Abstract

Therapeutic approaches for acute myeloid leukemia (AML) have witnessed minimal evolution in recent decades, primarily relying on advancements in supportive care and transplantation to drive improvements in overall survival rates. However, treatment with intensive chemotherapy may not be feasible for patients with advanced age or reduced fitness, and outcomes for patients with relapsed/refractory disease continue to be suboptimal. Several agents with a novel mechanism of action have been developed in the past decade and have shown efficacy in patients with both newly diagnosed and relapsed AML. Out of these, several FLT3 (FMS like tyrosine kinase 3) and IDH1/2 (isocitrate dehydrogenase 1/2) inhibitors have received regulatory approval in specific clinical settings and are available for clinical use. This is an actively expanding field with several ongoing clinical trials in advanced phases. We provide a focused narrative review of drugs from these two categories with available clinical data.

Introduction

Drug therapy for acute myeloid leukemia (AML) has remained largely unchanged since the introduction of the “7 + 3” regimen in 1973, with most of the subsequent improvement in survival attributable to advances in supportive care, infection control, and allogeneic stem cell transplantation.[1] [2] Risk-adapted use of intensive chemotherapy and stem cell transplantation following induction now allows 30 to 50%-of younger, medically fit patients to achieve long-term cure.[3] [4] Despite these advances, reliance on intensive chemotherapy presents several challenges that prevent optimal outcomes in specific clinical settings. First, intensive chemotherapy is often precluded by advanced age, reduced patient fitness, and/or financial limitations. A significant proportion of patients older than 60 years of age may not be candidates for intensive therapy and receive hypomethylating agents alone.[5] Improvements in survival over the past few decades have eluded older patients with AML, even in developed nations and necessitate newer nonchemotherapy approaches.[6] Second, relapsed or refractory disease is still associated with a poor long-term survival worldwide and is expected to benefit from newer therapies, similar to other hematologic malignancies.[7]

Several of these challenges are addressed by targeted oral agents, which represent the first drug approvals for AML in the past few decades. These small molecule inhibitors have demonstrated efficacy in both newly diagnosed and relapsed settings and are gradually transitioning to first-line therapy in combination or even as monotherapy, offering a new treatment approach for unfit patients who would not receive any treatment in the past.[4] [8] These advances are relevant for India, where despite a lower age of presentation, physiological frailty is evident and very few patients over the age of 60 years receive intensive chemotherapy with curative intent.[5] Further, survival after relapsed disease in India is suboptimal, with low rates of allogeneic stem cell transplantation, warranting the introduction of newer, less toxic treatment options.[9]

Oral agents for AML are categorized based on their distinct cellular targets, each exhibiting unique mechanisms for efficacy and toxicity. We present a succinct and targeted review that incorporates the available supporting evidence and clinical application of presently accessible targeted oral agents (FMS like tyrosine kinase 3 [FLT3] inhibitors and isocitrate dehydrogenase 1/2 [IDH1/2] inhibitors) for AML.

Isocitrate Dehydrogenase Inhibitors

Cellular Mechanism

IDH enzymes catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) by oxidative decarboxylation along with simultaneous reduction of NADP to NADPH. IDH1 and IDH2 are isozymes with significant sequence similarity and are mutated in several malignancies.[10] IDH3 is structurally distinct and does not have a defined pathogenic role at present. Relevant mutations in IDH1 and IDH2 were first identified in 2011, and since then have been consistently demonstrated at a frequency of 10 to 20%-in patients with AML.[11] [12] Mutations in IDH1/2 modify the metabolic pathway to produce R-2- hydroxyglutarate instead of α-KG, leading to inhibition of several α-KG-dependent enzymes. This leads to a cellular differentiation block by inhibiting several enzymes involved in histone and DNA methylation.[13] Downstream effects from altered cell differentiation and cell cycle control promote leukemogenesis in vitro and are viable targets for inhibition in patients with AML.[14] Both IDH1 and IDH2 mutations have a similar mechanism of contributing to pathogenesis of AML. T Common point mutations noted in IDH1 and IDH2 are R132H and R172K, respectively, and are mutually exclusive.

Enasidenib

IDH2 mutations are noted in approximately 10 to 12%-of patients with AML and frequently occur along with mutations in genes affecting epigenetic pathways (ASXL1, SRSF2, RUNX1, and STAG2).[15] Enasidenib is a selective IDH2 inhibitor that was first shown to be effective in mouse xenograft models, significantly reducing cellular 2-KG levels, promoting cellular differentiation and improving survival.[16] Its safety and clinical activity as monotherapy was documented in a phase 1b dose escalation study, which included 239 patients with relapsed AML. An overall response rate (ORR) of 40.4%-and a complete remission (CR) rate of approximately 19.3%-was observed, with a median time to CR of 3.8 months (range, 0.5–11.2). Median overall survival (OS) was 9.3 months, with survival at 1 year of approximately 39%.[17] The most significant nonhematologic toxicity was differentiation syndrome (DS), observed in approximately 8%-of patients. Further analysis of these data indicated that DS was more likely in patients with higher bone marrow blast counts and typically observed after a median of 30 days (range, 7–129) from starting treatment. Importantly, DS was reversed with temporary cessation of enasidenib and early initiation of steroids in all patients.[18]

Enasidenib exhibited effectiveness as a standalone treatment as well in 37 patients in the above cohort with previously untreated IDH2-mutated AML who were not eligible for standard therapy. In this cohort with a median age of 77 years, an ORR of 37.8%-and CR of 19%-was observed. Median OS was 10.4 months, indicating potential efficacy as first-line monotherapy.[19]

A recent phase 3 trial (IDHentify) evaluated patients older than 60 years of age with relapsed or refractory disease after failure of at least two lines of therapy. A total of 267 patients underwent randomization, with equal distribution between the enasidenib group and the conventional low-dose therapy group. Although no statistically significant disparities in OS were identified (6.8 vs. 6.2 months), the enasidenib cohort exhibited higher rates of complete response (26 vs. 3%) and ORR (41 vs. 11%).[20] A recent update of these data presented in the 2022 American Society of Clinical Oncology (ASCO) meeting showed a specific OS advantage for patients with the R172 mutation (14.6 vs. 7.8 months), which was not seen with patients with R140 mutations.[21]

Based on efficacy in patients with newly diagnosed AML, enasidenib was evaluated in a pragmatic combination with azacytidine in a phase II trial including patients with IDH2-mutated AML. A total of 26 patients were included (19 relapsed and 7 newly diagnosed) to receive enasidenib and azacytidine, with concomitant FT3 inhibitors and venetoclax allowed. Cumulative CR was noted in 100%-of newly diagnosed patients and 58%-with relapsed/refractory disease. This combination was well tolerated with a 6-month OS of 70%-in newly diagnosed patients with median OS not reached after 11 months of follow-up period.[22] Comparable outcomes were achieved in a multicenter phase 2 trial that randomized participants to receive either azacytidine alone or in combination with enasidenib. The combined therapy demonstrated a notably superior ORR of 74%-compared with 36%-in the azacytidine monotherapy group.[23]

Of significant clinical interest, enasidenib was found to be safe in combination with venetoclax for pretreated patients with IDH2-mutated AML, showing an ORR of 55%.[24] Further dose finding studies of this combination are ongoing.

Ivosidenib

Ivosidenib (AG-120) was the first in-class IDH1 inhibitor developed with activity against several solid tumors.[25] It's clinical activity in AML as monotherapy was documented in a phase 1 study including 258 patients with relapsed/refractory disease following a median of two prior lines of therapy.[26] The rate of CR + CR with incomplete count recovery (CRi) was 30%, with median time to CR of 2.7 months and median OS of 14.5 months. It was well tolerated with the most common nonhematologic toxicities being QTc prolongation (7.8%) and DS (3.9%). Based on these data, it received U.S. Food and Drug Administration (FDA) approval in 2018 for patients with relapsed/refractory IDH1-mutated AML.

Ivosidenib also demonstrated single-agent activity in newly diagnosed patients ineligible for standard chemotherapy (median age, 76 years), with CR + CRi rates of 42.4%-and a median OS of 12.6 months.[27] It's safety and activity in combination with azacytidine in a phase 1b trial in patients with IDH1-mutated AML formed the basis for the randomized phase 3 AGILE trial, which led to regulatory approval for newly diagnosed patients in this setting.[28] [29] This trial included 146 newly diagnosed patients who were randomized to azacytidine alone or in combination with ivosidenib. Combination therapy was associated with a higher median OS (24 vs. 7.9 months) and lower risk of treatment failure, relapse, or death (hazard ratio [HR] = 0.33, 95%-confidence interval [CI] = 0.16–0.69) compared with azacytidine alone. Unique nonhematologic adverse effects in the ivosidenib arm included QT prolongation in 20%-and DS in 14%-patients. Following the evidence from these findings, the FDA granted approval to ivosidenib in May 2022 for its utilization in combination with azacytidine as a treatment option for newly diagnosed patients with IDH1-mutated AML.

Ivosidenib and enasidenib are also being evaluated in combination with intensive cytotoxic chemotherapy in newly diagnosed patients with IDH1/2-mutated AML. In 2021, the publication of phase 1 data presented findings from a study involving a cohort of 60 patients who received ivosidenib and 91 patients who received enasidenib in combination with intensive chemotherapy.[30] This study observed CR in 55 and 47%-and CRi in 72 and 63%-patients with ivosidenib and enasidenib, respectively. The median OS in the ivosidenib cohort was not reached and with enasidenib was 25 months. Among patients achieving CRi, minimal residual disease (MRD) negativity was noted in 80 and 63%, respectively. This study indicated the feasibility of adding IDH1/2 inhibitors along with intensive chemotherapy for newly diagnosed patients.

Ivosidenib is metabolized by the CYP3A4 enzymes, and drug toxicity can potentially increase in the presence of strong CYP3A4 inhibitors such as posaconazole and voriconazole. The manufacturer recommends reducing the dose to 250 mg once a day when used with concomitant azoles due to a higher risk of QTc prolongation.[31] However, a population pharmacokinetic analysis observed that increasing area under the curve (AUC) in the presence of azoles was not associated with an increase in clinical toxicity, likely indicating a wide therapeutic window.[32] As a result, the current expert opinion is to exercise “caution” in the presence of azoles and monitor the QTc interval closely while continuing the drug at the full dose of 500 mg per day.[33]

No significant safety concerns were highlighted on using a combination of ivosidenib with azacytidine and venetoclax in a phase Ib/III study, indicating a potentially new combination for IDH1-mutated AML.[34]

Olutasidenib

Olutasidenib (FT-2102) is a potent, selective IDH1 inhibitor, designed to induce differentiation of cells with mutated IDH1.[35] It was first evaluated in a phase 1 trial including 31 patients with IDH1-mutated AML or MDS, where an ORR of approximately 33%-was documented.[36] Dose escalation and safety of combination with azacytidine was subsequently evaluated in a similar patient population, where an ORR of 39%- for single agent and 54%-for combination therapy was noted. Importantly, 40% patients had mutation clearance, with mIDH1 Variant Allele Frequency (VAF) of <1 href="https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0044-1779621#JR2351224-37" xss=removed>37]

The phase 1 component of a multicenter trial (NCT NCT02719574) evaluating olutasidenib was published in 2022, including patients with IDH1-mutated AML or MDS both as single agent (n = 32) and in combination with azacytidine (n = 46) For patients with relapsed AML, ORR of 41% as monotherapy and 46%-as combination were observed.[38] For treatment-naïve patients, response rates of 25%-for monotherapy and 77%-for combination were observed.

The phase II component of the multicenter trial planned to evaluate the efficacy of olutasidenib both as single agent and in combination with azacytidine for patients with AML/MDS. The final analysis included 153 patients with IDH1-mutated AML after a median of two lines of therapy, of which 147 were evaluable. In this subset, monotherapy with 150 mg twice a day was initiated, with ORR of 48%-and CR + CRi rates of 35%. The median duration of overall response was 11.7 months and median OS was 11.6 months.[39] Based on this study (2102-HEM-101), olutasidenib received FDA approval in December 2022 as monotherapy for patients with relapsed/refractory AML at a dose of 150 mg twice a day.

Phase 2 data on treatment-naïve patients was presented in 2021, in which patients were divided into four cohorts based on prior therapy and exposure to IDH1 inhibitors or Hypomethylating agents (HMAs).[40] In treatment-naïve patients, ORR of 64%-and CR of 45%-was documented. In R/R disease without previous HMA or IDH1 inhibitor exposure, similar response rates and median CR duration of 16 months was documented.

FMS-Like Tyrosine Kinase 3 Inhibitors

Cellular Mechanism

FLT3 is a receptor kinase required for hematopoietic cell proliferation and differentiation.[41] The presence of FLT3 mutations was initially discovered in patients with AML in 1996, and since then, it has been recognized as one of the most frequent mutations observed in AML. Approximately 25%-of all patients with AML have the FLT3 internal tandem duplication (FLT3-ITD) and 5%-have a tyrosine kinase domain (FLT3-TKD) mutation.[42] The pathogenic mechanism of the FLT3-ITD mutation is complex and is described in a succinct review by Friedman et al.[43] FLT3-ITD mutations give rise to the dissociation of the intracellular juxtamembrane domain from the FLT3 receptor, resulting in persistent downstream activation of phosphorylation and subsequent cellular proliferation.

Mutations in FLT3 do not lead to an AML phenotype in isolation, indicating that these mutations are late events with a greater role in altering disease phenotype than disease initiation, in contrast to BCR/ABL1 mutations in chronic myeloid leukemia.[44] Most initial studies therefore focused on combining FLT3 inhibitors with standard treatment rather than as monotherapy. FLT3 mutations also have a role in posttransplant relapse, providing an impetus for several studies using FLT3 inhibitors in posttransplant maintenance.[45]

First-Generation Inhibitors

Sorafenib, midostaurin, lestaurtinib, and sunitinib are among the first-generation FLT3 inhibitors, characterized by their ability to inhibit multiple kinases. As a result, several off target adverse events are noted with this group of drugs.[46]

Sorafenib

Sorafenib, an orally administered multikinase inhibitor, was developed in 2001 and subsequently gained approval for the treatment of various solid tumors. It was first demonstrated to have activity against AML cell lines in vitro in 2008, indicating potential clinical benefit. Importantly, sorafenib-induced apoptosis in AML was synergistic with cytarabine and BCL2 inhibitors.[47] Clinical activity and safety of sorafenib was demonstrated in a phase I study including 50 unselected patients with advanced MDS or relapsed acute leukemias. A significant reduction in blast count, especially in FLT3-mutated AML was observed with sorafenib monotherapy.[48] As a synergistic action with chemotherapy was known, further clinical studies were largely performed as part of combination therapy.[49]

Sorafenib was shown to be safe and effective in combination with intensive chemotherapy with idarubicin and cytarabine in a phase I/II study including 51 patients. The initial rates of CR were promising, being 75%-for the overall cohort and 93%-in those with FLT3 mutations.[50] Further follow-up of this study included 62 patients and confirmed a higher rate of initial CR and CR with Partial count recovery (CRp) in patients with FLT3 mutations (95 vs. 83%) but failed to show a durable clinical benefit. Survival was inferior among patients with FLT3 mutations compared with wild type FLT3, with OS of 15.5 vs. 42 months and DFS of 9.9 vs. 17.3 months, primarily owing to high rates of relapse in this subgroup.[51] A similar combination also failed to show any advantage of adding sorafenib to intensive chemotherapy in a randomized trial including 200 newly diagnosed patients unselected for FLT3 mutations.[52]

The SORAML trial, a recent randomized study, featured sorafenib in combination with intensive chemotherapy and enrolled newly diagnosed patients below the age of 60. This phase 2 trial examined the effects of sorafenib in the specified patient population, including 276 patients (chemotherapy + sorafenib 134, chemotherapy + placebo 133). Patients were not selected for FLT3 mutations, which were present in 17%-of patients in both arms. There was no significant difference in rates of CR among both arms (60 vs. 59%). After a median follow-up of 36 months, median event-free survival (EFS) was higher with sorafenib (21 vs. 9 months), but there was no difference in OS. A nonsignificant difference in EFS was noted in patients with FLT3 mutations (18 vs. 6 months). However, there was a significantly higher risk of hand–foot syndrome, diarrhea, and cardiac events in the sorafenib group.[53] Updated analysis published in 2021 after a median follow-up of 78 months demonstrated the sorafenib arm to have a higher EFS (41 vs. 27%) and relapse-free survival (53 vs. 36%) without any OS advantage (5-year OS 63 vs. 51%).[54]

The evaluation of sorafenib's effectiveness in a patient population with a high prevalence of FLT3 mutations has solely relied on a retrospective study encompassing 183 patients, with a median age of 52 years. Patients were compared based on whether the initial therapy was intensive chemotherapy alone or with sorafenib. After propensity matching, addition of sorafenib demonstrated a higher ORR (99 vs. 83%), similar rates of CR (79 vs. 74%), and a higher OS (42 vs. 13 months). As most of the above studies have not shown a uniform clinical benefit in a prospective setting, sorafenib is currently not approved for routine use in AML. Prospective studies including patients enriched for FLT3 mutations are expected to provide a clearer picture of its clinical efficacy.

Sorafenib is presently undergoing evaluation as an integral component of standard therapy for patients who have recently been diagnosed (NCT05404516) and as an adjunct to conditioning in the context of stem cell transplantation (NCT03247088).

Midostaurin

Midostaurin, classified as a first-generation multikinase inhibitor, exhibits inhibitory effects on FLT3, vascular endothelial growth factor receptor-2, c-kit, platelet-derived growth factor receptor-α (PDGFRα), and PDGFRβ. The clinical efficacy of midostaurin was demonstrated in a phase 2 trial involving a cohort of 20 patients diagnosed with FLT3-mutated AML or high-risk MDS. When administered as a standalone treatment, midostaurin exhibited noteworthy clinical activity, resulting in a substantial decrease in both blood and marrow blast counts.[55] Similar to sorafenib, most further studies evaluated midostaurin as part of combination therapy. The safety profile of midostaurin in conjunction with intensive chemotherapy was evaluated in a phase 1b trial involving 40 newly diagnosed patients below the age of 60, of whom 13 exhibited FLT3 mutations. The trial encompassed three distinct dosing schedules for midostaurin, and the results demonstrated a favorable safety profile. Importantly, midostaurin achieved a complete response in 92% of patients with FLT3 mutations, while maintaining an acceptable level of safety.[56]

Based on these data, it was evaluated in a phase 3 trial (RATIFY) that randomized 717 patients with FLT3 mutation at diagnosis to receive intensive chemotherapy alone or with midostaurin.[57] Initial rate of CR was similar with addition of midostaurin (58 vs. 53.5%) with median time to CR of 35 days. After a median follow-up of 59 months, OS was higher in the midostaurin group (74 vs. 25.6 months) with a 4-year OS of 51 versus 44%. However, several concerns were identified with this trial, which warrant further consideration.[58] For instance, the median age of patients with FLT3 mutations in this trial was much younger compared with published data and the study population was unusually enriched for FLT3-TKD mutations (22%-compared with 5–6%-in general). Patients with FLT3-TKD mutations, which do not result in worse prognosis compared with wild type FLT3, also experienced significant clinical benefit from midostaurin. This finding supports the approval of midostaurin by the FDA in 2017 for newly diagnosed patients with FLT3-mutated AML, as it demonstrates the efficacy of the treatment across different FLT3 mutation subtypes.

It is essential to remember that midostaurin has no significant activity in patients with relapsed/refractory AML with preclinical studies only documenting “blast reduction” with no durable response.[59] Ongoing studies are currently assessing the efficacy of midostaurin in combination with gemtuzumab (NCT03900949, NCT04385290) and CPX-351 (NCT04982354) as part of the treatment regimen for newly diagnosed patients. These trials aim to further explore the potential benefits of incorporating midostaurin into combination therapies and expand our understanding of its effectiveness in different treatment approaches.

Concomitant use of posaconazole or voriconazole is associated with a significant rise in downstream metabolites and a 1.4-fold rise in drug exposure.[60] However, no clear effect on excessive toxicity has been observed, except a possible correlation with pulmonary toxicity initially noted in the RATIFY trial. In this trial, no dose reduction was specified, and a subsequent analysis observed that a higher-dose intensity was associated with higher clinical benefit without any increase in toxicity.[61] Thus, the current recommendation is to continue the drug at full dose along with azoles while closely watching for pulmonary complications to achieve maximal efficacy.[62]

Second-Generation FLT3 Inhibitors

Nondurability of clinical response and limited single-agent activity are important limitations of first-generation FLT3 inhibitors. Use of FLT3 inhibitors is also fraught with development of resistance mediated by secondary mutations in either FLT3-TKD or other related genes including NRAS and AXL, which allow a proliferative signal even in the presence of FLT3 inhibitors.[63] Second-generation FLT3 inhibitors were developed with an intention to overcome these limitations and provide better efficacy as monotherapy.

Quizartinib

Quizartinib (AC-220) was the first compound selectively designed to inhibit mutant FLT3-ITD with high potency and specificity, intended to overcome limitations of first-generation drugs.[64] Quizartinib underwent its initial evaluation in a phase I trial that enrolled 76 patients with relapsed AML who had experienced treatment failure following a median of three prior therapies, irrespective of their FLT3 mutation status. The primary objective of the trial was to assess the safety and tolerability of quizartinib in this specific patient population. The study aimed to gather preliminary data on the efficacy and potential therapeutic benefits of quizartinib as a treatment option for relapsed AML patients who had exhausted multiple prior therapies. ORR was 30%, with higher responses in the FLT3-ITD-mutated subset, with a median OS of 14 weeks. The most common dose-limiting serious adverse event was QT prolongation, noted in 12%-of the population.[65]

The efficacy of quizartinib was subsequently evaluated in a phase 2 trial, specifically as a monotherapy, in a cohort of 333 patients with relapsed or refractory AML.[66] The study group was divided into two cohorts, first >60 years who progressed within 1 year of first-line therapy and second >18 years of age who received at least one salvage after progression. The rate of composite CR (CRc) in patients with FLT3 mutations in the first cohort was 56%-and in the second was 46%. QTc prolongation was noted in 10%-of patients.

The efficacy of quizartinib was assessed in a phase 3 trial known as QUANTUM-R, which specifically targeted patients with relapsed or refractory AML harboring FLT3-ITD mutations. In this trial, a total of 367 patients were randomly assigned to receive either quizartinib alone or salvage chemotherapy, with a ratio of 2:1.[67] The rate of CRc in the quizartinib group was 48%-and chemotherapy group was 27%. Median time to first CRc was 4.9 weeks for quizartinib. After a median follow-up of 23.5 months (interquartile range: 15–32), median OS was higher with quizartinib (6.2 vs. 4.7 months, p = 0.02). Grade 3 QTc prolongation was present in 4%-of patients in the quizartinib arm. Although this survival advantage may not be clinically significant, this trial demonstrated the feasibility of monotherapy with an oral drug in the relapsed/refractory setting.

Recently, data on front-line use of quizartinib was presented at the EHA 2022 meeting (Quantum-First study, EHA Abstract Erba H. 356965). A total of 539 patients were initiated on standard intensive chemotherapy and randomized to additionally receive quizartinib or placebo. Initial CR rates were similar (71 vs. 64%), although there was an increased risk of neutropenia with quizartinib. After a median follow-up of 39.2 months, OS was longer in the quizartinib arm (31.9 vs. 15 months). After censoring for hematopoietic stem cell transplantation, a trend to longer OS with quizartinib was observed (HR = 0.752; 95%-CI = 0.56–1.008). These data led to accelerated regulatory approval of quizartinib as first-line therapy for newly diagnosed patients with FLT3-ITD mutations. Further studies of quizartinib in combination with idarubicin/cytarabine and cladribine (NCT04047641) and with azacytidine/venetoclax (NCT04687761) are currently underway.

Quizartinib is also metabolized by hepatic enzymes, and a 2-fold rise in maximal concentration and AUC is noted on concomitant use of azoles (except fluconazole).[68] A dose-dependent increase in the risk of QTc prolongation is noted, and dose reduction is recommended when using with concomitant strong CYP3A4 inhibitors such as posaconazole and voriconazole.[69]

Gilteritinib

Gilteritinib, a small molecule inhibitor of FLT3 and multiple kinases (FLT3-ITD, FLT3-TKD, c-Kit, ALK, and AXL), exhibits potent and long-lasting inhibitory effects, particularly against FLT3-ITD. Its inhibitory activity surpasses that of first-generation inhibitors, suggesting superior efficacy.[70] Inhibition of AXL and FLT3-TKD is clinically relevant due to their role in mediating secondary resistance to FLT3 inhibitor therapy.[71]

Safety and dosing of gilteritinib was established in a phase 1/2 study including 252 patients with relapsed/refractory AML. More than 90%- inhibition of FLT3 signaling was observed with an ORR of 40%.[72] The most common toxicity was diarrhea and elevated liver enzymes. Further follow-up of these data indicated an ORR of 49%-in patients with mutated FLT3. Patients who received a daily dose of >80 mg exhibited a median response duration of 20 weeks, accompanied by a median OS of 31 weeks.[73]

The promising efficacy observed as a single agent prompted the initiation of the phase 3 ADMIRAL trial. This trial involved the randomization of 371 patients with relapsed/refractory AML to receive either gilteritinib alone or salvage chemotherapy.[74] FLT3-ITD mutations were present in 88.4%-of the overall cohort. CRc rate with gilteritinib was 54.3% compared with 21% with salvage chemotherapy (HR = 32.5; 95%-CI = 22.3–44). Median OS with gilteritinib was 9.3 versus 5.6 months (HR for death = 0.64; 95% CI = 0.49–0.83). A higher proportion of patients received an allogeneic transplant in the gilteritinib arm (25 vs. 15%), but a survival advantage was maintained after censoring at the time of transplant. Importantly, equivalent efficacy was also maintained in patients with a FLT3-TKD mutation.

Long-term data from this trial were recently published in June 2022 with a median follow-up period of 37 months. As most relapses occurred in the first 18 months, OS at the end of follow-up was similar to data from the ADMIRAL trial. Two-year survival probability was higher with gilteritinib (20.6 vs. 14.2%). Serious adverse events were noted in 20.3%-of patients receiving gilteritinib, the most common being elevated liver enzymes followed by cardiac events.[75] Although this study highlighted maximal clinical benefit for patients with FLT3-ITD high allelic ratio, a uniform benefit irrespective of FLT3-ITD allelic ratio and presence of comutations was confirmed in a subsequent analysis.[76] Based on these data, gilteritinib received regulatory approval for patients with relapsed/refractory AML with FLT3 mutations.

Gilteritinib was also evaluated recently in newly diagnosed patients with mutated FLT3 in a phase 3 trial (LACEWING study) in which 123 patients were randomized 1:1:1 to receive azacytidine alone, gilteritinib alone or both in combination.[77] Despite higher response rates (58.1 vs. 26.5%) and similar toxicity, no OS benefit was observed with combination therapy and the study was prematurely terminated.

Notable ongoing studies include gilteritinib in combination with venetoclax and azacytidine for newly diagnosed patients (NCT05520567), a head to head comparison with midostaurin (NCT04027309) and in combination with a Syk inhibitor lanraplenib for relapsed disease (NCT05028751).

Gilteritinib is also metabolized by the CYP3A4 enzyme system, and an increased AUC is observed when used concomitantly with azoles.[78] However, no dose reduction is currently recommended as no increase in clinical toxicity has been observed.[33]

Crenolanib

Crenolanib is a quinolone derivative initially developed as a PDGFR-α/β inhibitor targeting various solid tumors.[79] It's potential antileukemic properties were observed in vitro using a xenograft mouse model in 2013 with documentation of significant FLT3-ITD inhibition. Importantly, it was active against several FLT3-TKD (except F691L) mutations, which confer resistance to FLT3 inhibitor therapy, indicating a role in pretreated patients.[80] [81]

Crenolanib was evaluated in a phase 2 study including 38 patients following a median of 3.5 prior lines of therapy, of which 13 were tyrosine kinase inhibitor (TKI) naïve and 21 had received previous TKI.[82] Among TKI-naïve patients, CRi + multiple layers file sharing system (MLFS) of 31%-was observed, compared with 5%-of those who had received previous TKI. Patients with CRi/MLFS had higher EFS (median: 22 vs. 8 weeks, p = 0.003) and OS (55 vs. 15 weeks, p = 0.166) with acceptable toxicity.

Efficacy in relapsed/refractory disease in combination with azacytidine or salvage chemotherapy was published in 2018 in a phase 2 study enrolling 28 patients, of which 20 received crenolanib with intensive chemotherapy and eight with azacytidine. ORR was 46%, with four patients achieving MRD negativity. Median OS was 4.7 months (range, 0.4–27 months) with no significant grade 3/4 adverse events.[83] Both of the aforementioned studies demonstrated the efficacy of crenolanib in relapsed/refractory AML. Intriguingly, among the patients who experienced disease progression while on crenolanib, resistance to treatment was observed to be driven by non-FLT3-dependent mechanisms, such as the emergence of secondary mutations in NRAS and IDH2.[84]

Crenolanib is recently being evaluated in newly diagnosed patients in combination with standard therapy. In a phase 2 study, 29 newly diagnosed FLT3-mutated patients were treated with intensive chemotherapy in combination with crenolanib and demonstrated MRD negativity in 80%-of patients at the end of induction.[85] Long-term results of the trial were presented in the 2022 ASCO meeting and included data from 44 patients. With a median follow-up of 45 months, median OS was not reached and median EFS was 45 months.[86] Ongoing phase III trials include the comparison of crenolanib with midostaurin as a follow-up therapy after initial treatment (NCT03258931) and the evaluation of crenolanib in combination with intensive chemotherapy for relapsed/refractory patients (NCT03250338).

[Tables 1] and [2] provide a summary of key trial results and important characteristics of the mentioned drugs, respectively, specifically focusing on drug administration

References

Yates JW, Wallace Jr HJ, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 1973; 57 (04) 485-488
PubMedGoogle Scholar
1. Bertoli S, Tavitian S, Huynh A. et al. Improved outcome for AML patients over the years 2000-2014. Blood Cancer J 2017; 7 (12) 635
   CrossrefPubMedGoogle Scholar
2. Shah A, Andersson TM, Rachet B, Björkholm M, Lambert PC. Survival and cure of acute myeloid leukaemia in England, 1971-2006: a population-based study. Br J Haematol 2013; 162 (04) 509-516
   CrossrefPubMedGoogle Scholar
3. Khanal N, Shostrom V, Dhakal P. et al. Determinants of ten-year overall survival of acute myeloid leukemia: a large national cancer database analysis. Leuk Lymphoma 2022; 63 (04) 939-945
   CrossrefPubMedGoogle Scholar
4. Singh S, Lionel S, Jain H. et al. Real world data on unique challenges and outcomes of older patients with AML from resource limited settings: Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC). Blood 2022; 140 (Suppl. 01) 6096-6098
   CrossrefGoogle Scholar
5. Naur TMH, Jakobsen LH, Roug AS. et al. Treatment intensity and survival trends among real-world elderly AML patients diagnosed in the period 2001-2016: a Danish nationwide cohort study. Leuk Lymphoma 2021; 62 (08) 2014-2017
   CrossrefPubMedGoogle Scholar
6. Medeiros BC. Is there a standard of care for relapsed AML?. Best Pract Res Clin Haematol 2018; 31 (04) 384-386
   CrossrefPubMedGoogle Scholar
7. Löwenberg B, Huls G. The long road: improving outcome in elderly “unfit” AML?. Blood 2020; 135 (24) 2114-2115
   CrossrefPubMedGoogle Scholar
8. Philip C, George B, Ganapule A. et al. Acute myeloid leukaemia: challenges and real world data from India. Br J Haematol 2015; 170 (01) 110-117
   CrossrefPubMedGoogle Scholar
9. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 2010; 102 (13) 932-941
   CrossrefPubMedGoogle Scholar
10. Patel KP, Ravandi F, Ma D. et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol 2011; 135 (01) 35-45
    CrossrefPubMedGoogle Scholar
11. Im AP, Sehgal AR, Carroll MP. et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia 2014; 28 (09) 1774-1783
    CrossrefPubMedGoogle Scholar
12. Ye D, Ma S, Xiong Y, Guan K-L. R-2-hydroxyglutarate as the key effector of IDH mutations promoting oncogenesis. Cancer Cell 2013; 23 (03) 274-276
    CrossrefPubMedGoogle Scholar
13. Losman JA, Looper RE, Koivunen P. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013; 339 (6127) 1621-1625
    CrossrefPubMedGoogle Scholar
14. Molenaar RJ, Thota S, Nagata Y. et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia 2015; 29 (11) 2134-2142
    CrossrefPubMedGoogle Scholar
15. Yen K, Travins J, Wang F. et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov 2017; 7 (05) 478-493
    CrossrefPubMedGoogle Scholar
16. Stein EM, DiNardo CD, Pollyea DA. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017; 130 (06) 722-731
    CrossrefPubMedGoogle Scholar
17. Fathi AT, DiNardo CD, Kline I. et al; AG221-C-001 Study Investigators. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol 2018; 4 (08) 1106-1110
    CrossrefPubMedGoogle Scholar
18. Pollyea DA, Tallman MS, de Botton S. et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia 2019; 33 (11) 2575-2584
    CrossrefPubMedGoogle Scholar
19. DiNardo CD, Montesinos P, Schuh AC. et al. Outcomes for patients with late-stage mutant-IDH2 (m IDH2) relapsed/refractory acute myeloid leukemia (R/R AML) Treated with enasidenib vs other lower-intensity therapies in the randomized, phase 3 IDHentify trial. Blood 2021; 138 (Suppl. 01) 1243-1243
    CrossrefGoogle Scholar
20. De Botton S, Risueño A, Schuh AC. et al. Overall survival by IDH2 mutant allele (R140 or R172) in patients with late-stage mutant-IDH2 relapsed or refractory acute myeloid leukemia treated with enasidenib or conventional care regimens in the phase 3 IDHENTIFY trial. J Clin Oncol 2022; 40 (16) 7005
    CrossrefGoogle Scholar
21. Venugopal S, Takahashi K, Daver N. et al. Efficacy and safety of enasidenib and azacitidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy. Blood Cancer J 2022; 12 (01) 10
    CrossrefPubMedGoogle Scholar
22. DiNardo CD, Schuh AC, Stein EM. et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol 2021; 22 (11) 1597-1608
    CrossrefPubMedGoogle Scholar
23. Chan SM, Cameron C, Cathelin S. et al. Enasidenib in combination with venetoclax in IDH2-mutated myeloid malignancies: preliminary results of the phase Ib/II Enaven-AML trial. Blood 2021; 138 (Suppl. 01) 126
    Google Scholar
24. Popovici-Muller J, Lemieux RM, Artin E. et al. Discovery of AG-120 (ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med Chem Lett 2018; 9 (04) 300-305
    CrossrefPubMedGoogle Scholar
25. DiNardo CD, Stein EM, de Botton S. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018; 378 (25) 2386-2398
    CrossrefPubMedGoogle Scholar
26. Roboz GJ, DiNardo CD, Stein EM. et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 2020; 135 (07) 463-471
    CrossrefPubMedGoogle Scholar
27. DiNardo CD, Stein AS, Stein EM. et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J Clin Oncol 2021; 39 (01) 57-65
    CrossrefPubMedGoogle Scholar
28. Montesinos P, Recher C, Vives S. et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med 2022; 386 (16) 1519-1531
    CrossrefPubMedGoogle Scholar
29. Stein EM, DiNardo CD, Fathi AT. et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood 2021; 137 (13) 1792-1803
    CrossrefPubMedGoogle Scholar
30. Merchant SL, Culos K, Wyatt H. Ivosidenib: IDH1 inhibitor for the treatment of acute myeloid leukemia. J Adv Pract Oncol 2019; 10 (05) 494-500
    PubMedGoogle Scholar
31. Jiang X, Wada R, Poland B. et al. Population pharmacokinetic and exposure-response analyses of ivosidenib in patients with IDH1-mutant advanced hematologic malignancies. Clin Transl Sci 2021; 14 (03) 942-953
    CrossrefPubMedGoogle Scholar
32. DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood 2020; 135 (02) 85-96
    CrossrefPubMedGoogle Scholar
33. Lachowiez CA, Borthakur G, Loghavi S. et al. Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/− azacitidine in IDH1-mutated hematologic malignancies. J Clin Oncol 2020; 38 (15) 7500-7500
    CrossrefGoogle Scholar
34. Venugopal S, Watts J. Olutasidenib: from bench to bedside. Blood Adv 2023; 7 (16) 4358-4365
    CrossrefPubMedGoogle Scholar
35. Watts J, Baer MR, Yang J. et al. Phase 1 study of the IDH1m inhibitor FT-2102 as a single agent in patients with IDH1m acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Blood 2018; 132: 1453
    CrossrefGoogle Scholar
36. Watts JM, Baer MR, Yang J. et al. Olutasidenib (FT-2102), an IDH1m inhibitor as a single agent or in combination with azacitidine, induces deep clinical responses with mutation clearance in patients with acute myeloid leukemia treated in a phase 1 dose escalation and expansion study. Blood 2019; 134: 231
    CrossrefGoogle Scholar
37. Watts JM, Baer MR, Yang J. et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol 2023; 10 (01) e46-e58
    CrossrefPubMedGoogle Scholar
38. de Botton S, Fenaux P, Yee K. et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv 2023; 7 (13) 3117-3127
    CrossrefPubMedGoogle Scholar
39. Cortes JE, Esteve J, Bajel A. et al. Olutasidenib (FT-2102) in combination with azacitidine induces durable complete remissions in patients with mIDH1 acute myeloid leukemia. Blood 2021; 138: 698
    CrossrefGoogle Scholar
40. Lyman SD, James L, Vanden Bos T. et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 1993; 75 (06) 1157-1167
    CrossrefPubMedGoogle Scholar
41. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100 (05) 1532-1542
    CrossrefPubMedGoogle Scholar
42. Friedman R. The molecular mechanisms behind activation of FLT3 in acute myeloid leukemia and resistance to therapy by selective inhibitors. Biochim Biophys Acta Rev Cancer 2022; 1877 (01) 188666
    CrossrefPubMedGoogle Scholar
43. Shouval R, Shlush LI, Yehudai-Resheff S. et al. Single cell analysis exposes intratumor heterogeneity and suggests that FLT3-ITD is a late event in leukemogenesis. Exp Hematol 2014; 42 (06) 457-463
    CrossrefPubMedGoogle Scholar
44. Schmid C, Labopin M, Socié G. et al; Acute Leukemia Working Party of the European Group of Blood and Bone Marrow Transplantation. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood 2015; 126 (17) 2062-2069
    CrossrefPubMedGoogle Scholar
45. Larrosa-Garcia M, Baer MR. FLT3 inhibitors in acute myeloid leukemia: current status and future directions. Mol Cancer Ther 2017; 16 (06) 991-1001
    CrossrefPubMedGoogle Scholar
46. Zhang W, Konopleva M, Ruvolo VR. et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 2008; 22 (04) 808-818
    CrossrefPubMedGoogle Scholar
47. Borthakur G, Kantarjian H, Ravandi F. et al. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica 2011; 96 (01) 62-68
    CrossrefPubMedGoogle Scholar
48. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 2004; 104 (04) 1145-1150
    CrossrefPubMedGoogle Scholar
49. Ravandi F, Cortes JE, Jones D. et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 2010; 28 (11) 1856-1862
    CrossrefPubMedGoogle Scholar
50. Ravandi F, Arana Yi C, Cortes JE. et al. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia 2014; 28 (07) 1543-1545
    CrossrefPubMedGoogle Scholar
51. Serve H, Krug U, Wagner R. et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 2013; 31 (25) 3110-3118
    CrossrefPubMedGoogle Scholar
52. Röllig C, Serve H, Hüttmann A. et al; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol 2015; 16 (16) 1691-1699
    CrossrefPubMedGoogle Scholar
53. Röllig C, Serve H, Noppeney R. et al; Study Alliance Leukaemia (SAL). Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial. Leukemia 2021; 35 (09) 2517-2525
    CrossrefPubMedGoogle Scholar
54. Stone RM, DeAngelo DJ, Klimek V. et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005; 105 (01) 54-60
    CrossrefPubMedGoogle Scholar
55. Stone RM, Fischer T, Paquette R. et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 2012; 26 (09) 2061-2068
    CrossrefPubMedGoogle Scholar
56. Stone RM, Mandrekar SJ, Sanford BL. et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017; 377 (05) 454-464
    CrossrefPubMedGoogle Scholar
57. Keiffer G, Aderhold KL, Palmisiano ND. Upfront treatment of FLT3-mutated AML: a look back at the RATIFY trial and beyond. Front Oncol 2020; 10: 562219
    CrossrefPubMedGoogle Scholar
58. Fischer T, Stone RM, Deangelo DJ. et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010; 28 (28) 4339-4345
    CrossrefPubMedGoogle Scholar
59. Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y. Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol 2013; 72 (06) 1223-1234
    CrossrefPubMedGoogle Scholar
60. Ouatas T, Duval V, Sinclair K, Berkowitz N. Concomitant use of midostaurin with strong CYP3A4 inhibitors: an analysis from the Ratify trial. Blood 2017; 130: 381
    PubMedGoogle Scholar
61. Stemler J, Koehler P, Maurer C, Müller C, Cornely OA. Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma. Ann Hematol 2020; 99 (07) 1429-1440
    CrossrefPubMedGoogle Scholar
62. Lam SSY, Leung AYH. Overcoming resistance to FLT3 inhibitors in the treatment of FLT3-mutated AML. Int J Mol Sci 2020; 21 (04) 1537
    CrossrefPubMedGoogle Scholar
63. Zarrinkar PP, Gunawardane RN, Cramer MD. et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009; 114 (14) 2984-2992
    CrossrefPubMedGoogle Scholar
64. Cortes JE, Kantarjian H, Foran JM. et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol 2013; 31 (29) 3681-3687
    CrossrefPubMedGoogle Scholar
65. Cortes J, Perl AE, Döhner H. et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2018; 19 (07) 889-903
    CrossrefPubMedGoogle Scholar
66. Cortes JE, Khaled S, Martinelli G. et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2019; 20 (07) 984-997
    CrossrefPubMedGoogle Scholar
67. Li J, Kankam M, Trone D, Gammon G. Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite. Br J Clin Pharmacol 2019; 85 (09) 2108-2117
    CrossrefPubMedGoogle Scholar
68. Martínez-Cuadrón D, Rodríguez-Macías G, Rodríguez-Veiga R, Boluda B, Montesinos P. Practical considerations for treatment of relapsed/refractory FLT3-ITD acute myeloid leukaemia with quizartinib: illustrative case reports. Clin Drug Investig 2020; 40 (03) 227-235
    CrossrefPubMedGoogle Scholar
69. Lee LY, Hernandez D, Rajkhowa T. et al. Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood 2017; 129 (02) 257-260
    CrossrefPubMedGoogle Scholar
70. Eguchi M, Minami Y, Kuzume A, Chi S. Mechanisms underlying resistance to FLT3 inhibitors in acute myeloid leukemia. Biomedicines 2020; 8 (08) 245
    CrossrefPubMedGoogle Scholar
71. Perl AE, Altman JK, Cortes J. et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol 2017; 18 (08) 1061-1075
    CrossrefPubMedGoogle Scholar
72. Perl AE, Altman JK, Cortes JE. et al. Final results of the chrysalis trial: a first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Blood 2016; 128 (22) 1069
    CrossrefGoogle Scholar
73. Perl AE, Martinelli G, Cortes JE. et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 2019; 381 (18) 1728-1740
    CrossrefPubMedGoogle Scholar
74. Perl AE, Larson RA, Podoltsev NA. et al. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood 2022; 139 (23) 3366-3375
    CrossrefPubMedGoogle Scholar
75. Smith CC, Levis MJ, Perl AE, Hill JE, Rosales M, Bahceci E. Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib. Blood Adv 2022; 6 (07) 2144-2155
    CrossrefPubMedGoogle Scholar
76. Wang ES, Montesinos P, Minden MD. et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood 2022; 140 (17) 1845-1857
    CrossrefPubMedGoogle Scholar
77. Nuhoğlu Kantarcı E, Eşkazan AE. Gilteritinib in the management of acute myeloid leukemia: current evidence and future directions. Leuk Res 2022; 114: 106808
    CrossrefPubMedGoogle Scholar
78. Lewis NL, Lewis LD, Eder JP. et al. Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol 2009; 27 (31) 5262-5269
    CrossrefPubMedGoogle Scholar
79. Zimmerman EI, Turner DC, Buaboonnam J. et al. Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood 2013; 122 (22) 3607-3615
    CrossrefPubMedGoogle Scholar
80. Galanis A, Ma H, Rajkhowa T. et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 2014; 123 (01) 94-100
    CrossrefPubMedGoogle Scholar
81. Randhawa JK, Kantarjian HM, Borthakur G. et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (Pts) with activating FLT3 mutations. Blood 2014; 124 (21) 389
    CrossrefGoogle Scholar
82. Aboudalle I, Kantarjian HM, Ohanian MN. et al. Phase I–II study of crenolanib combined with standard salvage chemotherapy and crenolanib combined with 5-azacitidine in acute myeloid leukemia patients with FLT3 activating mutations. Blood 2018; 132: 2715
    CrossrefGoogle Scholar
83. Zhang H, Savage S, Schultz AR. et al. Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nat Commun 2019; 10 (01) 244
    CrossrefPubMedGoogle Scholar
84. Stone RM, Collins R, Tallman MS. et al. Effect of cytarabine/anthracycline/crenolanib induction on minimal residual disease (MRD) in newly diagnosed FLT3 mutant AML. J Clin Oncol 2017; 35 (15) 7016
    CrossrefGoogle Scholar
85. Wang ES, Goldberg AD, Walter RB, Collins R, Stone RM. Long-term results of a phase 2 trial of crenolanib combined with 7+3 chemotherapy in adults with newly diagnosed FLT3 mutant AML. J Clin Oncol 2022; 40 (16) 7007
    CrossrefGoogle Scholar
86. Choe S, Wang H, DiNardo CD. et al. Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv 2020; 4 (09) 1894-1905
    CrossrefPubMedGoogle Scholar
87. Ward PS, Patel J, Wise DR. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17 (03) 225-234
    CrossrefPubMedGoogle Scholar
88. Intlekofer AM, Shih AH, Wang B. et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 2018; 559 (7712) 125-129
    CrossrefPubMedGoogle Scholar
89. Reinbold R, Hvinden IC, Rabe P. et al. Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors. Nat Commun 2022; 13 (01) 4785
    CrossrefPubMedGoogle Scholar
90. Chang YT, Hernandez D, Alonso S. et al. Role of CYP3A4 in bone marrow microenvironment-mediated protection of FLT3/ITD AML from tyrosine kinase inhibitors. Blood Adv 2019; 3 (06) 908-916
    CrossrefPubMedGoogle Scholar
91. Kumar B, Garcia M, Weng L. et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia 2018; 32 (03) 575-587
    CrossrefPubMedGoogle Scholar
92. McMahon CM, Ferng T, Canaani J. et al. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov 2019; 9 (08) 1050-1063
    CrossrefPubMedGoogle Scholar
93. Aikawa T, Togashi N, Iwanaga K. et al. Quizartinib, a selective FLT3 inhibitor, maintains antileukemic activity in preclinical models of RAS-mediated midostaurin-resistant acute myeloid leukemia cells. Oncotarget 2020; 11 (11) 943-955
    CrossrefPubMedGoogle Scholar
94. McMahon CM, Canaani J, Rea B. et al. Mechanisms of acquired resistance to gilteritinib therapy in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood 2017; 130 (Suppl. 01) 29
    Google Scholar
95. Maschmeyer G, Bullinger L, Garcia-Vidal C. et al. Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN). Leukemia 2022; 36 (05) 1215-1226
    CrossrefPubMedGoogle Scholar
96. Dombret H, Seymour JF, Butrym A. et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126 (03) 291-299
    CrossrefPubMed30% blasts" style="color: rgb(1, 52, 118); outline-width: 0px; outline-color: transparent !important; padding-right: 10px;">Google Scholar
97. DiNardo CD, Jonas BA, Pullarkat V. et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 2020; 383 (07) 617-629

References

Yates JW, Wallace Jr HJ, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 1973; 57 (04) 485-488
PubMedGoogle Scholar
1. Bertoli S, Tavitian S, Huynh A. et al. Improved outcome for AML patients over the years 2000-2014. Blood Cancer J 2017; 7 (12) 635
   CrossrefPubMedGoogle Scholar
2. Shah A, Andersson TM, Rachet B, Björkholm M, Lambert PC. Survival and cure of acute myeloid leukaemia in England, 1971-2006: a population-based study. Br J Haematol 2013; 162 (04) 509-516
   CrossrefPubMedGoogle Scholar
3. Khanal N, Shostrom V, Dhakal P. et al. Determinants of ten-year overall survival of acute myeloid leukemia: a large national cancer database analysis. Leuk Lymphoma 2022; 63 (04) 939-945
   CrossrefPubMedGoogle Scholar
4. Singh S, Lionel S, Jain H. et al. Real world data on unique challenges and outcomes of older patients with AML from resource limited settings: Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC). Blood 2022; 140 (Suppl. 01) 6096-6098
   CrossrefGoogle Scholar
5. Naur TMH, Jakobsen LH, Roug AS. et al. Treatment intensity and survival trends among real-world elderly AML patients diagnosed in the period 2001-2016: a Danish nationwide cohort study. Leuk Lymphoma 2021; 62 (08) 2014-2017
   CrossrefPubMedGoogle Scholar
6. Medeiros BC. Is there a standard of care for relapsed AML?. Best Pract Res Clin Haematol 2018; 31 (04) 384-386
   CrossrefPubMedGoogle Scholar
7. Löwenberg B, Huls G. The long road: improving outcome in elderly “unfit” AML?. Blood 2020; 135 (24) 2114-2115
   CrossrefPubMedGoogle Scholar
8. Philip C, George B, Ganapule A. et al. Acute myeloid leukaemia: challenges and real world data from India. Br J Haematol 2015; 170 (01) 110-117
   CrossrefPubMedGoogle Scholar
9. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 2010; 102 (13) 932-941
   CrossrefPubMedGoogle Scholar
10. Patel KP, Ravandi F, Ma D. et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol 2011; 135 (01) 35-45
    CrossrefPubMedGoogle Scholar
11. Im AP, Sehgal AR, Carroll MP. et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia 2014; 28 (09) 1774-1783
    CrossrefPubMedGoogle Scholar
12. Ye D, Ma S, Xiong Y, Guan K-L. R-2-hydroxyglutarate as the key effector of IDH mutations promoting oncogenesis. Cancer Cell 2013; 23 (03) 274-276
    CrossrefPubMedGoogle Scholar
13. Losman JA, Looper RE, Koivunen P. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013; 339 (6127) 1621-1625
    CrossrefPubMedGoogle Scholar
14. Molenaar RJ, Thota S, Nagata Y. et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia 2015; 29 (11) 2134-2142
    CrossrefPubMedGoogle Scholar
15. Yen K, Travins J, Wang F. et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov 2017; 7 (05) 478-493
    CrossrefPubMedGoogle Scholar
16. Stein EM, DiNardo CD, Pollyea DA. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017; 130 (06) 722-731
    CrossrefPubMedGoogle Scholar
17. Fathi AT, DiNardo CD, Kline I. et al; AG221-C-001 Study Investigators. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol 2018; 4 (08) 1106-1110
    CrossrefPubMedGoogle Scholar
18. Pollyea DA, Tallman MS, de Botton S. et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia 2019; 33 (11) 2575-2584
    CrossrefPubMedGoogle Scholar
19. DiNardo CD, Montesinos P, Schuh AC. et al. Outcomes for patients with late-stage mutant-IDH2 (m IDH2) relapsed/refractory acute myeloid leukemia (R/R AML) Treated with enasidenib vs other lower-intensity therapies in the randomized, phase 3 IDHentify trial. Blood 2021; 138 (Suppl. 01) 1243-1243
    CrossrefGoogle Scholar
20. De Botton S, Risueño A, Schuh AC. et al. Overall survival by IDH2 mutant allele (R140 or R172) in patients with late-stage mutant-IDH2 relapsed or refractory acute myeloid leukemia treated with enasidenib or conventional care regimens in the phase 3 IDHENTIFY trial. J Clin Oncol 2022; 40 (16) 7005
    CrossrefGoogle Scholar
21. Venugopal S, Takahashi K, Daver N. et al. Efficacy and safety of enasidenib and azacitidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy. Blood Cancer J 2022; 12 (01) 10
    CrossrefPubMedGoogle Scholar
22. DiNardo CD, Schuh AC, Stein EM. et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol 2021; 22 (11) 1597-1608
    CrossrefPubMedGoogle Scholar
23. Chan SM, Cameron C, Cathelin S. et al. Enasidenib in combination with venetoclax in IDH2-mutated myeloid malignancies: preliminary results of the phase Ib/II Enaven-AML trial. Blood 2021; 138 (Suppl. 01) 126
    Google Scholar
24. Popovici-Muller J, Lemieux RM, Artin E. et al. Discovery of AG-120 (ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med Chem Lett 2018; 9 (04) 300-305
    CrossrefPubMedGoogle Scholar
25. DiNardo CD, Stein EM, de Botton S. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018; 378 (25) 2386-2398
    CrossrefPubMedGoogle Scholar
26. Roboz GJ, DiNardo CD, Stein EM. et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 2020; 135 (07) 463-471
    CrossrefPubMedGoogle Scholar
27. DiNardo CD, Stein AS, Stein EM. et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J Clin Oncol 2021; 39 (01) 57-65
    CrossrefPubMedGoogle Scholar
28. Montesinos P, Recher C, Vives S. et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med 2022; 386 (16) 1519-1531
    CrossrefPubMedGoogle Scholar
29. Stein EM, DiNardo CD, Fathi AT. et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood 2021; 137 (13) 1792-1803
    CrossrefPubMedGoogle Scholar
30. Merchant SL, Culos K, Wyatt H. Ivosidenib: IDH1 inhibitor for the treatment of acute myeloid leukemia. J Adv Pract Oncol 2019; 10 (05) 494-500
    PubMedGoogle Scholar
31. Jiang X, Wada R, Poland B. et al. Population pharmacokinetic and exposure-response analyses of ivosidenib in patients with IDH1-mutant advanced hematologic malignancies. Clin Transl Sci 2021; 14 (03) 942-953
    CrossrefPubMedGoogle Scholar
32. DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood 2020; 135 (02) 85-96
    CrossrefPubMedGoogle Scholar
33. Lachowiez CA, Borthakur G, Loghavi S. et al. Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/− azacitidine in IDH1-mutated hematologic malignancies. J Clin Oncol 2020; 38 (15) 7500-7500
    CrossrefGoogle Scholar
34. Venugopal S, Watts J. Olutasidenib: from bench to bedside. Blood Adv 2023; 7 (16) 4358-4365
    CrossrefPubMedGoogle Scholar
35. Watts J, Baer MR, Yang J. et al. Phase 1 study of the IDH1m inhibitor FT-2102 as a single agent in patients with IDH1m acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Blood 2018; 132: 1453
    CrossrefGoogle Scholar
36. Watts JM, Baer MR, Yang J. et al. Olutasidenib (FT-2102), an IDH1m inhibitor as a single agent or in combination with azacitidine, induces deep clinical responses with mutation clearance in patients with acute myeloid leukemia treated in a phase 1 dose escalation and expansion study. Blood 2019; 134: 231
    CrossrefGoogle Scholar
37. Watts JM, Baer MR, Yang J. et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial. Lancet Haematol 2023; 10 (01) e46-e58
    CrossrefPubMedGoogle Scholar
38. de Botton S, Fenaux P, Yee K. et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv 2023; 7 (13) 3117-3127
    CrossrefPubMedGoogle Scholar
39. Cortes JE, Esteve J, Bajel A. et al. Olutasidenib (FT-2102) in combination with azacitidine induces durable complete remissions in patients with mIDH1 acute myeloid leukemia. Blood 2021; 138: 698
    CrossrefGoogle Scholar
40. Lyman SD, James L, Vanden Bos T. et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 1993; 75 (06) 1157-1167
    CrossrefPubMedGoogle Scholar
41. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100 (05) 1532-1542
    CrossrefPubMedGoogle Scholar
42. Friedman R. The molecular mechanisms behind activation of FLT3 in acute myeloid leukemia and resistance to therapy by selective inhibitors. Biochim Biophys Acta Rev Cancer 2022; 1877 (01) 188666
    CrossrefPubMedGoogle Scholar
43. Shouval R, Shlush LI, Yehudai-Resheff S. et al. Single cell analysis exposes intratumor heterogeneity and suggests that FLT3-ITD is a late event in leukemogenesis. Exp Hematol 2014; 42 (06) 457-463
    CrossrefPubMedGoogle Scholar
44. Schmid C, Labopin M, Socié G. et al; Acute Leukemia Working Party of the European Group of Blood and Bone Marrow Transplantation. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood 2015; 126 (17) 2062-2069
    CrossrefPubMedGoogle Scholar
45. Larrosa-Garcia M, Baer MR. FLT3 inhibitors in acute myeloid leukemia: current status and future directions. Mol Cancer Ther 2017; 16 (06) 991-1001
    CrossrefPubMedGoogle Scholar
46. Zhang W, Konopleva M, Ruvolo VR. et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 2008; 22 (04) 808-818
    CrossrefPubMedGoogle Scholar
47. Borthakur G, Kantarjian H, Ravandi F. et al. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica 2011; 96 (01) 62-68
    CrossrefPubMedGoogle Scholar
48. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 2004; 104 (04) 1145-1150
    CrossrefPubMedGoogle Scholar
49. Ravandi F, Cortes JE, Jones D. et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 2010; 28 (11) 1856-1862
    CrossrefPubMedGoogle Scholar
50. Ravandi F, Arana Yi C, Cortes JE. et al. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia 2014; 28 (07) 1543-1545
    CrossrefPubMedGoogle Scholar
51. Serve H, Krug U, Wagner R. et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 2013; 31 (25) 3110-3118
    CrossrefPubMedGoogle Scholar
52. Röllig C, Serve H, Hüttmann A. et al; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol 2015; 16 (16) 1691-1699
    CrossrefPubMedGoogle Scholar
53. Röllig C, Serve H, Noppeney R. et al; Study Alliance Leukaemia (SAL). Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial. Leukemia 2021; 35 (09) 2517-2525
    CrossrefPubMedGoogle Scholar
54. Stone RM, DeAngelo DJ, Klimek V. et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005; 105 (01) 54-60
    CrossrefPubMedGoogle Scholar
55. Stone RM, Fischer T, Paquette R. et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 2012; 26 (09) 2061-2068
    CrossrefPubMedGoogle Scholar
56. Stone RM, Mandrekar SJ, Sanford BL. et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017; 377 (05) 454-464
    CrossrefPubMedGoogle Scholar
57. Keiffer G, Aderhold KL, Palmisiano ND. Upfront treatment of FLT3-mutated AML: a look back at the RATIFY trial and beyond. Front Oncol 2020; 10: 562219
    CrossrefPubMedGoogle Scholar
58. Fischer T, Stone RM, Deangelo DJ. et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010; 28 (28) 4339-4345
    CrossrefPubMedGoogle Scholar
59. Dutreix C, Munarini F, Lorenzo S, Roesel J, Wang Y. Investigation into CYP3A4-mediated drug-drug interactions on midostaurin in healthy volunteers. Cancer Chemother Pharmacol 2013; 72 (06) 1223-1234
    CrossrefPubMedGoogle Scholar
60. Ouatas T, Duval V, Sinclair K, Berkowitz N. Concomitant use of midostaurin with strong CYP3A4 inhibitors: an analysis from the Ratify trial. Blood 2017; 130: 381
    PubMedGoogle Scholar
61. Stemler J, Koehler P, Maurer C, Müller C, Cornely OA. Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma. Ann Hematol 2020; 99 (07) 1429-1440
    CrossrefPubMedGoogle Scholar
62. Lam SSY, Leung AYH. Overcoming resistance to FLT3 inhibitors in the treatment of FLT3-mutated AML. Int J Mol Sci 2020; 21 (04) 1537
    CrossrefPubMedGoogle Scholar
63. Zarrinkar PP, Gunawardane RN, Cramer MD. et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009; 114 (14) 2984-2992
    CrossrefPubMedGoogle Scholar
64. Cortes JE, Kantarjian H, Foran JM. et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol 2013; 31 (29) 3681-3687
    CrossrefPubMedGoogle Scholar
65. Cortes J, Perl AE, Döhner H. et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2018; 19 (07) 889-903
    CrossrefPubMedGoogle Scholar
66. Cortes JE, Khaled S, Martinelli G. et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2019; 20 (07) 984-997
    CrossrefPubMedGoogle Scholar
67. Li J, Kankam M, Trone D, Gammon G. Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite. Br J Clin Pharmacol 2019; 85 (09) 2108-2117
    CrossrefPubMedGoogle Scholar
68. Martínez-Cuadrón D, Rodríguez-Macías G, Rodríguez-Veiga R, Boluda B, Montesinos P. Practical considerations for treatment of relapsed/refractory FLT3-ITD acute myeloid leukaemia with quizartinib: illustrative case reports. Clin Drug Investig 2020; 40 (03) 227-235
    CrossrefPubMedGoogle Scholar
69. Lee LY, Hernandez D, Rajkhowa T. et al. Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood 2017; 129 (02) 257-260
    CrossrefPubMedGoogle Scholar
70. Eguchi M, Minami Y, Kuzume A, Chi S. Mechanisms underlying resistance to FLT3 inhibitors in acute myeloid leukemia. Biomedicines 2020; 8 (08) 245
    CrossrefPubMedGoogle Scholar
71. Perl AE, Altman JK, Cortes J. et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol 2017; 18 (08) 1061-1075
    CrossrefPubMedGoogle Scholar
72. Perl AE, Altman JK, Cortes JE. et al. Final results of the chrysalis trial: a first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Blood 2016; 128 (22) 1069
    CrossrefGoogle Scholar
73. Perl AE, Martinelli G, Cortes JE. et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 2019; 381 (18) 1728-1740
    CrossrefPubMedGoogle Scholar
74. Perl AE, Larson RA, Podoltsev NA. et al. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood 2022; 139 (23) 3366-3375
    CrossrefPubMedGoogle Scholar
75. Smith CC, Levis MJ, Perl AE, Hill JE, Rosales M, Bahceci E. Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib. Blood Adv 2022; 6 (07) 2144-2155
    CrossrefPubMedGoogle Scholar
76. Wang ES, Montesinos P, Minden MD. et al. Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Blood 2022; 140 (17) 1845-1857
    CrossrefPubMedGoogle Scholar
77. Nuhoğlu Kantarcı E, Eşkazan AE. Gilteritinib in the management of acute myeloid leukemia: current evidence and future directions. Leuk Res 2022; 114: 106808
    CrossrefPubMedGoogle Scholar
78. Lewis NL, Lewis LD, Eder JP. et al. Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol 2009; 27 (31) 5262-5269
    CrossrefPubMedGoogle Scholar
79. Zimmerman EI, Turner DC, Buaboonnam J. et al. Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood 2013; 122 (22) 3607-3615
    CrossrefPubMedGoogle Scholar
80. Galanis A, Ma H, Rajkhowa T. et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 2014; 123 (01) 94-100
    CrossrefPubMedGoogle Scholar
81. Randhawa JK, Kantarjian HM, Borthakur G. et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (Pts) with activating FLT3 mutations. Blood 2014; 124 (21) 389
    CrossrefGoogle Scholar
82. Aboudalle I, Kantarjian HM, Ohanian MN. et al. Phase I–II study of crenolanib combined with standard salvage chemotherapy and crenolanib combined with 5-azacitidine in acute myeloid leukemia patients with FLT3 activating mutations. Blood 2018; 132: 2715
    CrossrefGoogle Scholar
83. Zhang H, Savage S, Schultz AR. et al. Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nat Commun 2019; 10 (01) 244
    CrossrefPubMedGoogle Scholar
84. Stone RM, Collins R, Tallman MS. et al. Effect of cytarabine/anthracycline/crenolanib induction on minimal residual disease (MRD) in newly diagnosed FLT3 mutant AML. J Clin Oncol 2017; 35 (15) 7016
    CrossrefGoogle Scholar
85. Wang ES, Goldberg AD, Walter RB, Collins R, Stone RM. Long-term results of a phase 2 trial of crenolanib combined with 7+3 chemotherapy in adults with newly diagnosed FLT3 mutant AML. J Clin Oncol 2022; 40 (16) 7007
    CrossrefGoogle Scholar
86. Choe S, Wang H, DiNardo CD. et al. Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv 2020; 4 (09) 1894-1905
    CrossrefPubMedGoogle Scholar
87. Ward PS, Patel J, Wise DR. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17 (03) 225-234
    CrossrefPubMedGoogle Scholar
88. Intlekofer AM, Shih AH, Wang B. et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 2018; 559 (7712) 125-129
    CrossrefPubMedGoogle Scholar
89. Reinbold R, Hvinden IC, Rabe P. et al. Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors. Nat Commun 2022; 13 (01) 4785
    CrossrefPubMedGoogle Scholar
90. Chang YT, Hernandez D, Alonso S. et al. Role of CYP3A4 in bone marrow microenvironment-mediated protection of FLT3/ITD AML from tyrosine kinase inhibitors. Blood Adv 2019; 3 (06) 908-916
    CrossrefPubMedGoogle Scholar
91. Kumar B, Garcia M, Weng L. et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia 2018; 32 (03) 575-587
    CrossrefPubMedGoogle Scholar
92. McMahon CM, Ferng T, Canaani J. et al. Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov 2019; 9 (08) 1050-1063
    CrossrefPubMedGoogle Scholar
93. Aikawa T, Togashi N, Iwanaga K. et al. Quizartinib, a selective FLT3 inhibitor, maintains antileukemic activity in preclinical models of RAS-mediated midostaurin-resistant acute myeloid leukemia cells. Oncotarget 2020; 11 (11) 943-955
    CrossrefPubMedGoogle Scholar
94. McMahon CM, Canaani J, Rea B. et al. Mechanisms of acquired resistance to gilteritinib therapy in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood 2017; 130 (Suppl. 01) 29
    Google Scholar
95. Maschmeyer G, Bullinger L, Garcia-Vidal C. et al. Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN). Leukemia 2022; 36 (05) 1215-1226
    CrossrefPubMedGoogle Scholar
96. Dombret H, Seymour JF, Butrym A. et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126 (03) 291-299
    CrossrefPubMed30% blasts" style="color: rgb(1, 52, 118); outline-width: 0px; outline-color: transparent !important; padding-right: 10px;">Google Scholar
97. DiNardo CD, Jonas BA, Pullarkat V. et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 2020; 383 (07) 617-629