Summary of our recommendations for gilteritinib administration
| Issue . | Management . |
|---|---|
| Target drug dose | Gilteritinib: 120 mg orally once daily with or without food The estimated half-life of gilteritinib is 113 h |
| Optimize dosing | P-gp and strong CYP3A inducers may decrease gilteritinib exposure Strong CYP3A inhibitors may increase gilteritinib exposure (Cmax increased ∼20% and AUC increased ∼120%) but gilteritinib dose adjustment is not required Gilteritinib may reduce the effects of drugs that target the 5HT2B receptor or the σ nonspecific receptor (eg, escitalopram, fluoxetine, sertraline) |
| Monitoring and management of DS | Patients treated with gilteritinib may develop differentiation syndrome, which can be fatal or life-threatening if not treated Of 319 patients, 3% experienced DS, which occurred as early as 2 days and up to 75 days after gilteritinib initiation and has been observed with or without concomitant leukocytosis; full blood count and biochemical monitoring is recommended 1-2× weekly for at least the first month of therapy If DS is suspected, initiate dexamethasone 10 mg postoperatively/IV every 12 h and taper after a minimum of 3 days if resolution of symptoms; DS may recur with premature discontinuation of corticosteroid treatment; if severe signs and/or symptoms persist for >48 h after initiation of corticosteroids, interrupt gilteritinib until signs and symptoms improve |
| Hepatic impairment | If ALT and/or AST >5× ULN (or >3× ULN with elevation of total bilirubin), interrupt gilteritinib until improvement to grade ≤1; restart gilteritinib at 80 mg daily |
| Pancreatitis | Lipase elevation reported in 4% Interrupt gilteritinib until pancreatitis is resolved; resume gilteritinib at 80 mg |
| PRES | 1% experienced PRES63 with symptoms including seizure and altered mental status; symptoms have resolved after discontinuation of gilteritinib Discontinue gilteritinib in patients who develop PRES |
| Monitoring for prolonged QT syndrome | 7% have an increase from baseline QTc >60 ms; prolonged interval >500 ms is rare (1%); if QTcF >500 ms, interrupt gilteritinib and resume at 80 mg when QTc interval returns to ≤480 ms; substitute QT prolonging with non-QT prolonging coadministered drugs if possible |
| Patients with renal impairment | Mild or moderate renal impairment does not affect gilteritinib |
| When to cease therapy? | Median time to first response was 1.8 mo and 3.6 mo to CR As response may be delayed, in the absence of disease progression or unacceptable toxicity, treatment of a minimum of 6 mo is recommended to allow time for a clinical response |
| Assessment for drug resistance mutations at disease progression | Mutations in the RAS/MAPK signaling pathway (N/KRAS, PTPN11), FLT3-F691L gatekeeper mutations or BCR-ABL1 fusions35 |
| Issue . | Management . |
|---|---|
| Target drug dose | Gilteritinib: 120 mg orally once daily with or without food The estimated half-life of gilteritinib is 113 h |
| Optimize dosing | P-gp and strong CYP3A inducers may decrease gilteritinib exposure Strong CYP3A inhibitors may increase gilteritinib exposure (Cmax increased ∼20% and AUC increased ∼120%) but gilteritinib dose adjustment is not required Gilteritinib may reduce the effects of drugs that target the 5HT2B receptor or the σ nonspecific receptor (eg, escitalopram, fluoxetine, sertraline) |
| Monitoring and management of DS | Patients treated with gilteritinib may develop differentiation syndrome, which can be fatal or life-threatening if not treated Of 319 patients, 3% experienced DS, which occurred as early as 2 days and up to 75 days after gilteritinib initiation and has been observed with or without concomitant leukocytosis; full blood count and biochemical monitoring is recommended 1-2× weekly for at least the first month of therapy If DS is suspected, initiate dexamethasone 10 mg postoperatively/IV every 12 h and taper after a minimum of 3 days if resolution of symptoms; DS may recur with premature discontinuation of corticosteroid treatment; if severe signs and/or symptoms persist for >48 h after initiation of corticosteroids, interrupt gilteritinib until signs and symptoms improve |
| Hepatic impairment | If ALT and/or AST >5× ULN (or >3× ULN with elevation of total bilirubin), interrupt gilteritinib until improvement to grade ≤1; restart gilteritinib at 80 mg daily |
| Pancreatitis | Lipase elevation reported in 4% Interrupt gilteritinib until pancreatitis is resolved; resume gilteritinib at 80 mg |
| PRES | 1% experienced PRES63 with symptoms including seizure and altered mental status; symptoms have resolved after discontinuation of gilteritinib Discontinue gilteritinib in patients who develop PRES |
| Monitoring for prolonged QT syndrome | 7% have an increase from baseline QTc >60 ms; prolonged interval >500 ms is rare (1%); if QTcF >500 ms, interrupt gilteritinib and resume at 80 mg when QTc interval returns to ≤480 ms; substitute QT prolonging with non-QT prolonging coadministered drugs if possible |
| Patients with renal impairment | Mild or moderate renal impairment does not affect gilteritinib |
| When to cease therapy? | Median time to first response was 1.8 mo and 3.6 mo to CR As response may be delayed, in the absence of disease progression or unacceptable toxicity, treatment of a minimum of 6 mo is recommended to allow time for a clinical response |
| Assessment for drug resistance mutations at disease progression | Mutations in the RAS/MAPK signaling pathway (N/KRAS, PTPN11), FLT3-F691L gatekeeper mutations or BCR-ABL1 fusions35 |
AUC, area under the curve; Cmax, maximum or peak concentration; DS, differentiation syndrome; P-gp, P-glycoprotein; PRES, posterior reversible encephalopathy syndrome.