Safety of FLT3 inhibitors in patients with acute myeloid leukemia

Figures & data

Figure 1. Specificity of inhibition of different classes of protein with kinase activity by type II and type I inhibitors. The octagon plots the TK’s classes. In each TK class, for every TKI, we drew a peak from the center; the peak represents the number of TKs in the class that are inhibited by a specific TKI. The figures composed of joining the peaks are representative of the spectrum of inhibition of each TKI. Larger figures mean wider TK inhibition; TK: tyrosine-kinase family, include FLT3; TKL tyrosine-kinase like family; STE: Serine/Threonine protein kinase family; casein kinase 1 family; AGC: protein kinase A, G, and C family; CAMK: Ca2+/calmodulin-dependent protein kinase family; CMGC: CDKs, GSKs, MAP kinases, and CDK-like kinases family. Reproduced with permission from Marconi G, et al. The safety profile of FLT3 inhibitors in the treatment of newly diagnosed or relapse/refractory acute myeloid leukemia. Expert opinion on drug safety. April 21. 10.1080/14740338.2021.1913120. [99].

Table 1. Characteristics of FLT3 inhibitors in clinical development

FLT3 INHIBITOR	TYPE OF INHIBITOR	NON-FLT3 TARGETS	FLT3-TKD MUTATION ACTIVITY	DOSE	METABOLIC PATHWAY	MAJOR TOXICITIES
Midostaurin	First generation. Type I	c-KIT, PKC, PDGFR, VEGFR	Yes	50 mg b.i.d.	Liver: CYP3A4	Gastrointestinal, myelosuppression
Sorafenib	First generation.Type II	c-KIT, PDGFR, RET, VEGFR	No	400 mg b.i.d.	Liver: CYP3A4 as well as UGT1A9	Rash, hemorrhage, myelosuppression
Gilteritinib	Second generation.Type I	AXL, EML4-ALK	Yes	120 mg daily	Liver: CYP3A4	Elevated transaminases, diarrhea
Quizartinib	Second generation.Type II	c-KIT, PDGFR, RET	No	30–60 mg q.o.d	Liver: CYP3A4	QTc prolongation, myelosuppression
Crenolanib	Second generation.Type I	PDGFR, c-KIT	Yes	100 mg t.i.d.	Cytochrome P450	Gastrointestinal

Legend: PDGFR, platelet-derived growth factor receptor; tid, three times daily; TKD, tyrosine kinase domain; VEGFR, vascular endothelial growth factor receptor.

Table 2. Management according to renal, hepatic and cardiac comorbidity of the different FLT3 inhibitors

FLT3 INHIBITOR	RENAL FAILURE	LIVER FAILURE	CARDIAC DYSFUNCTION
Midostaurin	- Mild or moderate: no dose adjustment. - Severe: no experience	- Child-Pugh A or B: no dosage adjustment – Child-Pugh C: no experience	- QTc interval > 500 ms: suspend - QTc interval 470–500 ms: reduce to 50 mg q.o.d
Sorafenib	- Mild, moderate or severe: no dose adjustment. - No data in dialysis patients	- Child-Pugh A or B: no dosage adjustment – Child-Pugh C: no experience	Periodic monitoring of ECG and electrolytes (magnesium, potassium, calcium) in patients at risk of developing QT interval prolongation
Gilteritinib	- Mild or moderate: no dose adjustment. - Severe: no experience	- Child-Pugh A or B: no dosage adjustment – Child-Pugh C: no experience	QTc interval >500 ms: Interrupt; when QTc interval returns to within 30 msec of baseline or ≤480 ms, resume therapy at a reduced dose of 80 mg q.o.d. QTc interval increased by >30 ms on ECG on day 8 of cycle 1: Confirm on day 9. If confirmed, consider dose reduction to 80 mg q.o.d.
Quizartinib	No data in patients with glomerular filtration rate lower than 25 ml/min	No data in patients with Child-Pugh B or C	QT interval prolongation: consider drug reduction
Crenolanib	No data	No data	No data

Table 3. Recommendation for dose adjustment of each FLT3 inhibitor based on co administration with other drugs with metabolism by PYP3A4

	MIDOSTAURIN	SORAFENIB	GILTERITINIB	QUIZARTINIB	CRENOLANIB
Rifampicin (strongCYP3A4 inducer)	Avoid concurrent use	Avoid concurrent use	Avoid concurrent use	Avoidconcurrent use	No data available. Use with caution (crenolanib is metabolized by CYP450).
Fluconazole (moderateCYP3A4 inducer)	Dose adjustment not required	Dose adjustment not required	Dose adjustment not required	Dose adjustment not required	No data available. Use with caution (crenolanib is metabolized by CYP450).
Itraconazole/Posaconazole (strong CYP3A inhibitor)	Consider alternative therapy; if concomitant use unavoidable, monitor closely for midostaurin-related toxicity	Not studied, but probably dose adjustment not required (based on Itraconazole data)	Consider alternative therapy; if concomitant use unavoidable, monitor closely for gilteritinib-related toxicity	Reduce dose to 30 mg daily	No data available. Use with caution (crenolanib is metabolized by CYP450).