinib significantly improved overall survival (OS) compared to SC with 1-year survival rates of 37% vs. 17%. To inform the value of gilteritinib, this study aimed to assess the cost-effectiveness of gilteritinib for the treatment of R/R FLT3mut+ AML from a US third-party payer's perspective. Methods: A cost-effectiveness analysis (CEA) model was developed using monthly cycles and a 3% discount rate to assess the incremental cost effectiveness of gilteritinib compared to SC over a lifetime horizon. The model structure comprised a decision tree followed by two three-state partitioned survival models. The decision tree component stratified patients based on whether they received allogeneic hematopoietic stem cell transplantation (HSCT) following treatment initiation. The partitioned survival components included three health states: event-free survival (EFS), alive and post-event, and death. The selected model structure was chosen because HSCT is a key clinical event that has a significant impact on treatment outcomes for the target population. The efficacy inputs (OS and EFS) varied by HSCT status. The efficacy inputs for OS and EFS without HSCT were estimated based on the ADMIRAL trial. The efficacy inputs for OS and EFS with HSCT were assumed to be the same for both gilteritinib and SC and were based on available literature (Evers 2018). Parametric survival models or HRs were used to predict probabilities of being in different health states until year 3. Afterwards, all patients who remained alive were considered long-term survivors and their mortality risk was twice that of the general population based on literature. Treatment costs (drug, administration, and hospitalization), adverse event (AE) costs, subsequent HSCT costs, medical costs for each health state, FLT3 mutation testing, post-progression treatment, and terminal care costs were obtained from public databases and literature. For SC, the same regimen composition (i.e., LDAC, azacitidine, MEC, and FLAG-IDA) as the ADMIRAL trial was considered to estimate the treatment costs. All costs were inflated to 2018 US dollar (USD). Utilities for each health state were derived from the ADMIRAL trial and disutilities for AEs were derived from the literature. Total incremental costs, total incremental LYs, and total incremental QALYs were calculated. Incremental cost-effectiveness ratios (ICERs), defined as the incremental cost per additional gain in health effect (i.e., LY and QALY), were used to assess the economic value of gilteritinib relative to SC. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also performed to test the robustness of the base-case results. Results: Over a lifetime horizon, the base-case model estimated that treatment with gilteritinib led to an increase of 1.55 discounted LYs and an increase of 1.29 discounted QALYs at an additional cost of $141,097 relative to SC; the corresponding incremental cost per LY gained was $90,761, and incremental cost per QALY gained was $109,741. Cost-effectiveness was most sensitive to gilteritinib cost, HSCT rate, and discount rate. In the PSA, the estimated probability that gilteritinib is cost-effective was 93.5% at an acceptable willingness-to-pay threshold of $150,000/QALY. Conclusions: Gilteritinib demonstrated greater LY and QALY improvements compared with SC. With an ICER of $109,741/QALY, gilteritinib is a cost-effective strategy from a US third-party payer's perspective, based on the $150,000/QALY threshold recommended by the US Institute for Clinical and Economic Review. Compared to SC, gilteritinib represents a new active treatment option for R/R FLT3mut+ AML patients that provides better health outcomes with a favorable cost-effectiveness profile. Disclosures Zeidan: Trovagene: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ariad: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Agios: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria. Qi:Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study; Analysis Group, Inc.: Employment. Pandya:Astellas Pharmaceuticals: Employment. Garnham:Astellas: Employment. Yang:Analysis Group, Inc.: Employment; Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study. Shah:Astellas: Employment.

Emerging Mutations at Relapse in Patients with FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia Who Received Gilteritinib Therapy in the Phase 3 Admiral Trial

Smith: Revolution Medicines: Research Funding; Astellas Pharma: Research Funding; fujiFilm: Research Funding; Abbvie: Research Funding. Levis:Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Daiichi Sankyo Inc: Consultancy, Honoraria. Perl:Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; BioMed Valley Discoveries: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Bayer: Research Funding; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding. Martinelli:Daiichi Sankyo: Consultancy, Honoraria; Roche: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Janssen: Consultancy, Other: trial grant; Amgen: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Novartis: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant. Berman:Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding. Montesinos:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Abbvie: Research Funding; Astellas: Research Funding; Al Therapeutics: Research Funding; Forma: Research Funding; Incyte: Research Funding; Kite: Research Funding; Takeda: Research Funding. Larson:Celgene: Consultancy; Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials. Yokoyama:Astellas: Other: Travel expenses. Recher:Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yoon:MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Janssen: Consultancy; Genentech, Inc.: Research Funding; Amgen: Consultancy, Honoraria; Yuhan Pharma: Research Funding; Novartis: Consultancy, Honoraria. Hill:Astellas: Employment; Ligacept, LLC.: Other: Stock, Patents & Royalties. Rosales:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties.

Cost-Effectiveness Analysis of Gilteritinib Versus Best Supportive Care (BSC) for the Treatment of Relapsed or Refractory (R/R) FLT3 Mutation-Positive (FLT3mut+) Acute Myeloid Leukemia (AML)

Cost-Effectiveness Analysis of Gilteritinib Versus Best Supportive Care (BSC) for the Treatment of Relapsed or Refractory (R/R) FLT3 Mutation-Positive (FLT3mut+) Acute Myeloid Leukemia (AML)

The Relationship between Transplant Status and Patient-Reported Outcomes in Patients with FLT3-Mutated Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML): Results from the Phase 3 Admiral Study

The Relationship between Transplant Status and Patient-Reported Outcomes in Patients with FLT3-Mutated Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML): Results from the Phase 3 Admiral Study

Abstract CT184: Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial

Abstract Introduction: Gilteritinib is a potent/selective oral inhibitor of FMS-like tyrosine kinase 3 (FLT3). Based upon interim analysis response rates from the ADMIRAL Phase III study of gilteritinib vs salvage chemotherapy (SC) in patients (pts) with R/R FLT3mut+ AML (NCT02421939), gilteritinib became the first FLT3 inhibitor approved as single agent therapy in this population. Here we present the final results of this pivotal trial. Methods: Adults with confirmed FLT3mut+ AML (FLT3-ITD and/or FLT3-TKD D835 or I836 mutations) refractory to induction chemotherapy or in untreated first relapse were randomized (2:1) to receive continuous 28-day cycles of 120 mg/day gilteritinib or pre-randomization selected SC: low-dose cytarabine (LoDAC), azacitidine (AZA), mitoxantrone/etoposide/cytarabine (MEC), or fludarabine/cytarabine/granulocyte colony-stimulating factor/idarubicin (FLAG-IDA). Prior FLT3 inhibitor use, other than midostaurin or sorafenib, was excluded. Overall survival (OS) and the combined rate of complete remission/complete remission with partial hematologic recovery (CR/CRh) were co-primary endpoints. Secondary endpoints were event-free survival (EFS) and CR rate; safety/tolerability was also examined. Results: A total of 371 pts were randomized: 247 to gilteritinib and 124 to SC (MEC, 25.7%; FLAG-IDA, 36.7%; LoDAC, 14.7%; AZA, 22.9%). Median age was 62 years (range, 19-85). Baseline FLT3 mutations were: FLT3-ITD, 88.4%; FLT3-TKD, 8.4%; both FLT3-ITD and FLT3-TKD, 1.9%; unconfirmed, 1.3%. Overall, 39.4% of pts had refractory AML and 60.6% had relapsed AML. Patients randomized to gilteritinib had significantly longer OS (9.3 months) than SC (5.6 months; hazard ratio [HR] for death = 0.637; P=0.0007); 1-year survival rates were 37.1% and 16.7%, respectively. The CR/CRh rates for gilteritinib and SC were 34.0% and 15.3%, respectively (P=0.0001); CR rates were 21.1% and 10.5% (2-sided P=0.0106). Median EFS was 2.8 months and 0.7 months in the gilteritinib and SC arms, respectively (HR 0.793, P=0.0830). Common adverse events (AEs) in all randomized pts were febrile neutropenia (43.7%), anemia (43.4%), and pyrexia (38.6%). Common grade ≥3 AEs related to gilteritinib were anemia (19.5%), febrile neutropenia (15.4%), thrombocytopenia (12.2%), and decreased platelet count (12.2%). Adjusted for exposure duration, serious treatment-emergent AEs per patient year were less common with gilteritinib (7.1%) than SC (9.2%). Conclusions: In patients with R/R FLT3mut+ AML, the potent, selective FLT3 inhibitor gilteritinib resulted in significantly longer OS and higher response rates compared with chemotherapy and had a favorable safety profile. These results change the treatment paradigm for salvage therapy of R/R FLT3mut+ AML and establish gilteritinib as the new standard of care. Citation Format: Alexander E. Perl, Giovanni Martinelli, Jorge E. Cortes, Andreas Neubauer, Ellin Berman, Stefania Paolini, Pau Montesinos, Maria R. Baer, Richard A. Larson, Celalettin Ustun, Francesco Fabbiano, Antonio Di Stasi, Robert Stuart, Rebecca Olin, Margaret Kasner, Fabio Ciceri, Wen-Chien Chou, Nikolai Podoltsev, Christian Recher, Hisayuki Yokoyama, Naoko Hosono, Sung-Soo Yoon, Je-Hwan Lee, Timothy Pardee, Amir T. Fathi, Chaofeng Liu, Xuan Liu, Erkut Bahceci, Mark J. Levis. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT184.