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The 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.

Additional file 1. Supplementary Material.

Additional file 1. Prevention, recognition, and management of adverse events associated with gemtuzumab ozogamicin use in acute myeloid leukemia.

These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Acute Myeloid Leukemia and discuss the clinical evidence that support the recommendations. The updates described in this article focus on the acute promyelocytic leukemia (APL) section, featuring recommendations for additional induction/consolidation regimens in patients with low- or intermediate-risk APL, and providing guidance on maintenance strategies for APL.

Background Marrow angiogenesis plays an important role in the pathogenesis of acute myeloid leukemia (AML). Among the most prominent pro-angiogenic factors produced by AML cells are the angiopoietins (Ang-1/2), ligands of the Tie2 endothelial cell receptor. Elevated expression of Ang-2 is an independent prognostic factor for overall survival in AML. Trebananib (AMG 386) is a first-in-class neutralizing peptibody that provides potent and selective inhibition of angiopoietins by sequestering Ang1 and Ang2 and preventing their interaction with the Tie2 receptor. Purpose Here we evaluated the safety, tolerability, pharmacokinetic profile, and biologic effects of trebananib in de novo and relapsed/refractory AML patients considered to be poor candidates for standard induction chemotherapy. Methods Thirteen AML patients were enrolled in single agent arm A of this open-label, non-randomized phase Ib trial. ([ClinicalTrials.gov][1] ID: [NCT01555268][2], NCI-2011-02979). Drug was administered at two dose levels (15 and 30 mg/kg) via weekly intravenous infusion over 1 hour. Circulating angiogenic factor levels (Ang-2, VEGF-A/C/D, HGF, IL-8, FGF-1/2, G-CSF, PlGF) in the plasma were measured by multiplex flow cytometry prior to first dose, on cycle 1 day 29 (following 4 weekly doses of trebananib), and at the end of study. Results Median age was 76 years (range 53-82). Nine patients were male (69%). Two patients had de novo, 7 had refractory, and 4 had relapsed AML. One patient had undergone prior allogeneic stem cell transplantation. Aside from one possibly drug-related incident of grade 3 mucositis on the 15 mg/kg cohort, no other dose-limiting toxicities were reported. The most common toxicities were abdominal bloating, diarrhea, edema, and weight gain. Preliminary pharmacokinetic analysis of trebananib was dose-proportional. At the 15 and 30 mg/kg dose levels, median Cmaxand AUC on Day 1 were 193 and 473 ug/mL and 11,670 and 35,217 ug-hr/mL, respectively. No neutralizing antibodies to trebananib were detected. Among seven AML patients with consecutive plasma samples, therapy was associated with marked elevations of Ang-2 levels (from 15 to 336-fold higher than baseline) after 1-4 weeks of therapy (Table 1). Induction of Ang-2 did not differ significantly between the 15 mg/kg and 30 mg/kg cohorts. Ang-2 levels measured in bone marrow or plasma samples at the same time point were comparable. In contrast, levels of other angiogenic growth factors (VEGF-A/C/D, IL-8, G-CSF, HGF, FGF-1/2, PlGF) were not consistently altered by trebananib therapy. One AML patient (on the 15 mg/kg cohort) had a partial response with >50% decrease in marrow blasts. Two patients (15 mg/kg, 30 mg/kg) had stable disease over >1 cycle. Conclusions We report here the preliminary results of phase 1b study evaluating the safety, tolerability, pharmacokinetic profile, and biologic effects of trebananib in adult AML patients. Weekly infusions of trebananib administered at 15 and 30 mg/kg were well tolerated. Drug pharmacokinetics were similar to those previously reported in solid tumor patients. Trebananib resulted in substantial elevations in measurable circulating and marrow Ang-2 levels in AML patients, presumably due to a negative compensatory feedback loop resulting from potent in vivo Ang-1/2 inhibition. Arm B of this study (trebananib plus low dose cytarabine) is currently accruing. Further in depth studies examining the biological effects of trebananib on marrow angiogenesis and clinical response in AML patients are ongoing. Disclosures: Becker: Millenium: Research Funding. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01555268&atom=%2Fbloodjournal%2F122%2F21%2F2701.atom

Summary Background Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. Methods In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations ( FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Findings Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Interpretation Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Funding Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.