The FDA recently approved gilteritinib based on the ADMIRAL clinical trial comparing gilteritinib (Xospata) to salvage chemotherapy in adult patients with relapsed or refractory (resistant to treatment) acute myeloid leukemia (AML) with an FLT3 mutation. As a tyrosine kinase inhibitor, gilteritinib inhibits the signal transduction cascade of many proteins and thereby blocks phosphorylation pathways, which ultimately starves the cancerous cells of energy to proliferate.

Patients were randomized (2:1) where the treatment group (gilteritinib) received 120 mg by mouth daily for a continuous 28-day cycle or prespecified salvage chemotherapy, which included either intensive cytotoxic chemotherapy or a low-intensity regimen. The main endpoint of this study was overall survival, which was 9.3 months in gilteritinib compared with 5.6 months for patients receiving salvage chemotherapy with a hazard ratio of 0.64 (95% CI, 0.490, 0.830), P = .0004.

The phase III ADMIRAL trial was an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in adult patients with FLT3 mutations who are refractory or relapsed after first-line AML therapy. The primary trial endpoint was overall survival. The study enrolled 371 patients with relapsed or refractory AML and positive for FLT3 mutations present in bone marrow or whole blood. Subjects were randomized in a 2:1 ratio (n = 247) to gilteritinib 120 mg PO and (n = 124) to get salvage chemotherapy.

Overall survival was defined as the time from randomization to death from any cause. The median overall survival was 9.3 months for patients receiving gilteritinib and 5.6 months for those on salvage chemotherapy (HR 0.64; 95% CI, 0.49-0.83; 1-sided P = .0004). These results were comparable to the intensive chemotherapy strata (HR 0.66; 95% CI, 047-0.93) and the low-intensity regimen strata (HR 0.56; 95% CI, 0.38-0.84). One-year survival rates were 37% for patients who received gilteritinib compared with 17% for patients who received salvage chemotherapy.

Overall, 8% of all patients discontinued gilteritinib treatment permanently due to an adverse reaction. The most common adverse reactions leading to discontinuation were pneumonia, sepsis, and dyspnea. Drug interactions were expected or experienced with P-glycoprotein and strong CYP3A inducers, which decreases the efficacy of gilteritinib when used concomitantly. Strong CYP3A inhibitors increase gilteritinib’s toxicity and amplify its side effects. Use with selective serotonin reuptake inhibitors also reduces the effectiveness of those medications, so it is essential to avoid using them together.

The adverse reactions occurring in at least 20% of patients receiving gilteritinib were increased transaminase, myalgia, arthralgia, fatigue, malaise, fever, mucositis, edema, rash, noninfectious diarrhea, dyspnea, nausea, cough, constipation, eye disorders, headache, dizziness, hypotension, vomiting, and renal impairment, and anemia was the most common treatment-emergent adverse event.

Given the fact that AML has poor prognosis, the FDA granted this application priority review and fast-track designation, and the drug increases overall survival compared with salvage chemotherapy. The findings of the ADMIRAL trial changed the treatment paradigm for patients with AML with FLT3 mutations. Other warnings and precautions are posterior reversible encephalopathy syndrome, prolonged QT interval (>500 msec), pancreatitis, and embryo-fetal toxicity (contraceptives are strongly recommended in females of reproductive age).

The ADMIRAL trial demonstrated that the use of gilteritinib as monotherapy significantly increased overall survival (9.3 months vs. 5.6 months) compared with salvage chemotherapy in adult patients with refractory or relapsed AML with FLT3 mutations.

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