Acute myeloid leukemia transformed to a targetable disease

Khalil Saleh1 , Nadine Khalifeh-Saleh1 & Hampig Raphael Kourie*,1
1 Hematology–Oncology Department, Faculty of Medicine, Saint Joseph University of Beirut, Beirut, Lebanon *Author for correspondence: [email protected]

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the monoclonal prolifera- tion of immature progenitors. It is the most common acute leukemia in adults and its incidence increases
with age. The standard traditional treatment in fit patients was the ‘3 + 7’ regimen and cytarabine consoli- dation followed or not with allogeneic stem cell transplantation. Recently, several targeted therapies such as gemtuzumab ozogamicin targeting the CD33+ AML, midostaurin, gilteritinib and crenolanib inhibiting FLT3-positive AML and ivosidenib and enasidenib blocking IDH-mutated AML have been approved. These new drugs led to the change of the landscape of the treatment of AML and transforming this disease to a targetable one. We aimed in this paper to review the implications of each new target, the mechanisms of action of these new drugs and we discuss all the studies leading to the approval of these new drugs in their indications according to each target.

First draft submitted: 23 October 2019; Accepted for publication: 30 March 2020; Published online: 16 April 2020

Keywords: acute myeloid leukemia • crenolanib • enasidenib • FLT3 • gemtuzumab ozogamicin • gilteritinib • IDH1/2 • ivosidenib • midostaurin • quizartinib
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the occurrence of multiple genetic and epigenetic alterations that lead to proliferation of immature progenitor cells and block cellular differentiation [1]. AML is the most frequent acute leukemia in adults with a median age at diagnosis of 68 years and its incidence increases with age [2]. In younger patients with de novo AML, the 5-year overall survival (OS) is 40–50% [3].
Traditional treatment regimens include the standard ‘3 + 7’ regimen which consists of 7 days of continuous cytarabine with 3 days of daunorubicin or idarubicin [4]. In patients with relapsed or refractory (R/R) AML or those with secondary myeloid neoplasm or in elderly patients, the prognosis is significantly worse and the 5-year OS falls to 5–10% [5–7]. Nowadays, a variety of recurrent gene mutations and molecular aberrations that trigger the emergence of AML had been detected using molecular profiling by next-generation sequencing and PCR. The detection of such driver mutations in AML leads to the development of new investigational drugs as targeted therapy and the improvement of outcomes in high-risk AML. FLT3, which is mutated in 30–35% in patients with newly diagnosed AML and recurrent mutations in IDH1 and IDH2, are the most studied targets in the treatment of AML [8]. IDH1 mutations occur in approximately 6–10% of patients with AML while IDH2 mutations occur in approximately 9–13% of patients with AML [9]. We reviewed in this paper the most developed targeted therapies in the treatment of AML such as gemtuzumab ozogamicin (GO), which is the first approved targeted therapy in AML and directed against CD33+ AML, new FLT3 inhibitors such as midostaurin, quizartinib, crenolanib and giltertinib and IDH inhibitors: ivosidenib which is an IDH1 inhibitor and enasidenib which is an IDH2 inhibitor. Table 1 resumes the incidence of each target.

Gemtuzumab ozogamicin
GO is a humanized immunoglobulin 4 monoclonal antibody directed against CD33 and conjugated the DNA toxin calicheamicin, a potent antitumor antibiotic [10]. GO binds to CD33 antigen which is expressed on the surface of approximately 90% of AML myeloblasts [11]. GO/CD33 complexes are internalized into lysosomes, contributing to intracellularly release of calicheamicin and leading to single and double-strand breaks and cellular death [12]. GO was the first targeted therapy that received accelerated approval by the US FDA in 2000 for the

10.2217/fon-2019-0670 C⃝ 2020 Future Medicine Ltd Future Oncol. (2020) 16(14), 961–972 ISSN 1479-6694 961

Table 1. Incidence of target and drugs.
Target Incidence Drugs US FDA approval Drug indication
CD33 90% GO September 2017 Newly diagnosed CD33+ AML
R/R CD33+ AML

FLT3-ITD FLT3-TKD
20–30% 7%
Midostaurin Quizartinib
Crenolanib Geltiritinib
April 2017 None
None November 2018
Newly diagnosed AML in combination with AML R/R FLT3-mutated AML

IDH1 6–10% Ivosidenib July 2018 R/R IDH1-mutated AML
IDH2 9–13% Enasidenib August 2017 R/R IDH2-mutated AML
AML: Acute myeloid leukemia; GO: Gemtuzumab ozogamicin; R/R: Relapsed or refractory.

treatment of elderly patients ≥60 years with CD33+ AML in first relapse [13]. Larson et al. reported the results of three open-label, single-arm, Phase II studies evaluating GO as monotherapy at a dosage of 9 mg/m2 given in two doses separated by 2 weeks in patients with CD33+ AML in first recurrence. A total of 277 patients were
included of whom 71 patients (26%) achieved remission which was defined as ≤5% blasts in the bone marrow without leukemic blasts in the peripheral blood, neutrophil recovery to ≥1500/μl, hemoglobin ≥9 g/dl and independence from red blood cells and platelets transfusions. Grade 3 or 4 hyperbilirubinemia and hepatic AST and ALT elevations were reported in 29, 18 and 9% of patients, respectively [14]. GO was withdrawn from the market on 21 June 2010 based on the preliminary results of the S0106 Phase III trial.
The S0106 trial is a randomized multicenter Phase III trial initiated by the Southwest Oncology Group to evaluate the addition of GO to standard chemotherapy in previously untreated adults aged between 18 and 60 years with de novo AML. GO was administered at a dosage of 6 mg/m2 on day 4 in combination with daunorubicin 45 mg/m2 push on days 1 through 3 and cytarabine 100 mg/m2 by continuous intravenous infusions on days 1 through 7. The control group received daunorubicin 60 mg/m2 on days 1 through 3 with the same doses of cytarabine. Patients who achieved complete remission (CR) received three courses of high dose cytarabine. Overall, 637 patients were included. The CR rate was 69% in the GO group compared with 70% in the standard group (p = 0.59). The 5-year OS rate was 46% in the GO group compared with 50% in the control group (p = 0.85). The GO group had higher induction mortality (5.5 vs 1.4%) [15]. However, the ALFA 0701 trial is a multicenter, randomized, open-label Phase III trial which evaluated the addition of fractioned dose of GO to induction chemotherapy and consolidation in patients with de novo AML aged between 50 and 70 years. In this pivotal study, the median event-free survival (EFS) and the median OS were significantly longer in the GO group compared with standard group (19.6 vs 11.9 months; p = 0.00018; 34 vs 19.2 months; p = 0.046, respectively). In a subgroup analysis, the benefit was limited to patients with favorable or intermediate-risk karyotype [16]. Lately, a meta-analysis of individual patients data from five randomized controlled trials showed the addition of GO to did not increase the CR or CR with incomplete peripheral blood recovery rates (odds ratio [OR] = 0.91; 95% CI: 0.77–1.07; p = 0.3). However, it was associated with significantly lower risk of relapse (OR = 0.81; 95% CI: 0.73–0.90; p = 0.0001) and a significantly longer OS (OR = 0.90; 95% CI: 0.82–0.98; p = 0.01) [17].
Overall, GO was re-approved by the FDA in September 2017 as a reduced fractioned dose for the treatment of newly diagnosed CD33+ AML in adults and for R/R CD33+ AML in adults and children ≥2 years [18].

FLT3 inhibitors
FLT3 is a tyrosine kinase receptor usually expressed in early myeloid progenitors [19]. It has been thought that FLT3 plays a crucial role in maturation and differentiation of hematopoietic precursors [20]. When FLT3 binds to its ligand, the receptors dimerized at the membrane leading to autophosphorylation and activation of downstream regulatory pathways via RAS, MEK, PI3K, AKT and STAT-5 and contributing to cellular growth and differentiation [21]. The mutation of ITD in the juxtamembrane domain of FLT3 was found in approximately 20–30% of patients with newly diagnosed AML leading to constitutive activation of FLT3. Mutations in the FLT3 TKD are detected in 7% of patients with newly diagnosed AML [22]. FLT3-ITD mutations are associated with higher rate of relapse, poor prognosis and inferior OS. However the prognosis impact of FLT3-TKD mutations remains unclear [23]. In order to improve outcomes in patients with AML harboring FLT3 mutations, inhibitors of mutant FLT3 were developed

including the nonspecific first-generation FLT3 inhibitors such as sorafenib and midostaurin and the more selective and potent second-generation FLT3 inhibitors such as quizartinib, crenolanib and gilteritinib.

Midostaurin
Midostaurin is a first-generation FLT3 inhibitor which targets ITD and TKD mutations. In addition, it is a multi-targeted kinase inhibitor against VEGFR, protein kinase C, c-KIT and PDGFR-β [24]. It has initially been developed as a protein kinase C inhibitor for treatment of solid tumors which were either refractory to conventional chemotherapy of unresponsive to standard treatment [25]. In a Phase Ib trial of 95 patients, aged 18–60 years, with previously untreated AML, midostaurin was evaluated in combination with daunorubicin and cytarabine induction and high-dose cytarabine post remission therapy. The CR rate for the midostaurin 50 mg twice daily dose schedule was 80% (92% in FLT3-mutant patients and 74% in FLT3-wild type). The 1 and 2 years OS probabilities in patients with FLT3-mutant AML was 0.85 and 0.62, respectively, and were similar to the FLT3 wild-type group (0.78 and 0.52, respectively). No grade 3 or 4 nausea or vomiting was seen. This Phase Ib trial showed that the addition of midostaurin to standard chemotherapy was associated with high CR and OS in younger patients with previously untreated AML [26].
Stone et al. reported the results of RATIFY trial, a multicentric, international, randomized, double-blind, placebo- controlled Phase III trial. In this study, the addition of midostaurin to standard chemotherapy was compared with placebo and standard regimen in 717 patients of 18–59 years with newly diagnosed AML with either ITD subtype or TKD subtype FLT3 mutations. Midostaurin or placebo were given at a dose of 50 mg orally twice daily on days 8–21 of each induction or consolidation cycle followed by up to 1 year of midostaurin or placebo maintenance. ITD mutations were found in 77% of patients and TKD mutations in 23%. The median OS in the midostaurin group was 74.7 months (95% CI: 31.5 months to not reached) versus 25.6 months (95% CI: 18.6–42.9) in the placebo group. The hazard ratio for death was 0.78 (one-sided p = 0.009) and for event or death was 0.78 (one-sided p = 0.002). The 4-year OS rate was 51.4% in the midostaurin group versus 44.3% in the placebo. Allogenic stem cell transplantation (ASCT) during the first remission was performed in 25% of patients (28.1% in the midostaurin group vs 22.7% in the placebo group; p = 0.10). The median OS was not reached in both arms. The 4-year OS rate was 63.7% in the midostaurin group versus 55.7% in the placebo group (p = 0.08) with a 24.3% lower risk of death with midostaurin [23].
Based on these results, the FDA and the EMA approved midostaurin for the treatment of adults with newly diagnosed FLT3-mutated AML in combination with standard daunorubicin and cytarabine induction and cytara- bine consolidation in April and September 2017, respectively. However, midostaurin maintenance therapy was not approved by the FDA, whereas maintenance therapy with midostaurin was included in the EMA approval [27,28].
More recently, Schlenk et al. reported the results of Phase II trial evaluating the addition of midostaurin to intensive chemotherapy followed by ASCT and single-agent maintenance therapy of 12 months in patients with newly diagnosed FLT3-ITD mutant AML including older patients. A total of 284 patients were treated, including 86 old (61–70 years) patients. The CR rate including CR with incomplete hematological recovery after induction therapy was 76.4% (younger 75.8% and older 77.9%). The 2-year EFS were 39 and 34% in younger and older patients, respectively, and the 2-year OS rate was 53 and 46% in younger and older patients, respectively [29].

Quizartinib
Quizartinib is an oral highly potent second-generation class III receptor TKI and is more selective FLT3 inhibitor for AML. It has also activity against PDGFR and KIT [30]. Quizartinib is only efficacious against ITD mutations and has no significant inhibition on TKD mutations [31]. In contrast, it has been thought that emergence of TKD mutations could be a mechanism of resistance to quizartinib [24].
In a Phase I open-label, escalation-dose first-in-human study, quizartinib was evaluated in 76 patients with R/R AML irrespective of FLT3-ITD mutation status. The overall response rate (ORR) was 30% (23/76) with 13% of CR (10/76). The OR9R in the group of FLT3-ITD mutant AML was 53% (9/17) compared with 14% in patients with FLT3-ITD-negative patients. Nine patients of 22 (41%) with FLT3-ITD indeterminate/not tested status responded. The median OS was 14.0 weeks (18.0 weeks in the group of FLT3-ITD mutant AML, 10 weeks in FLT3-ITD-negative patients and 19.0 weeks in patients with indeterminate status). The most frequent drug- related adverse events were nausea (16%), prolonged QT interval (12%), vomiting (11%) and dysguesia (11%). The maximal tolerated dose 200 mg/day and grade 3 QT interval prolongation was the dose-limiting toxicity [32].

Quizartinib was then evaluated in an open-label, multicenter, single-arm Phase II trial in patients with R/R AML unselected for FLT3 status. Quizartinib was initially given at a dosage of 200 mg then the doses were amended for all patients to 135 mg/day for men and 90 mg/day for women due to higher than acceptable rate of grade 3 QT prolongation. Response rates were similar to Phase I trial reported by Cortes et al. [33]. Due to the absence of evidence concerning the optimal dose of quizartinib, a randomized, open-label Phase IIb trial was conducted which evaluated quizartinib at a dose of either 30 or 60 mg daily which could be escalated to 60 and 90 mg, respectively, in case of no response or loss of response. A total of 76 patients with R/R FLT3-ITD-mutated AML were randomized. The composite complete response rate was 47% in both groups. The 60-mg group presented a longer OS (27.3 vs 20.9 weeks), longer duration of composite complete remission (CRc; 9.1 vs 4.2 weeks) and a higher hematopoietic stem cell transplantation rate (42 vs 32%) [34]. Based on the results of this Phase IIb study, the dose of 60 mg per day was selected for future quizartinib studies.
The randomized, controlled, open label Phase III QuANTUM-R trial compared quizartinib (60 mg orally once daily) versus investigator’s choice of salvage chemotherapy from three regimens in patients with R/R FLT3- ITD AML after standard therapy with or without ASCT. The three regimens included: subcutaneous low-dose cytarabine, intravenous mitoxantrone, etoposide and cytarabine or FLAG-IDA (fludarabine, cytarabine, idarubicine and intravenous granulocyte colony-stimulating factor). A total of 367 patients were enrolled. After a median follow- up of 23.5 months, the median OS was 6.2 months in the quizartinib group compared with 4.7 months in the chemotherapy group (hazard ratio [HR] = 0.76; 95% CI: 0.58–0.98; p = 0.02). Grade 3 QT prolongation occurred in 3% of patients by central reading and there was no grade 4 QT prolongation [35]. The FDA has granted breakthrough therapy designation to quizartinib for the treatment of adult patients with R/R AML harboring FLT3-ITD mutation on August 2018. However, on May 2019 the FDA voted against quizartinib for adult patients with R/R FLT3-ITD mutant AML. In fact, the FDA conducted its own efficacy analysis of QuANTUM-R data and concluded to a gain of 6 weeks in term of OS (26.9 weeks for quizartinib vs 20.4 weeks for salvage chemotherapy, HR = 0.77; 95% CI: 0.59–0.99; p = 0.019). There was no significant difference in term of EFS (6.0 vs 3.7 weeks, HR = 0.9; 95% CI: 0.71–1.16; p = 0.114). In addition, the EMA has adopted a negative opinion on the Marketing Authorization Application for quizartinib for the treatment of R/R FLT3-ITD-mutated AML on October 2019.
The QuANTUM-first, a Phase III randomized double-blind, placebo-control study is comparing quizartinib versus placebo administered with standard induction and consolidation therapy then continuation therapy for up to 36 cycles in patients with newly diagnosed FLT3-ITD-mutated AML (NCT02668653).

Crenolanib
Crenolanib is a second-generation, potent and selective inhibitor of FLT3-ITD, FLT3-TKD and FLT3/D835. It also inhibits PDGFRα/β and KIT [36,37]. In a Phase I trial evaluating single-agent crenolanib in patients with R/R AML with FLT3 mutation, the ORR was 50% with a CR rate of 39% among patients who had no previous exposure to FLT3 inhibitors (18 patients). However, the ORR among patients who were treated with prior FLT3 inhibitors (36 patients) was 31% with a CR rate of 17%. Activity was shown in both patients with TKD and ITD mutations [38]. We think that it is too earlier based on the results of this Phase I trial to conclude that prior exposure to FLT3 inhibitor will decrease response to novel generation FLT3 inhibitors. Recently, the results of a Phase II trial concerning tolerability and efficacy of crenolanib in association with cytarabine/anthracycline chemotherapy in younger patients with newly diagnosed FLT3-mutated AML were presented at last American Society of Hematology (ASH). A total of 23 of 27 patients achieved CR after one cycle of induction and the overall CR rate was 85%; 19 of 27 patients remain alive and free of disease with a median follow-up of 29.3 months [39]. Ongoing trials are evaluating crenolanib in combination with chemotherapy and one head-to-head Phase III trial is comparing crenolanib with midostaurin in newly diagnosed FLT3-mutated AML (NCT03258931).

Gilteritinib
Gilteritinb is an oral second-generation dual FLT3/AXL inhibitor which has been initially developed to target patients with FLT3-ITD mutations [40]. However, in vitro, gilteritinib has shown selective kinase inhibition of FLT3 and highly potent activity against all classes of FLT3 activating mutations including ITD and TKD mutations [41]. In fact, Axl-1, an oncogenic tyrosine kinase, is overexpressed in patients with AML [42] and has been implicated in the resistance to other FLT3 inhibitors such as midostaurin and quizartinib [24]. Gilteritinib was evaluated in a first- in-human, international, open-label, dose-escalation and dose-expansion Phase I–II trial (CHRYSALIS study) in patients with R/R AML irrespective of FLT3 status. A total of 252 patients were enrolled. The maximum tolerated

dose (MTD) was 300 mg/day. The ORR of patients in the full analysis set (249 patients) was 40%. A total of 19 patients (8%) achieved CR, ten patients (4%) achieved CR with incomplete platelets recovery, 46 patients (18%) achieved complete remission with partial hematological recovery (CRh) and 25 patients (10%) achieved partial response. The median OS was 25 weeks (30 weeks in patients with FLT3-mutated AML and 17 weeks in patients with FLT3-negative AML). The starting dose of gilteritinib selected for future studies was 120 mg/day. The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (39%), anemia (24%), thrombocytopenia (13%), sepsis (11%) and pneumonia (11%). Commonly reported treatment-related adverse events were diarrhea (16%), fatigue (15%), elevated AST (13%) and elevated ALT (10%) [43].
The results of the randomized, open-label, multicenter Phase III ADMIRAL study were recently published. This Phase III trial evaluated the efficacy and safety of gilteritinib compared with salvage chemotherapy in patients with R/R FLT3-mutated AML. A total of 371 patients were enrolled in the study: 247 were randomly assigned to receive gilteritinib (120 mg/day) and 124 patients to receive salvage chemotherapy. The pre-randomization selected salvage chemotherapies were low-dose cytarabine; azacitidine; mitoxantrone, etoposide and cytarabine (MEC); and fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-IDA). The median OS in the gilteritinib group was 9.3 versus 5.6 months in the salvage chemotherapy group (HR: 0.64; 95% CI: 0.49–0.83; p
< 0.001). The 1-year survival rate was 37.1% in the experimental arm versus 16.7% in the control arm. The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI: 0.58–1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference: 18.6% points; 95% CI: 9.8–27.4). The most frequent treatment-related adverse events of
any grade which occurred in ≥10% of patients during the first 30 days of treatment with gilteritinib were anemia (33%), increased ALT or AST (24%), febrile neutropenia (21%), thrombocytopenia (19%), constipation (17%), pyrexia (15%), fatigue (15%), decreased neutrophil count (14%), increased blood ALP (13%) [44]. Based on the preliminary results of ADMIRAL study, the FDA approved gilteritinib for the treatment of patients with R/R AML harboring FLT3 mutation in November 2018 [45]. One of the limitations of the ADMIRAL trial is that front-line treatment for newly diagnosed FLT3-mutated AML changed during the recruitment when the FDA-approved midostaurin in first-line treatment and a little number of patients received midostaurin before gilteritinib. It is unknown if prior exposure to FLT3 inhibitors contributes to lower response to other inhibitors as mentioned above with crenolanib or whether leukemia that relapsed after or are refractory to first-line treatment including FLT3 inhibitors is less dependent on FLT3 for its growth.
Furthermore, an ongoing open-label, dose escalation/expansion Phase I trial is evaluating the efficacy and safety of the combination of giletritinib with induction and consolidation chemotherapy followed by maintenance therapy with single-agent gilteritinib in patients with newly diagnosed AML (NCT02236013). Available data of 62 patients enrolled, CR occurred in 94% in the idarubicin cohort and 6% achieved CRc. However, in the daunorubicin cohort, 60% of patients achieved CR and 40% of patients achieved CRh [46]. Table 2 resumes the key Phase III trials of FLT3 inhibitors in the treatment of newly diagnosed or R/R AML.

IDH1 & IDH2 inhibitors
IDH1 mutations occur in approximately 6–10% of patients with AML and IDH2 mutations occur in approximately 9–13% of patients with AML [9]. IDH enzymes play a crucial role in the citric acid cycle and catalyze the oxidative decarboxylation of isocitrate to α-KG. Mutant IDH proteins confer a neomorphic activity contributing to the reduction of α-KG to the oncometabolite R-2-hydroxybutarate [47].
Increased concentrations of 2-HG competitively inhibit α-KG-dependent enzymes, including histone demethy- lases and TET family of proteins, important for DNA demethylation and consequently, contribute to hyperme- thylation of DNA and impair normal differentiation [48]. Ivosidenib and enasidenib, which are oral potent IDH1 and IDH2 inhibitors, respectively, are approved for the treatment of IDH-mutant R/R AML.

Ivosidenib
Ivosidenib (AG-120) is a small-molecular, oral targeted inhibitor of mutant IDH1 who was developed for treatment of patients with relapsed or refractory AML with IDH1 mutations. Dinardo et al. reported the results of a multicenter, open-label, dose-escalation and dose-expansion Phase I trial evaluating ivosidenib in patients 18 years or older with an ECOG performance status (PS) between 0 and 2 and documented IDH1-mutated hematologic cancer [9]. Ivosidenib was given orally and daily in a 28-day cycles. Overall, 258 patients were treated with ivosidenib of

Table 2. Key Phase III trials of FLT3 inhibitors.
References Phase/patients Patients population Agent End point

NCT03512197
III/502
Newly diagnosed FLT3-negative AML
Midostaurin vs placebo in combination with induction and consolidation therapy followed by 1-year maintenance
EFS

NCT03258931
III/510
Newly diagnosed FLT3-mutated AML
Midostaurin vs crenolanib in combination with induction and consolidation therapy followed by 1-year maintenance
EFS

NCT02668653 (QuANTUM-First)
III/536
Newly diagnosed AML with FLT3-ITD mutation Quizartinib vs placebo in combination with induction and consolidation followed by 36 cycles of maintenance
EFS

NCT02298166
III/276
R/R AML with FLT3 mutations
Crenolanib or placebo with reinduction therapy (mitoxantrone + aractyine) and consolidation + HSCT and 1-year maintenance of crenolanib or placebo
EFS
OS

NCT03250338
III/322
R/R FLT3-mutated AML
Crenolanib vs placebo in combination with standard chemotherapy
EFS

NCT02752035
II-III/323
Newly diagnosed AML with FLT3 mutation unfit for intensive induction CT
Gliteritinib, gilteritinib + azacitidine or azacitidine alone
OS

NCT02421939 (ADMIRAL)
III/371
R/R AML with FLT3 mutation
Gilteritinib vs salvage chemotherapy (LoDAC, azacitidine, MEC, FLAG-IDA)
OS
CR/CRh rate

NCT03182244
III/318
R/R AML with FLT3 mutation
Gilteritinib vs salvage chemotherapy (LoDAC, MEC, FLAG)
OS

NCT02927262
II/98
FLT3-mutated AML in first CR
Gilteritinib vs placebo as maintenance therapy after induction + consolidation
RFS

NCT02997202
III/346
FLT3-ITD-mutated AML in first CR
Gilteritinib vs placebo as maintenance therapy after ASCT
RFS

NCT04027309 (HOVON 156 AML)
III/768
Newly diagnosed AML or MDS with excess blasts-2 with FLT3 mutation and eligible for intensive chemotherapy
Gilteritinib vs midostaurin in combination with induction and consolidation therapy followed by 1-year maintenance
EFS

AML: Acute myeloid leukemia; ASCT: Allogeneic stem cell transplantation; CR: Complete remission; CRh: Complete remission with partial hematological recovery; CT: Chemotherapy; EFS: Event-free survival; FLAG-IDA: GCSF, fludarabine, cytarabine, idarubicin; HSCT: hematopoietic stem cell transplantation; ITD: Internal tandem duplication; LoDAC: Low dose cytarabine; MDS: Myelodysplastic syndrome; MEC: Mitoxantrone, etoposide, cytarabine; OS: Overall survival; R/R: Relapsed or refractory; RFS: Relapse-free survival.

whom 179 patients presented R/R AML. The MTD was not defined. Based on pharmacokinetics, available safety and efficacy data, the dosage of 500 mg daily was selected for the dose-expansion phase. In the primary efficacy population (125 patients), the rate of CR or CRh was 30.4%, the CR rate was 21.6% and the ORR was 41.6%. The median duration of response was 6.5 months and the median duration of CR was 9.3 months. With a median follow-up of 14.8 months, the median OS in the primary efficacy population was 8.8 months. The median OS in patients who experienced CR or CRh was not reached at the data cut-off date and the 18-month survival rate was 50.1%. Among patients with CR or CRh, 21% had no residual detectable IDH1 mutations on digital PCR assay. The authors found that no specific single gene mutation predicted clinical response or resistance to treatment. The most common adverse events were diarrhea (30.7%), leukocytosis (29.6%), febrile neutropenia (28.5%), nausea (27.9%), fatigue (25.7%), dyspnea (24.6%), prolongation of the QT interval (24.6%), peripheral edema (21.8%), anemia (21.8%), pyrexia (21.2%) and cough (20.7%). The most frequent grade 3 or higher treatment-related adverse events were QT interval prolongation (7.8%), IDH differentiation syndrome (3.9%), thrombocytopenia (3.4%), anemia (2.2%) and leukocytosis (1.7%) [9]. Based on these results, the FDA approved ivosidenib for the treatment of adults with R/R AML harboring IDH1 mutations on the 20 July 2018 [49].
Ivosidenib is being evaluated in combination with azacitidine in a Phase Ib trial including patients with newly diagnosed AML harboring IDH1 mutations and ineligible for intensive induction chemotherapy (NCT02677922). Dinardo et al. presented the preliminary results at last ASCO 2019 [50]. Ivosidenib was administered at a dosage of 500 mg once daily with subcutaneous azacitidine 75 mg/m2 day 1 to 7 in a 28-day cycles. At the time of analysis, 23 patients received treatment. The median age was 76 years. The ORR was 78%. The rate of CR was 57% and the rate of CR and CRh was 70%. The median time to response was 1.8 months and the median time to CR was 3.5 months. The median duration of response was not reached. In patients with CR or CRh, the clearance of IDH1 mutation was seen in 63% of patients (10/16). The most common all grades treatment-related AEs were QT interval prolongation (26%), IDH differentiation syndrome (17%) and leukocytosis (13%). The most

Table 3. Most important ongoing trials of enasidenib or ivosidenib.
References Phase/patients Patients population Agent End point

NCT02632708 I/153
Newly diagnosed AML (de novo or secondary) with an IDH1 and/or IDH2 mutation
Ivosidenib or enasidenib in combination with induction and consolidation therapy and maintenance with ivosidenib or enasidenib
Safety and tolerability of ivosidenib and enasidenib with standard chemotherapy

NCT04044209 II/45
IDH1 mutated R/R AML or high-risk MDS
Ivosidenib and nivolumab (immune checkpoint inhibitor)
ORR
Change in duration of response

NCT03471260 Ib–II/48
IDH1-mutated hematologic malignancies (high-risk MDS, MPN, R/R AML)
Ivosidenib with venetoclax with or without azacitidine
Safety and tolerability MTD
ORR

NCT03471260 II/86
Maintenance post salvage induction chemotherapy in patients with IDH2 mutated R/R AML
Enasidenib
EFS

NCT03683433 II/50 IDH2-mutated R/R AML Enasidenib with azacitidine ORR

NCT03173248 (AGILE)
III/392
Previously untreated IDH1 mutated AML and unfit for intensive induction chemotherapy
Ivosidenib with azacitidine vs placebo with azacitidine
OS

NCT02577406 (IDENTIFY)
III/316
R/R AML with IDH2 mutation
Enasidenib vs CCR such as BSC, azacitidine, LoDAC, IDAC
OS

NCT03839771 (HOVON150AML)
III/968
Newly diagnosed AML or MDS-EB2 (de novo or secondary) with IDH1 or IDH2 mutation and eligible for intensive chemotherapy
Ivosidenib (for IDH1 mutation) or enasidenib (for IDH2 mutation) with induction and consolidation therapy followed by maintenance therapy vs placebo plus induction and consolidation therapy and maintenance therapy
EFS

AML: Acute myeloid leukemia; BSC: Best supportive care; CCR: Conventional care regimens; EFS: Event-free survival; IDAC: Intermediate dose cytarabine; LoDAC: Low dose cytarabine; MDS: Myelodysplastic syndrome; MPN: Myeloproliferative neoplasm; MTD: Maximum tolerated dose; ORR: Overall response rate; OS: Overall survival; MDS-EB2: Myelodysplastic syndrome with excess of blasts 2; R/R: Relapsed or refractory.

common grade 3 or higher adverse event (AEs) were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%) and QT interval prolongation (13%) [50]. Based on this study, the FDA approved ivosidenib as first-line treatment for patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy [51]. Furthermore, an ongoing open-label, multicenter, Phase I trial (NCT02632708) was evaluating the efficacy of ivosidenib or enasidenib in patients with previously untreated AML (de novo or secondary) with documented IDH1 or IDH2 mutations. Ivosidenib or enasidenib were combined to standard chemotherapy. Ivosidenib was given at a dosage of 500 mg orally once daily in combination
with daunorubicin 60 mg/m2 /day or idarubicin 12 mg/m2 /day × 3 days with cytarabine 200 mg/m2 /day 7 days. At data cut-off date, 27 patients were treated with ivosidenib with a median age of 60 years. The ORR was 86% in patients (12/14) with de novo AML and 44% in patients (4/9) with secondary AML. The CR rate in all patients was 63%. Six patients in the ivosidenib group proceeded to HSCT [52].

Enasidenib
Enasidenib (AG-221) is a first-in class, small molecule, oral, selective inhibitor of IDH2 and is the first oral targeted therapy approved in the USA for the treatment of R/R AML with IDH2 mutation.
Enasidenib was evaluated in a first-in-human, open-label, multinational Phase I/II trial in patients with R/R IDH-2 mutant advanced myeloid malignancies (NCT01915498). Eligibility criteria were patients with 18 years or older, ECOG PS of 0–2 and confirmed diagnosis of AML or of myelodysplastic syndromes with refractory anemia with excess blasts and IDH2 mutation. This trial assessed the safety, MTD, pharmacodynamic and pharmacokinetic profiles and the efficacy of enasidenib in these patients. The MTD was not reached at doses ranging from 50 to 650 mg per day. Based on pharmacological profiles and demonstrated efficacy the dosage of 100mg per day was selected for the expansion phase. In an interim safety and efficacy analysis of 239 patients enrolled, the ORR in patients with R/R AML, defined as CR, CRh, partial remission and morphologic leukemia-free state was 40.3% with median response duration of 5.8 months. CR was observed in 19.3% of patients. IDH2-R140 mutation was found in 75% of patients and IDH2-R172 in 24% of patients. Median time to first response was 1.9 months (range: 0.5–9.4 months). The ORR for patients treated with enasidenib at a dosage of 100 mg once daily (107 patients) was 38.5% with a complete response in 20.2% of patients. Stem cell transplant was performed in 10% of patients. The median OS in patients with relapsed or refractory AML was 9.3 months (19.7 months in patients with CR

Newly diagnosed acute myeloid leukemia in fit patients

IDH mutation
No target FLT3 mutation CD33 expression

Clinical trial
or 3 + 7 regimen + midostaurin

Clinical trial or gilteritinib
or
hypomethylat
ing agents
Clinical trial or 3 + 7 regimen
Clinical trial or 3 + 7 regimen Clinical trial or 3 + 7 regimen
+/- gemtuzumab ozogamicin

Clinical trial or
hypomethyl- ating agents

Clinical trial or ivosidenib (IDH1m) or enasidenib
(IDH2m)

Clinical trial
or gemtuzumab ozogamicin

Figure 1. Proposed algorithm for the treatment of acute myeloid leukemia in fit patients.

and 14.4 months in patients with non-CR response) at a median follow-up of 7.7 months. Treatment-emerged adverse events (TEAE) occurred in 195 patients (82%). The most frequent treatment-related TEAE were indirect hyperbilirubinemia (38%) and nausea 23%. Grade 3 or 4 TEAEs were observed in 99 patients (41%), the most common was indirect hyperbilirubinemia (12%) and differentiation syndrome (7%). Serious TEAE occurred in 58 patients (24%), the most common was differentiation syndrome (8%), leukocytosis (4%), tumor lysis syndrome (3%), nausea (2%) and hyperbilirubinemia (2%) [3]. Based on the results of this pivotal study, the FDA approved enasidenib for the treatment of patients with relapsed or refractory AML with IDH2 mutation in August 2017 [53].
Recently, Stein et al. reported an update of the results. A total of 345 patients were enrolled at 21 sites of whom 280 patients presented R/R AML and 214 patients received 100 mg of enasidenib once daily. IDH2-R140Q mutations were found in 76% of patients and IDH2-R172 mutations were found in 24% of patients. The ORR in the 100 mg cohort was 38.8%; 19.6% of patients presented CR. There was no significant difference in ORR between patients with IDH2-R140 mutations and patients with IDH2-R172 mutations (35.8 vs 47.1%; p = 0.187). The median OS was 8.8 months. There was no statistical difference in median OS in patients with IDH2-R140 mutations and patients with IDH2-R172 (8.2 vs 10.6 months). The median OS for patients with CR and treated with 100 mg once daily of enasidenib was 22.9 months. The magnitude of 2-HG reduction was associated with CR in patients with IDH2-R172 mutations. The most common grade 3 or 4 treatment-related adverse events were indirect hyperbilirubinemia (10%), thrombocytopenia (7%) and differentiation syndrome (6%) [54].
Enasidenib was also evaluated as monotherapy in previously untreated older patients with IDH2-mutant AML in an open-label, multicenter, signal arm Phase I/II study. Patients with newly diagnosed IDH2-mutant AML, who were not candidates for standard AML treatments and who had ECOG PS of 0–2 were selected. A total of 39 patients were enrolled, of whom 29 patients were treated with the recommended 100 mg daily dose in the study extension phase. Median age was 77 years (range: 58–87). IDH2-R140 mutations were found in 67% of patients and IDH2-R172 in 31% of patients. Co-mutation burden was significantly higher in the subgroup of patients with IDH2-R140 mutations versus patients with IDH2-R172 mutations (mean 3.9 vs 2.3; p = 0.0088). The ORR was 30.8%, the median time to first response was 1.9 months and the median time to best response

was 3.7 months. CR was observed in seven patients (18%). There was no significant difference in OR between patients with IDH2-R140 mutations and IDH2-R172 mutations (31 and 33%). The estimated median OS was 11.3 months and the median OS in responding patients was not reached. The most common treatment-related TEAE were similar to those observed in previous studies such as indirect hyperbilirubinemia (31%), nausea (23%), rash (18%), fatigue (18%), decreased appetite (18%) and anemia (15%). Treatment-related grade 3–4 TEAEs were observed in 49% of patients. The most common were indirect hyperbilirubinemia (13%), anemia (13%) differentiation syndrome (10%), thrombocytopenia (8%) and tumor lysis syndrome (8%) [55].
The differentiation syndrome (DS) is a clinical syndrome characterized by dyspnea, culture-negative fever, weight gain, hypoxia, unexplained hypotension, acute kidney injury and pulmonary infiltrates which can be fatal if not treated. The DS occurred after a median time of 30 days after the beginning of IDH inhibitors (range: 7–129 days). Patients who presented DS received symptomatic treatment with corticosteroids such as dexamethasone 10 mg twice daily for a median duration of 12 days (range: 4–43 days). Corticosteroids are continued until signs and symptoms are significantly improved. In addition, empiric treatment for other possible causes such as anti-infective agents and hydroxyurea for management of co-occuring leukocytosis are also recommended. Hospitalization is indicated in patients with rapidly progressing symptoms (especially respiratory symptoms), development of hypoxia, renal failure and rising white blood cells count. Two of 34 patients (6%) who experienced DS with ivosidenib died [56,57].
It is to be noted that a novel concept in patients with AML without intent to cure was adopted by the FDA to approve IDH1 and IDH2 inhibitors. In fact, clinical benefit was important for regulatory-decision making. Febrile neutropenia and severe infection were lower in patients with durable CR/CRh compared with patients who do not responded to these agents and these patients were less dependent of transfusions. Despite response of patients with CRh were less durable than patients with CR, it provided transient clinical benefit to patients [57]. Table 3 summarizes the most important ongoing trials evaluating enasidenib and ivosidenib in patients with R/R AML or in newly diagnosed untreated AML in combination with intensive chemotherapy or hypomethylating agents. Figure 1 showed a proposed algorithm for the treatment of AML in fit patients.

Future perspective
Targeted therapies are changing the landscape of treatment of AML and have approved as monotherapy in relapsed/refractory disease. The next step is to integrate these targeted therapies in induction therapy to improve outcomes in patients with driver mutations. Venetoclax which is a Bcl2 inhibitor is approved in combination with hypomethylating agents or low dose cytarabine for the treatment of frail or elderly patients. Other targeted therapies are under investigation such as dual affinity retargeting agents targeting CD3 and CD123, bispecific antibodies, antibody-drug conjugates (such as IMGN632 an investigational anti-CD123), FLT3 and/or IDH inhibitors. In the future, AML could be cured with targeted therapies and may be without chemotherapy.

Executive summary
Gemtuzumab ozogamicin
•Gemtuzumab ozogamicin was withdrawn from market in June 2010 due to higher induction mortality.
•Gemtuzumab ozogamicin was re-approved by the US FDA in 2017 for the treatment of newly diagnosed CD33+ AML with induction as fractioned schedule in adults and for CD33+ relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults and children ≥2 years.
FLT3 inhibitors
•Midostaurin is approved by the FDA for the treatment of adults with newly diagnosed FLT3-mutated AML in combination with standard daunorubicin and cytarabine induction and cytarabine consolidation.
•Quizartinib was not approved by the FDA for the treatment of R/R AML. An ongoing Phase III trial is evaluatin quizartinib in newly diagnosed FLT3-mutated AML in combination with chemotherapy (QuANTUM-first).
•Gilteritinib is approved by the FDA for the treatment of R/R FLT3-mutated AML. IDH inhibitors
•Ivosidenib, which is an IDH1 inhibitor, is approved for the treatment of adults with relapsed or refractory AML harboring IDH1 mutations.
•Ivosidenib is approved in first-line treatment in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.
•Enasidenib, which is an IDH2 inhibitor, is approved for the treatment of patients with relapsed or refractory AML with IDH2 mutation.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan- cial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

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