ADMIRAL Trial Research Articles

PF251 GILTERITINIB PROLONGS SURVIVAL IN PATIENTS WITH FLT3‐MUTATED RELAPSED/REFRACTORY AML WHO HAVE COMMON AML CO‐MUTATIONS OR A HIGH FLT3‐ITD ALLELIC RATIO

Background:Treatment with the FLT3 inhibitor, gilteritinib, resulted in superior response rates and overall survival compared with salvage chemotherapy in patients with FLT3‐mutated (FLT3 mut+) relapsed/refractory AML in the phase 3 ADMIRAL study.Aims:We analyzed the impact of baseline co‐mutations and baseline FLT3‐internal tandem duplication (ITD) allelic ratio on achievement of complete remission/complete remission with partial hematologic recovery (CR/CRh) and overall survival.Methods:A total of 37 recurrently mutated genes in AML (Archer Core Myeloid Panel) were analyzed by next‐generation sequencing; the cutoff for co‐mutation positivity (co‐mut+) was ≥0.027. Baseline FLT3‐ITD allelic ratio (FLT3‐ITD to FLT3 wild‐type DNA) was measured by the LeukoStrat® CDx FLT3 Mutation Assay. The median FLT3‐ITD allelic ratio value of 0.77 was used to define high (≥0.77) vs low (<0.77) FLT3‐ITD allelic ratio.Results:An analysis of 361 FLT3 mut+ patients identified four major co‐mutation cohorts, each with ≥10% of the patients: NPM1 (n = 173; 47.9%), DNMT3A (n = 115; 31.9%), DNMT3A/NPM1 (n = 86; 23.8%), and WT1 (n = 65; 18.0%). In addition, seven patients (1.9%) had all three co‐mutations (ie, NPM1, DNMT3A, and WT1). The gilteritinib arm had superior CR/CRh rates and overall survival across all four major co‐mutation cohorts, with the greatest survival benefit in patients with DNMT3A/NPM1 co‐mut+ (Table). In FLT3‐ITD allelic ratio analyses (n = 335), gilteritinib conferred longer overall survival than salvage chemotherapy in patients with a high or low FLT3‐ITD allelic ratio (gilteritinib: high FLT3‐ITD allelic ratio, 7.1 months vs low FLT3‐ITD allelic ratio, 10.6 months; salvage chemotherapy: high FLT3‐ITD allelic ratio, 4.3 months vs low FLT3‐ITD allelic ratio, 6.9 months). In both arms, overall survival was longer in the low FLT3‐ITD allelic ratio cohort than in the high FLT3‐ITD allelic ratio cohort, but the difference in the gilteritinib arm was not statistically significant (gilteritinib: hazard ratio = 1.341, P = 0.0712; salvage chemotherapy: hazard ratio = 2.01, P = 0.0021).Summary/Conclusion:The ADMIRAL trial shows that the clinical benefit of gilteritinib in FLT3 mut+ relapsed/refractory AML is maintained regardless of NPM1, DNMT3A, DNMT3A/NPM1, or WT1 co‐mut+ or high FLT3‐ITD allelic ratio.image

Effect of gilteritinib on survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) AML who have common AML co-mutations or a high FLT3-ITD allelic ratio.

7000 Background: The FLT3 inhibitor, gilteritinib, showed superior response and overall survival (OS) compared with salvage chemotherapy (SC) in patients (pts) with FLT3mut+ R/R AML in the phase 3 ADMIRAL study. We analyzed the impact of baseline co-mutations and FLT3-ITD allelic ratio (AR) on response and OS. Methods: A total of 37 recurrently mutated genes in AML (Archer Core Myeloid Panel) were analyzed by next-generation sequencing; the cutoff for co-mutation positivity (co-mut+) was ≥0.027. Baseline FLT3-ITD AR ( FLT3-ITD to FLT3 wild-type DNA) was measured by the LeukoStrat CDx FLT3 Mutation Assay. The median FLT3-ITD AR value of 0.77 was used to define high (≥0.77) vs low (<0.77) FLT3-ITD AR. Results: Analysis of 361 FLT3mut+ pts identified four major co-mutation cohorts, each with ≥10% of pts: NPM1 (n=173; 47.9%), DNMT3A (n=115; 31.9%), DNMT3A/NPM1 (n=86; 23.8%) , and WT1 (n=65; 18.0%). In addition, seven pts (1.9%) had all three co-mutations (ie, NPM1, DNMT3A, and WT1). The gilteritinib arm had superior response rates and OS across all four major co-mutation cohorts, with the greatest survival benefit in pts with DNMT3A/NPM1 co-mut+ (Table). In FLT3-ITD AR analyses (n=335), gilteritinib conferred longer OS than SC in pts with a high or low FLT3-ITD AR (gilteritinib: high FLT3-ITD AR, 7.1 mos vs low FLT3-ITD AR, 10.6 mos; SC: high FLT3-ITD AR, 4.3 mos vs low FLT3-ITD AR, 6.9 mos). In both arms, OS was longer in the low FLT3-ITD AR cohort than the high FLT3-ITD AR cohort but the difference in the gilteritinib arm was not statistically significant (gilteritinib: HR=1.341, P=0.0712; SC: HR=2.01, P=0.0021). Conclusions: The ADMIRAL trial shows that the clinical benefit of gilteritinib in FLT3mut+ R/R AML is maintained regardless of NPM1, DNMT3A, DNMT3A/ NPM1, or WT1 co-mut+ or high FLT3-ITD AR. Clinical trial information: NCT02421939. [Table: see text]

ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutation: background and design of the ADMIRAL trial.

Acute myeloid leukemia (AML) is a heterogeneous disease with cure rates of only 30-40% in patients <60years old. Cytogenetic and molecular markers have improved our understanding of the different prognostic entities in AML. FLT3 mutations are present in 30-40% of AML cases, conferring a poor prognosis with reduced survival. AXL activates FLT3, impacting adversely on outcome. Both FLT3 and AXL constitute promising molecular targets. ASP2215 (gilteritinib) is a novel, dual FLT3/AXL inhibitor with promising early phase trial data (NCT02014558). A Phase III randomized multicenter clinical trial, comparing ASP2215 to salvage chemotherapy in relapsed/refractory AML with FLT3-mutations is now open to recruitment (NCT02421939). Trial design and objectives are discussed here.

Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions

We performed a cumulative meta-analysis of available studies to evaluate the effect of intravenous platelet glycoprotein (GP) IIb/IIIa antagonists on survival at 30 days and 6 months after percutaneous coronary intervention (PCI). Compounds that block the GP IIb/IIIa receptor substantially reduce myocardial infarctions (MIs) and repeat revascularization. We included 12 trials, which enrolled 20,186 patients in all, in the analysis. Overall, 30-day mortality was significantly reduced with GP IIb/IIIa inhibition (odds ratio 0.73, 95% confidence interval 0.55 to 0.96, p = 0.024). Although 10 of the 12 trials showed a beneficial effect of GP IIb/IIIa inhibitor treatment on mortality, no individual trial detected a statistically significant mortality benefit. The 30-day mortality benefit became significant at the p <0.05 level with addition of the ADMIRAL trial and was further enhanced by the CADILLAC trial. No significant heterogeneity was detected in the collection of trials. At 6 months, the odds ratio was 0.84 (95% confidence interval 0.69 to 1.03, p = 0.087). This survival benefit amounts to preventing ∼1 of every 3 deaths that occur within 30 days after PCI, saving 2.8 lives/1,000 patients treated (number needed to treat, 357). Thus, patients who undergo PCI can expect significantly lower 30-day mortality, in addition to known reductions in nonfatal MI and repeat procedures, with GP IIb/IIa inhibition. There also is increasing evidence that mortality reductions are preserved at 6 months.

Primary stenting with abciximab in acute myocardial infarction complicated by cardiogenic shock (the ADMIRAL trial)

Primary stenting with abciximab in acute myocardial infarction complicated by cardiogenic shock (the ADMIRAL trial)

Defining the optimal pharmacotherapy of non-ST-segment elevation (NSTE) acute coronary syndromes (ACS): a rapidly moving target.

Acute coronary syndromes (ACS) represent a spectrum of disease, including unstable angina, non ST-elevation myocardial infarction, and ST-elevation myocardial infarction. In patients with cardiovascular disease, ACS represents the most common diagnosis for hospital admission, accounting for nearly 1.5 million hospital admissions in 1999. Similarly, although improvements in medical therapy have resulted in a dramatic decline in mortality from acute myocardial infarction (MI) over the last four decades, MI remains the most common cause of in-hospital death in industrialized nations. The approach to managing patients with acute coronary syndromes has evolved dramatically over the past decade and, in many respects, represents a rapidly moving target in light of recent advances in pharmacotherapy and catheter-based revascularization. A number of recently-published studies, including the TACTICS Trial, the ADMIRAL Trial, and the TARGET Trial, provide novel information about the relative merits of pharmacologic therapy and invasive intervention, A common theme from these studies is that there is a growing consensus among cardiologists that combination therapy with these two modalities may actually provide the best clinical outcomes in ACS patients.