*1.1.1.1.4 Lestaurtinib*

Lestaurtinib (CEP-701) is an orally bioavailable first generation FLT3 inhibitor. It is derived from the bacterial fermentation product K-252a as indolocarbazole alkaloid compound. Except inhibition of FLT3 Lestaurtinib also inhibits JAK2, tropomyosin receptor kinases and neurotrophin receptors [29–33]. In a phase 2 trial lestaurtinib was administered as monotherapy in untreated older patients with AML not considered fit for intensive chemotherapy, irrespective of FLT3 mutation status. This study involved 29 patients with median age of 73 years. Lestaurtinib was administered orally at doses of 60 mg and 80 mg twice daily for 8 weeks. Clinical activity was evident in 8 (30%) patients, including 3 (60%) of 5 FLT3 mutant patients and 5 (23%) of 22 evaluable FLT3 WT patients, the difference in response rates between mutation groups not reaching statistical significance. Lestaurtinib was generally well tolerated. Commonly observed toxicities included mild nausea (8 patients), emesis (5 patients), constipation (5 patients), diarrhea (6 patients), and elevations in alkaline phosphatase concentration (13 patients) [34]. Another phase 1/2 trial in 14 heavily pretreated AML patients treated with CEP-701 at an initial dose of 60 mg orally twice daily, showed clinical evidence of biologic

activity and measurable clinical response in 5 patients with significant reductions in bone marrow and peripheral blood blasts and minimal drug related toxicities [35]. A randomized assessment from UK AML 15 and AML 17 trials confirmed no statistically significant benefit observed in the combination of lestaurtinib with standard chemotherapy for newly diagnosed AML patients mostly younger than 60 years.

#### *1.1.1.1.5 Tandutinib*

Tandutinib (MLN518) is FLT3, KIT, PDGFR and type III receptor tyrosine kinases inhibitor. Tandutinib induces apoptosis and inhibits FLT3/ITD phosphorylation, cellular proliferation, and signaling of the MAPK and PI3K pathways [36]. In a phase 1 trial tandutinib was given orally (from 50–700 mg twice daily) in 40 patients with either AML or high-risk myelodysplastic syndrome (MDS) with only 8 patients with FLT3-ITD mutations. Even among the patients with FLT3-ITD mutations who were treated at potentially effective doses, response evaluation was often not possible because of rapid disease progression, sudden disease-related clinical deterioration, or tandutinib-related toxicity. Tandutinib treatment was associated muscular weakness, nausea, vomiting and less often diarrhea [37].

#### *1.1.1.2 Second and next generation FLT3 inhibitors*

#### *1.1.1.2.1 Quizartinib*

Quizartinib (AC220) is a selective and highly potent second-generation class III receptor TKI that selectively inhibits FLT3/STK1, CSF1R/FMS, SCFR/KIT, and PDGFRs in a dose dependent manner [38]. Quizartinib was first tested in phase I dose-escalation trial in patients with relapsed and refractory AML patients irrespective of FLT3 mutation status. Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients, with a median of three prior therapies and responses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR). The median duration of response was 13.3 weeks and the median survival was 14 weeks. The most common treatment-related adverse events were nausea, vomiting, and prolonged QT interval. The maximum tolerated dose (MTD) was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation [39]. In another 2-part, phase 1, multicenter, open-label, sequential group doseescalation trial of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia a total of 19 patients were enrolled. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤ 1 QT prolongation was observed at MTD [40]. In a large phase 2 trial assigning 333 (157 in cohort 1 and 176 in cohort 2) r/r AML patients were enrolled. In cohort 1 56% of FLT3-ITD-positive patients and 36% of FLT3-ITD-negative patients achieved composite complete remission and in cohort 2 46% FLT3-ITD-positive patients achieved composite complete remission whereas 30% of FLT3-ITD-negative patients achieved composite complete remission. Across both cohorts the most common grade 3 or worse treatment-related adverse events were febrile neutropenia, anaemia, thrombocytopenia, QTcF prolongation, neutropenia, leucopenia thrombocytopenia and pneumonia [41]. Preliminary results of a randomized phase 3 study (QuANTUM-R) in patients with FLT3-ITD mutated r/r AML enrolled 367 patients, randomized 2:1 to receive quizartinib or 1 of 3 preselected investigator's

**245**

*1.1.1.2.3 Gilteritinib*

*Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

the 2 arms [42].

*1.1.1.2.2 Crenolanib*

choice therapy.(low-dose cytarabine, mitoxantrone, etoposide, and intermediatedose cytarabine or fludarabine, cytarabine, and granulocyte-colony stimulating factor with idarubicin). The results showed a significantly improved median OS for quizartinib (6.2 vs. 4.7 months; p = 0.017) and an improved cCR rate (48% vs. 27%, p = 0.0001). Rates of treatment-emergent adverse events were comparable between

Crenolanib (CP868596) is a benzamidine quinolone derivative, a second generation RTK inhibiting FLT3-ITD and -TKD mutations. It is potent, selective, and invulnerable to resistance-conferring kinase domain mutation. As a type I pan-FLT3 inhibitor crenolanib inhibits FLT3/WT, FLT3/ITD, FLT3-TKD, PDGFRα/β, KIT, and FLT3/D835 [43]. In nearly one third of AML patients treated with FLT3 inhibitors in different clinical trials a resistance point mutations like D835 and F691 are occurring during disease progression [44, 45]. As a more potent RTK inhibitor crenolanib could inhibit both FLT3/ITD and resistant FLT3/D835 mutants and less disruptive of erythroid colony growth, which may result in relatively lessmyelosuppression [46]. In a phase 1 trial of FLT3-ITD positive AML crenolanib was given to 69 patients divided in three cohorts, cohort A patients with R/R FLT3 AML who had not received prior FLT3 inhibitors, cohort B patients progressing on prior TKIs and cohort C patients who developed FLT3 + AML after prior MDS. Crenolanib therapy resulted in a 39% CRi and 11% PR (6 D835, 9 ITD, 3 ITD + D835) amongst the patients in cohort A with an ORR of 50% [47]. In a phase II trial, the tolerability and efficacy of crenolanib combined with standard 7 + 3 induction chemotherapy was examined in 29 patients with newly diagnosed FLT3 mutant AML. 21 of 29 (72%) patients achieved a CR after one cycle of induction with cytarabine/anthracycline/crenolanib. An additional 3 patients achieved a CR either after re-induction (1 patient) or after treatment with HiDAC or HSCT (1 patient each) [48]. In another study with the same inclusion criteria in which 26 patients were enrolled the most common advere events which led to crenolanib dose reductions were periorbital edema, delayed count recovery, LFT elevation, nausea and rash [49]. Also crenolanib was investigated in a patients with a first relapsed/primary refractory AML. The study enrolled 8 patients, received HAM followed by crenolanib. 6 patients were evaluable for responses with a complete remission rate of 67% (2 CR, 2 CRi), including 2 pts who were refractory to front line chemotherapy. 2 of 3 patients with FLT3 activating mutations (1 with ITD and 1 with D835) achieved complete remission with complete count recovery; the third pt (FLT3-ITD) had 10% residual blasts after 1 cycle of induction [50]. Ohanian et al. studied the effect of crenolanib combined with idarubicin and high-dose Ara-C in 13 pts (median age of 51 years) with multiply relapsed/refractory FLT3+ AML. The ORR in 11 pts evaluable for response was 36% (1 CR, 3 CRi; 2 not evaluable because of early discontinuation of therapy). The median OS for all patients was 259 days; median OS by prior therapies was 259 days for patients with ≤2 prior therapies, and 53 days for patients with ≥3 prior therapies. No dose-limiting toxicities were observed at any of the dose levels explored and there were no dose reductions required. Non-hematologic adverse events assessed as possibly or probably related to crenolanib were all grade 1

in severity, including: nausea, vomiting, diarrhea, and abdominal pain [51].

Gilteritinib (ASP2215) is a selective next-generation novel dual FLT3 (to a lesser extent to FLT3-TKD than -ITD)/AXL inhibitor. Gilteritinib was investigated

#### *Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

choice therapy.(low-dose cytarabine, mitoxantrone, etoposide, and intermediatedose cytarabine or fludarabine, cytarabine, and granulocyte-colony stimulating factor with idarubicin). The results showed a significantly improved median OS for quizartinib (6.2 vs. 4.7 months; p = 0.017) and an improved cCR rate (48% vs. 27%, p = 0.0001). Rates of treatment-emergent adverse events were comparable between the 2 arms [42].
