May 29, 2019–Gilteritinib (XOSPATA, Astellas Pharma US, Inc.), indicated for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test.
November 28, 2018–Gilteritinib (XOSPATA, Astellas Pharma US Inc.) for treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test. (With Pharmacist's Applications to Practice)
May 29, 2019
On May 29, 2019, the Food and Drug Administration approved the addition of overall survival data in labeling for gilteritinib (XOSPATA, Astellas Pharma US, Inc.), indicated for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test.
Approval was based on the ADMIRAL trial (NCT02421939), which included 371 adult patients with relapsed or refractory AML having a FLT3 ITD, D835, or I836 mutation by the LeukoStrat® CDx FLT3 Mutation Assay. Patients were randomized (2:1) to receive XOSPATA 120 mg once daily (n=247) over continuous 28-day cycles or prespecified salvage chemotherapy (n=124). Salvage chemotherapy included either intensive cytotoxic chemotherapy or a low-intensity regimen.
For the analysis, overall survival (OS) was measured from the randomization date until death by any cause. The median OS was 9.3 months for patients receiving gilteritinib and 5.6 months for those on the chemotherapy arm (HR 0.64; 95% CI: 0.49,0.83; 1 sided p-value=0.0004). The results were consistent in the intensive chemotherapy stratum (HR 0.66; 95% CI: 0.47-0.93) and the low-intensity regimen stratum (HR 0.56; 95% CI: 0.38-0.84).
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. Prescribing information contains a Boxed Warning alerting health care professionals and patients about the risk of differentiation syndrome, which may be life-threatening or fatal if not treated.
The recommended gilteritinib dose is 120 mg orally once daily.
This application used the Real-Time Oncology Review and Assessment Aid pilot programs. FDA granted this application priority review and fast track designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by calling 1-800-FDA-1088.
November 28, 2018, with PAP
On November 28, 2018, the Food and Drug Administration approved gilteritinib (XOSPATA, Astellas Pharma US Inc.) for treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test.
The FDA also approved an expanded indication for a companion diagnostic, to include use with gilteritinib. The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, Inc., is used to detect the FLT3 mutation in patients with AML.
Approval of gilteritinib was based on an interim analysis of the ADMIRAL trial (NCT02421939), which included 138 adult patients with relapsed or refractory AML having a FLT3 ITD, D835, or I836 mutation by the LeukoStrat CDx FLT3 Mutation Assay. Gilteritinib was given orally at a dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit. After a median follow-up of 4.6 months (range: 2.8 to 15.8), 29 patients achieved complete remission (CR) or CR with partial hematologic recovery (CRh) (21%, 95% CI: 14.5, 28.8).
Among the 106 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 33 (31.1%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. For the 32 patients who were independent of both RBC and platelet transfusions at baseline, 17 (53.1%) remained transfusion-independent during any 56-day post-baseline period.
The most common adverse reactions occurring in ≥ 20% of patients were myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness and vomiting.
The recommended gilteritinib dose is 120 mg orally once daily.
FDA granted this application priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Pharmacist’s Applications to Practice
Gilteritinib for the Treatment of Patients with FMS-Like Tyrosine Kinase 3 Mutation–Positive Relapsed or Refractory Acute Myeloid Leukemia
Author: Jeff Engle, PharmD MS
Hematology/Oncology Clinical Pharmacist
University of Minnesota Masonic Cancer Clinic
Fairview Specialty Pharmacy
What is the potential role for gilteritinib in the treatment of relapsed or refractory acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutation?
- FLT3 mutations occurring in the internal tandem domain (ITD) or tyrosine kinase domain (TKD) are found in approximately 30% of patients with AML and are associated with poor prognosis.1,2
- Gilteritinib exhibits its antileukemic affect by targeting common FLT3 ITD and TKD mutations, including known mechanisms of resistance of other FLT3 inhibitors.3
- Approval by the U.S. Food and Drug Administration (FDA) was based on the phase 3 randomized multicenter ADMIRAL trial comparing gilteritinib to salvage chemotherapy.4-6
- Study population: 371 adult patients with relapsed or refractory AML and an FLT3 ITD, D835, or I836 mutation
- 247 patients received gilteritinib, and 124 received salvage chemotherapy.
- Gilteritinib 120 mg daily
- Investigator’s choice: low-dose cytarabine, azacitidine, mitoxantrone, etoposide, and cytarabine; or fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor
- Coprimary endpoints: overall survival (OS) and the combined rate of complete remission (CR) and complete remission with partial hematologic (CRh) recovery
- Efficacy results
- OS: 9.7 months for gilteritinib and 5.6 months for salvage chemotherapy (hazard ratio [HR]: 0.637; p = .0007)
- CR/CRh rates: 34% for gilteritinib and 15.3% for salvage chemotherapy (p = .0001)
- 1-year survival rate: 37.1% for gilteritinib and 16.7% for salvage chemotherapy
- Safety results
- Most common adverse events (any grade): myalgia or arthralgia (42%), transaminase increased (41%), fatigue or malaise (40%), fever (35%), noninfectious diarrhea (34%), dyspnea (34%), edema (34%), rash (30%), pneumonia (30%), nausea (27%), stomatitis (26%), cough (25%), headache (21%), hypotension (21%), dizziness (20%), and vomiting (20%).
- Most common adverse effects, grade 3 or higher: febrile neutropenia (15.4%), thrombocytopenia (12.2%)
- National Comprehensive Cancer Network lists gilteritinib as a category-2A recommendation for patients with relapsed or refractory AML with FLT3 mutation. Sorafenib with a hypomethylating agent is an option for these patients as well, on the basis of clinical trials.7-9 With a manageable side-effect profile, high CR/CRh rate, improved OS, and ability to target common resistance pathways to earlier-generation FLT3 tyrosine kinase inhibitors, gilteritinib may become the preferred treatment for patients with FLT3-positive relapsed or refractory AML.
What role can the pharmacist play in the management of patients on gilteritinib?
- Pharmacists can ensure that appropriate laboratory and clinical monitoring is done upon initiation of gilteritinib, including these:5
- Complete blood counts: baseline, weekly for the first month, every other week for the second month, and monthly thereafter
- Comprehensive metabolic panel with creatinine phosphokinase: baseline, weekly for the first month, every other week for the second month, and monthly thereafter
- Electrocardiogram (ECG): baseline, days 8 and 15 of cycle 1, and prior to the start of cycles 2 and 3
- Pharmacists can ensure that appropriate dose modifications are made for gilteritinib-related toxicities, including these:5
- QTc interval increase by >30 msec at day 8 of cycle 1: Confirm reading with ECG on day 9 and, if confirmed, consider dose reduction to 80 mg.
- QTc interval > 500 msec: Withhold gilteritinib, and when QTc interval returns to within 30 msec of baseline or ≤ 480 msec, resume at 80 mg.
- Pancreatitis: Withhold gilteritinib until pancreatitis is resolved and resume at 80 mg.
- Posterior reversible encephalopathy syndrome: Discontinue gilteritinib.
- Grade 3 or higher treatment-related toxicity: Withhold gilteritinib until toxicity is resolved and resume at 80 mg.
- Gilteritinib is metabolized through CYP3A4 and is an inhibitor of 5HT2B receptors. Pharmacists can screen for drug-drug interactions and recommend against concomitant use of CYP3A4 inhibitors or inducers and drugs that target 5HT2B receptors (e.g., escitalopram, fluoxetine, sertraline).5
- Currently, gilteritinib is approved for the treatment of patients with FLT3-mutated AML following relapse or AML that is refractory to standard chemotherapy. Gilteritinib showed improved survival in patients who received either intensive salvage chemotherapy or less intensive salvage chemotherapy. The main limitation of the study is that, during enrollment, the standard of care changed for patients with FLT3-mutated AML: administration of midostaurin, another FLT3 inhibitor, is now standard of care to combine with 7+3 for induction chemotherapy candidates. Accordingly, a small minority of patients had previously received FLT3 inhibitors in the ADMIRAL trial. Patients who relapse after, or are refractory to, intensive chemotherapy with midostaurin may have disease that is less dependent on FLT3 signaling and thus less sensitive to FLT3 inhibition.6 Gilteritinib also targets common FLT3 resistance mutations, so testing for FLT3 ITD, D835, or I836 mutations at the time of disease progression on previous FLT3-targeted therapy is warranted.
- Clinical trials are ongoing to determine the efficacy of gilteritinib in other AML treatment settings, including in combination with standard intensive chemotherapy for newly diagnosed patients, in combination with hypomethylating agents for older patients with newly diagnosed disease, and in combination with chemotherapy, immunotherapy, or venetoclax for relapsed or refractory disease.10
- Administer gilteritinib with or without food. It should be administered for a minimum of 6 months to allow adequate time for a clinical response.5
- Gilteritinib should be stored at room temperature and handled as hazardous waste.5
- A copay assistance card is available with gilteritinib, and a free medication program for qualifying patients is offered through the manufacturer (Astellas Pharma Support Solutions).11
- Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93(9):3074-3080.
- Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 2010;116(24):5089-5102.
- Lee LY, Hernandez D, Rajkhowa T, et al. Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood. 2017;129(2):257-260.
- Gorcea CM, Burthem J, Tholouli E. ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutations: background and design of the ADMIRAL trial. Future Oncol. 2018;14(20):1995-2004.
- Xospata (gilteritinib) [package insert]. Northbrook, IL: Astellas Pharma Inc.; 2018.
- Perl AE, Martinelli G, Cortes JE, et al. 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. American Association for Cancer Research Annual Meeting, April 2, 2019. Abstract CT184.
- National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2019). https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed May 20, 2019.
- Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655-4662.
- Muppidi MR, Portwood S, Griffiths EA, et al. Decitabine and sorafenib therapy in FLT-3 ITD-mutant acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2015;15 Suppl: S73-79.
- U.S. National Library of Medicine. ClinicalTrials.gov. Gilteritinib ongoing clinical trials in acute myeloid leukemia. Available at https://clinicaltrials.gov/ct2/results?cond=Acute+Myeloid+Leukemia&term=gilteritinib&cntry=&state=&city=&dist=. Accessed May 30, 2019.
- Astellas Pharma Support Solutions. Available at https://www.astellaspharmasupportsolutions.com/products/xospata/patient_assistance/index.aspx. Accessed May 30, 2019.