Keywords
myeloid - leukemia - FLT3 - midostaurin - gilteritinib - sorafenib
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
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% after treatment. DS was observed in 13%
patients, which was reversible with drug discontinuation.[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
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
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
Table 1
Key evidence for FLT3 and IDH1/2 inhibitors showing clinical efficacy
|
Drug
|
Key study showing efficacy
|
N
|
Type
|
Clinical setting
|
Clinical use
|
Major finding
|
Regulatory approval received
|
|
Sorafenib
|
SORAML
|
276
|
Phase 2
|
Newly diagnosed AML
|
Combination with IC
|
Higher EFS (21 vs. 9 mo), similar CR and OS
|
No
|
|
Midostaurin
|
RATIFY
|
717
|
Phase 3 RCT
|
Newly diagnosed AML with FLT3-ITD
|
Combination with IC
|
Median OS 74 vs. 25 mo
|
Yes
|
|
Quizartinib
|
Quantum-FIRST
|
539
|
Phase 3 RCT
|
Newly diagnosed AML with FLT3-ITD
|
Combination with IC
|
Median OS 31 vs. 15 mo
|
Yes
|
|
Gilteritinib
|
ADMIRAL
|
247
|
Phase 3 RCT
|
Relapsed/refractory AML with IDH1 mutations
|
Monotherapy vs. salvage chemotherapy
|
Median OS 9.3 vs. 5.6 mo
|
Yes
|
|
Crenolanib
|
Wang et al, 2022[77]
|
44
|
Phase 2
|
Newly diagnosed AML with FLT3-mutated
|
Combination with IC
|
Median OS NR, median EFS 45 mo
|
No
|
|
Ivosidenib
|
AGILE
|
146
|
Phase 3 RCT
|
Newly diagnosed AML with IDH1 mutation
|
Combination with azacytidine
|
Median OS 24 vs. 7.9 mo
|
Yes
|
|
Enasidenib
|
IDHentify
|
319
|
Phase 3 RCT
|
Relapsed/refractory AML with IDH2 mutations
|
Monotherapy
|
Higher ORR (41 vs. 11%) and CR (26 vs. 3%), similar OS
|
Yes
|
|
Olutasidenib
|
–
|
153
|
Phase 2
|
Relapsed/refractory AML with IDH1 mutations
|
Monotherapy
|
ORR 48%, CR + CRi 35%, median OS 11.7 mo
|
Yes
|
Abbreviations: AML, acute myeloid leukemia; CR, complete remission; CRi, CR with incomplete
count recovery; EFS, event-free survival; FLT3, FMS like tyrosine kinase 3; IC, intensive
chemotherapy; IDH, isocitrate dehydrogenase; NR, not reported; ORR, overall response
rate; OS, overall survival; RCT, randomized controlled trial.
Table 2
Salient details of clinical use of FLT3 and IDH1/2 inhibitors in acute myeloid leukemia
|
Drug name
|
Common dose used
|
Monotherapy/combination
|
Important nonhematologic toxicities
|
|
Sorafenib
|
400 mg twice a day on D10 to 19 of induction
|
Combination with IC
|
Diarrhea (10% with Gd 3) and hand foot syndrome (7% with Grade 3)
|
|
Midostaurin
|
50 mg twice a day from D8 to D21 of induction
|
Combination with IC
|
Anemia, thrombocytopenia, skin rash/desquamation (14%)
|
|
Quizartinib
|
40 mg once a day from D8 to D21 of induction
|
Combination with IC
|
Neutropenia, QT prolongation (2.3% Grade 3)
|
|
Gilteritinib
|
120 mg once a day
|
Monotherapy
|
Febrile neutropenia, thrombocytopenia
|
|
Crenolanib
|
100 mg TID from D8 of induction
|
Combination with IC
|
Diarrhea (18% with Gd 3)
|
|
Ivosidenib
|
500 mg once a day
|
Combination with IC
|
Differentiation syndrome (14%)
|
|
Enasidenib
|
100 mg once a day
|
Monotherapy
|
Differentiation syndrome (13%), hyperbilirubinemia (26%)
|
Abbreviations: FLT3, FMS like tyrosine kinase 3; Gd, grade; IC, intensive chemotherapy;
IDH, isocitrate dehydrogenase; TID, three times a day.
A Primer on Resistance to Targeted Oral Agents
A Primer on Resistance to Targeted Oral Agents
With accumulating data on disease progression on targeted oral agents, several molecular
mechanisms of resistance have emerged. In case of IDH1 inhibitors, both primary and
secondary resistance to therapy may be noted.[87] Occurrence of oncogenic comutations in DNMT3A, NPM1, ASXL1, SRSF2, and NRAS and receptor tyrosine kinase pathway are associated with primary resistance to IDH1
inhibitors. Secondary resistance is mediated by either the emergence of new IDH2 mutations
or alternate site IDH1 mutations (the most common, R132-S280F), which restore intracellular
concentrations of 2-hydroxyglutarate (2-HG).[88] Similarly, acquired transmutations in IDH2 restore 2-HG levels leading to clinical
resistance to enasidenib.[89] These mutations are present in active enzyme sites (including R132 in IDH1 and R140/R172
in IDH2) and significantly increase the IC50 required for enzyme inhibition, leading
to resistance to therapeutically achieved concentrations.[87]
Secondary IDH1 mutations can be overcome using newer IDH1 inhibitors, including IDH224,
FT-2102, and DS1001B, which strongly bind to the mutated enzyme despite secondary
mutations. This provides a potential to shift to alternate IDH1 inhibitors after failure
of first-line therapy.[90]
Similarly, primary resistance to FLT3 inhibitors is known to be mediated by the site
of FLT3-ITD mutations, each of which confer differing sensitivities to enzyme inhibition.
Resistance is also mediated by the tumor microenvironment, where FLT3-mutated leukemia
stem cells are protected and high CYP3A4 activity reduces local drug exposure.[91]
[92] Secondary resistance is mediated by either mutations in alternate signaling pathways
or selection of clones with resistance conferring FLT3 mutations.[93] Similar mechanisms are active in case of quizartinib.[94] In contrast, resistance to gilteritinib and crenolanib is mediated by mutations
in alternate genes, including NRAS and IDH2, implying the need for alternate approaches to overcome the same.[95]
Risk of Infections with Targeted Agents
Risk of Infections with Targeted Agents
It is vital to consider the risk of infections when using targeted agents, especially
in the context of relapsed/refractory disease and in combination with other chemotherapeutic
agents. The incidence of infectious complications associated with targeted agents
can be estimated based on data from initial clinical trials. However, it is important
to note that these complications may be reported variably as “infections,” “febrile
neutropenia,” or “fever.” The occurrence of these complications is contingent upon
whether the drug is administered as monotherapy, in combination with chemotherapy,
or in a posttransplant setting. [Table 3] provides a summary of these findings. Guidelines on the same were recently published
by a multiple European societies in a joint venture.[96]
Table 3
Overall incidence of infections in pivotal trials compared with placebo when used
with intensive chemotherapy, low-dose therapy/monotherapy, or posttransplant maintenance
|
Targeted agent combined with chemotherapy
|
Targeted agent used as monotherapy
|
Targeted agent in posttransplant setting
|
|
Infections in drug arm
|
Infections in control arm
|
Infections in drug arm
|
Infections in control arm
|
Infections in drug arm
|
Infections in control arm
|
|
SORAML
|
|
|
SORMAIN
|
|
Sorafenib
|
55%
|
48%
|
N/A
|
N/A
|
26.2%
|
23%
|
|
RATIFY
|
|
|
NCT01477606
|
|
Midostaurin
|
52%
|
50%
|
N/A
|
N/A
|
56%
|
–
|
|
Quantum first
|
Quantum-R
|
|
|
|
Quizartinib
|
|
|
31%
|
28%
|
–
|
–
|
|
LACEWING
|
ADMIRAL
|
|
|
|
Gilteritinib
|
35.6%
|
21.3%
|
46.7%
|
36.7%
|
–
|
–
|
|
AGILE
|
NCT02074839
|
|
|
|
Ivosidenib
|
28%
|
34%
|
18%
|
N/A
|
–
|
–
|
|
AG221-AML-005
|
IDHENTIFY
|
|
|
|
Enasidenib
|
37%
|
25%
|
2.5%
|
12.1%
|
–
|
–
|
Abbreviation: N/A, not applicable.
IDH1/2 Inhibitors
No specific increase in infectious complications have been noted with these agents.
In initial trials of these agents as monotherapy, pulmonary infections were noted
in 15 to 20% of patients, similar to other settings in AML. It must be noted that
a higher risk of Clostridial infections was noted on combination with intensive chemotherapy
in the initial phase 1 study with IDH1/2 inhibitors but has not been observed elsewhere.[30]
FLT3 Inhibitors
A recent clinical guideline assessed the risk of infections with midostaurin. The
median incidence of febrile neutropenia was 35% and pneumonia was 9%, with sepsis
ranging from 4 to 18%.[96] No excess risk of fungal or viral infections was observed. With quizartinib, the
risk of sepsis as monotherapy was similar to salvage chemotherapy, with a slightly
higher risk of pneumonia, warranting close monitoring.
Discussion
Intensive chemotherapy and stem cell transplantation may not be feasible (advanced
age, reduced fitness, or logistic barriers) or effective (relapsed / refractory disease)
in certain settings with AML.[8]
[97] In this setting, the combination of venetoclax with HMAs has significantly improved
initial response rates and survival.[97]
[98] However, drug development for AML has lagged behind other hematologic malignancies
and availability of targeted oral inhibitors represents the next important step forward
in the treatment of AML.
Limitations
The limitations of this review lie in its narrative nature and lack of systematic
literature selection and analysis, potentially introducing bias in the included studies.
Without a predefined search strategy and inclusion criteria, certain studies may be
overlooked, affecting the validity of findings.
Generalizability and Future Perspectives
Generalizability and Future Perspectives
The findings of our narrative review on FLT3 and IDH1/2 inhibitors in AML should be
interpreted in the context of drug availability and regional differences. Although
our review focused on both FLT3 and IDH1/2 inhibitors, it is important to note that
only FLT3 inhibitors are currently available in India, while the availability of other
inhibitors may vary worldwide. This limitation may affect the generalizability of
our findings to regions where IDH1/2 inhibitors are commonly used in clinical practice.
Additionally, variations in drug approval processes, treatment guidelines, and health
care infrastructure across different countries can further influence the applicability
of our findings. Therefore, caution should be exercised when extrapolating the results
of our review to patient populations in regions where specific inhibitors are not
available or where treatment practices differ. Further studies and collaborations
across different regions are warranted to validate the efficacy and safety of IDH1/2
inhibitors in AML beyond the scope of our current review.
Conclusion
Drug therapy for AML is a field of active development, and several drugs with novel
mechanisms including venetoclax, glasdegib, SYK, and menin inhibitors under evaluation.
The ultimate aim of targeted therapy for AML is the use of continuous low-toxicity
regimens with a high response rate (similar to chronic myeloid leukemia) to improve
survival for in this difficult to treat disease.
