*1.1.1.2.2 Crenolanib*

*Acute Leukemias*

*1.1.1.1.5 Tandutinib*

*1.1.1.2.1 Quizartinib*

*1.1.1.2 Second and next generation FLT3 inhibitors*

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.

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].

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

**244**

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].

#### *1.1.1.2.3 Gilteritinib*

Gilteritinib (ASP2215) is a selective next-generation novel dual FLT3 (to a lesser extent to FLT3-TKD than -ITD)/AXL inhibitor. Gilteritinib was investigated in 252 patients with relapsed or refractory acute myeloid leukaemia in one of seven dose-escalation (n = 23) or dose-expansion (n = 229) cohorts. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. In the full analysis 249 patients were included, 8% achieved complete remission, 4% complete remission with incomplete platelet recovery, 18% complete remission with incomplete haematological recovery, and 10% partial remission. The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (39%), anaemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%) [52]. In another open-label phase 1 study in 24 Japanese patients with relapsed/refractory acute myeloid leukemia the ORR among patients with mutated FLT3 was 80% and among FLT wildtype was 36.4%. The MTD was 200 mg/d, dose-limiting toxicities were grade 3 tumor lysis syndrome and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope [53]. The phase 3 ADMIRAL trial assessing oral gilteritinib 120 mg per day versus salvage chemotherapy in adult r/r FLT3 mutated AML patients led to an FDA approval for gilteritinib. 369 adults with FLT3 mutated AML in first relapse or refractory to front-line therapy were enrolled. The 21% of patients who achieved had a median time to response of 3.6 months [54].

## *1.1.1.2.4 Cabozantinib*

Cabozantinib is an oral tyrosine kinase inhibitor of multiple receptor tyrosine kinases and exhibits anti-tumor activity in several cancers [55, 56]. It inhibits FLT3, MET, AXL, vascular endothelial growth factor receptor, and KIT. In a study among 18 patients with relapsed/refractory AML, 5 harboring FLT3/ITD mutations no patients had a marrow response according to formal criteria. 4 patients had peripheral blast reductions, 2 of these 4 patients transiently cleared circulating blasts, 1 patient experienced a reduction in marrow blasts, and 1 had stable disease [57] (**Table 1**).

### **1.2 Mutations in epigenetic modifiers: regulators of DNA methylation and chromatin modification drugs**

#### *1.2.1 IDH inhibitors*

For the first time IDH1 mutations in AML were identified in 2009 by sequencing an acute myeloid leukemia genome. IDH is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG). 5-methylcytosine (5mC) coverts to 5-hydroxymethylcytosine (5hmc) as a result of interaction between α-KG and TET2 which promotes DNA and histone demethylation [58]. Approximately 8–19% of AML cases carry IDH2 mutations, with another 7–14% carrying IDH1 mutations [59]. IDH1/2 are found with higher frequency in older patients and patients with a normal karyotype [60, 61]. IDH1 mutations almost exclusively occur at R132 while IDH2 involve substitutions at R140 or R172 [62]. While IDH2-R172 may represent a distinct genomic subgroup, which mutual exclusivity with NPM1 and with a distinct DNA methylation profile [63]. Some studies showed that IDH1 and IDH2-R172 mutation may predict a worse clinical outcome especially in CN-AML, while the IDH2-R140 concomitant NPM1 mutation may be associated with better prognosis in AML [63–65]. More further studies are needed due to the conflicting data about the prognostic impact of IDH1/2 mutations in AML.

**247**

*1.2.1.1 Enasidenib*

*Selected AML targeted agents.*

**Table 1.**

Enasidenib (AG-221) is the first oral IDH mutation–specific inhibitor. It is a bivalent inhibitor of R140Q and R172K mutated IDH2 and induces terminal differentiation of leukemic blasts into neutrophils in vivo [66]. IDH2 inhibitor enasidenib (AG-221/CC-90007) showed promising activity as a single agent in patients with mutated IDH2 in first-in-human phase 1/2 study with 345 patients enrolled. Median age was 68 years. 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. 19.6% attained complete remission, 10.3% proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8%. 43.1% red blood cell transfusion–dependent and 40.2% platelet transfusion– dependent patients achieved transfusion independence. Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation

CD33-targeted therapy Inhibition of CD33 Gemtuzumab Ozogamicin

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

Signaling and kinase pathway mutations inhibitors (FLT3 tyrosine kinase inhibitors)

Second and next generation FLT3 inhibitors

Mutations in epigenetic modifiers: Regulators of DNA methylation and chromatin modification drugs (IDH inhibitors)

Hedgehog Inhibition (Smoothened

inhibitors)

**Drug Class Mechanism of action Agent**

Pro-apoptotic agents (Bcl-2 inhibitors) Inhibition of BCL2 Venetoclax

Polo-like kinase inhibitors Inhibition of Plk1 Volasertib E-selectin inhibitors Inhibition of E-selectin Uproleselan Checkpoint inhibitors Inhibition of PD-1 Nivolumab

Midostaurin (PKC412)

Sorafenib Sunitinib Lestaurtinib Tandutinib

Quizartinib Crenolanib Gilteritinib Cabozantinib

Glasdegib Sonidegib Vismodegib

Pembrolizumab

Vadastuximab talirine

Inhibition of IDH2 Enasidenib Inhibition of IDH1 Ivosidenib

Inhibition of CTLA-4 Ipilimumab

inhibition of of HH/GLI

signalling

First-generation FLT3 inhibitors Inhibition of FLT3

*Acute Leukemias*

3.6 months [54].

(**Table 1**).

*1.2.1 IDH inhibitors*

mutations in AML.

*1.1.1.2.4 Cabozantinib*

**chromatin modification drugs**

in 252 patients with relapsed or refractory acute myeloid leukaemia in one of seven dose-escalation (n = 23) or dose-expansion (n = 229) cohorts. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. In the full analysis 249 patients were included, 8% achieved complete remission, 4% complete remission with incomplete platelet recovery, 18% complete remission with incomplete haematological recovery, and 10% partial remission. The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (39%), anaemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%) [52]. In another open-label phase 1 study in 24 Japanese patients with relapsed/refractory acute myeloid leukemia the ORR among patients with mutated FLT3 was 80% and among FLT wildtype was 36.4%. The MTD was 200 mg/d, dose-limiting toxicities were grade 3 tumor lysis syndrome and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope [53]. The phase 3 ADMIRAL trial assessing oral gilteritinib 120 mg per day versus salvage chemotherapy in adult r/r FLT3 mutated AML patients led to an FDA approval for gilteritinib. 369 adults with FLT3 mutated AML in first relapse or refractory to front-line therapy were enrolled. The 21% of patients who achieved had a median time to response of

Cabozantinib is an oral tyrosine kinase inhibitor of multiple receptor tyrosine kinases and exhibits anti-tumor activity in several cancers [55, 56]. It inhibits FLT3, MET, AXL, vascular endothelial growth factor receptor, and KIT. In a study among 18 patients with relapsed/refractory AML, 5 harboring FLT3/ITD mutations no patients had a marrow response according to formal criteria. 4 patients had peripheral blast reductions, 2 of these 4 patients transiently cleared circulating blasts, 1 patient experienced a reduction in marrow blasts, and 1 had stable disease [57]

**1.2 Mutations in epigenetic modifiers: regulators of DNA methylation and** 

ing an acute myeloid leukemia genome. IDH is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG). 5-methylcytosine (5mC) coverts to 5-hydroxymethylcytosine (5hmc) as a result of interaction between α-KG and TET2 which promotes DNA and histone demethylation [58]. Approximately 8–19% of AML cases carry IDH2 mutations, with another 7–14% carrying IDH1 mutations [59]. IDH1/2 are found with higher frequency in older patients and patients with a normal karyotype [60, 61]. IDH1 mutations almost exclusively occur at R132 while IDH2 involve substitutions at R140 or R172 [62]. While IDH2-R172 may represent a distinct genomic subgroup, which mutual exclusivity with NPM1 and with a distinct DNA methylation profile [63]. Some studies showed that IDH1 and IDH2-R172 mutation may predict a worse clinical outcome especially in CN-AML, while the IDH2-R140 concomitant NPM1 mutation may be associated with better prognosis in AML [63–65]. More further studies are needed due to the conflicting data about the prognostic impact of IDH1/2

For the first time IDH1 mutations in AML were identified in 2009 by sequenc-

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#### **Table 1.**

*Selected AML targeted agents.*

#### *1.2.1.1 Enasidenib*

Enasidenib (AG-221) is the first oral IDH mutation–specific inhibitor. It is a bivalent inhibitor of R140Q and R172K mutated IDH2 and induces terminal differentiation of leukemic blasts into neutrophils in vivo [66]. IDH2 inhibitor enasidenib (AG-221/CC-90007) showed promising activity as a single agent in patients with mutated IDH2 in first-in-human phase 1/2 study with 345 patients enrolled. Median age was 68 years. 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. 19.6% attained complete remission, 10.3% proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8%. 43.1% red blood cell transfusion–dependent and 40.2% platelet transfusion– dependent patients achieved transfusion independence. Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation

syndrome (6%) [67]. These results led to the FDA approval of enasidenib in r/r IDH2 mutated AML patients on 1 August 2017. With regard to predictors of response, the IDH2 mutation allele burden at study entry had no effect on response rate [66]. In a open-label, multicenter, phase 1 study patients 134 newlydiagnosed mIDH1 or mIDH2 AML were treated with induction therapy in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib (mIDH2) 100 mg daily. Among the 77 enasidenib-treated patients evaluable for efficacy, a response of CR, CRi, or CRp was achieved in 73% patients with de novo AML and in 63% patients with sAML. The most frequent co-occurring baseline mutations for patients with IDH2 mutations were DNMT3A, SRSF2 and ASXL1 [68].

## *1.2.1.2 Ivosidenib*

Ivosidenib (AG-120) is a potent and selective IDH1 mutation small-molecule inhibitor. In phase 1, multicenter, open-label, dose-escalation and dose-expansion study 258 patients received ivosidenib orally, daily, in 28-day cycles. In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4%, the rate of complete remission was 21.6% and the overall response rate was 41.6%. The median durations of these responses were 8.2 months, 9.3 months, and 6.5 months, respectively. No residual detectable IDH1 mutations on digital polymerase-chain-reaction assay were detected in 21% patients who had a complete remission or complete remission with partial hematologic recovery. The most common adverse events (in ≥20% of the patients), irrespective of a relationship to ivosidenib, were diarrhea, leukocytosis, febrile neutropenia, nausea, fatigue, dyspnea, prolongation of the QT interval. Peripheral edema, anemia, pyrexia, cough and and differentiation syndrome [69]. The results of this study led to the FDA approval of ivosidenib in r/r IDH1 mutated AML patients on 2 may 2019. Prescribing information contains a boxed warning about the risk of differentiation syndrome which may be life-threatening or fatal. In a open-label, multicenter, phase 1 study patients 134 newlydiagnosed mIDH1 or mIDH2 AML were treated with induction therapy in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib (mIDH2) 100 mg daily. Among the 41 ivosidenib-treated patients evaluable for efficacy, a response of CR, CRi or CRp was achieved in 93% patients with de novo AML and 46% patients with sAML. Twenty-one patients received ≥1 cycle of consolidation therapy and 11 patients received maintenance after consolidation. Seventeen patients proceeded to HSCT. For patients with IDH1 mutations the most frequent co-occurring baseline mutations were DNMT3A, NPM1 and NRAS. MRD-negative CRs using flow cytometry were observed in 89% of patients with IDH1 positive mutational status [68].

#### **1.3 Pro-apoptotic agents**
