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Abstract

Acute myeloid leukemia (AML) is a heterogenous and complex disease characterized by rapid cellular proliferation, an aggressive clinical course, and generally high mortality. While progress has been made in the understanding of the genetic and molecular biology of the disease, the standard of care for patients had only changed minimally over the past 40 years. Recently, rapid movement of potentially useful agents from bench to bedside has translated into new therapies either recently approved or in clinical trials. These therapies include improved chemotherapies, mutationally targeted inhibitors, pro-apoptotic agents, microenvironment targeting molecules, cell cycle checkpoint inhibitors, and epigenetic regulators. Furthermore, advances in immunotherapy employ monoclonal and bispecific antibodies, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, and vaccines provide an alternative pathway for AML treatment. In this review, we discuss the recent results of completed or ongoing clinical trials with these novel therapeutic agents in AML.

Keywords

AML checkpoint inhibitors FLT3 IDH1/2 immunotherapy pro-apoptotic inhibitors targeted therapy

Acute myeloid leukemia (AML) is an aggressive, heterogeneous, myeloid malignancy; in 2018 an estimated 19,520 new cases and 10,670 deaths occurred in the US.¹ The disease is particularly difficult to treat in older adults who account for the majority of patients; thus, the 5-year overall survival is only approximately 27%.² Since the 1970s, initial standard therapy, for those fit enough to receive it, consisted of the ‘7 + 3’ regimen, which includes 7 days of continuous infusion cytarabine and 3 days of an anthracycline.³ Over the next 35 years, a plethora of clinical trials attempting to augment AML treatment have been performed with little change in the standard of care. However, recent data detailing the molecular ontogeny of AML have elucidated causal pathways which have led to targeted drug development;^4,5 new guidelines emphasize molecular studies in both diagnostic and relapsed settings.⁶ Owing to these discoveries, eight new drugs in a variety of classes were approved between 28 April 2017 and 28 November 2018 (Table 1).⁷ This novel arsenal of diverse therapies, sometimes in combination with previously used chemotherapy, have drastically altered the landscape of AML treatment and has promulgated new treatment paradigms. This paper reviews the novel therapies approved for AML as well as the pipeline of compounds likely to affect treatment in the near future.

Table 1.

Recent approved drugs for AML with indications.⁷

Drug	Date of approval	Indication
Midostaurin (Rydapt) Novartis	28 April 2017	Treatment of adult patients with newly diagnosed AML who are FLT3+^* in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation
Enasidenib (Idhifa) Celgene	1 August 2017	Treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 (IDH2) mutation^*
CPX-351 (Vyxeos) Jazz Pharmaceuticals	3 August 2017	Treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia related changes (AML-MRC)
Gemtuzumab ozogamicin (Mylotarg) Pfizer	1 September 2017	Treatment of adults with newly diagnosed CD33-ositive AML and for treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and older. May be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML.
Ivosidenib (Tibsovo) Agios	20 July 2018	Adult patients with relapsed or refractory AL with a susceptible IDH1 mutation^*
Glasdegib (Daurismo) Pfizer	21 November 2018	In combination with low-dose cytarabine for the treatment of newly diagnosed AML in adults who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.
Venetoclax (Venclexta) Abbvie/Genetech	21 November 2018	In combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly diagnosed AML in adults who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.
Gilteritinib (Xospata) Astellas Pharma	28 November 2018	Treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation^*

Mutational analysis detected by an FDA approved test.

AML, acute myeloid leukemia.

Conventional chemotherapy

While an anthracycline and cytarabine have been the mainstay of treatment, novel packaging of these agents has led to an important therapeutic advance. CPX-351, a liposomal formulation of daunorubin and cytarabine which releases the drugs in fixed 5:1 molar ratio, was evaluated in a randomized phase II trial followed by a randomized phase III trial compared with standard induction.^8,9 In a population 60–75 years of age with newly diagnosed secondary AML, CPX-351 was associated with a superior overall remission rate (47.7% versus 33.3%, two-sided p = 0.016) and overall survival (OS; 9.56 months versus 5.95 months, HR 0.69; 95% CI 0.52–0.90; one-sided p = 0.003) with an improved safety profile except for more prolonged myelosuppression. These results led to FDA approval of this drug in adult patients of any age with secondary AML [after myelodysplastic syndrome (MDS) or prior anticancer therapy] plus those with MDS-related chromosomal abnormities and/or background marrow dysplasia.

Smoothened inhibition

The Hedgehog (Hh) signaling pathway is vital for embryogenesis and fetal development.¹⁰ Aberrant signaling in this pathway affects the proliferation of leukemia stem cells, and upregulation results in chemoresistance in AML cell lines.¹¹ Furthermore, Hh signaling is vital in the maintenance of murine leukemic stem cells in chronic myeloid leukemia (CML) models.^12,13 FLT3 signaling also interacts with the Hh pathway in myeloid leukemias.¹⁴ This pathway is tightly regulated by two transmembrane proteins, patched (PTCH), which is a negative regulator, and smoothened (SMO), a positive regulator.¹⁵

Glasdegib is an oral agent that inhibits the Hh pathway by interacting with smoothened.¹⁶ In vitro and in vivo studies with this agent demonstrated growth inhibition of AML cell lines and human leukemia stem cells.¹⁷ In two phase I trials in adult patients with myeloid malignancies, glasdegib was well-tolerated and was associated with a response rate as high as 49%.^18,19 A multicohort phase Ib study evaluated glasdegib in combination with low-dose cytarabine, decitabine, or standard induction therapy. These combinations were deemed to be well tolerated with a recommended phase II dose of 100 mg daily. A total of 31% of patients across all three arms of the study achieved complete response (CR) or complete response with incomplete blood count recovery (CRi), with responses of 8.7%, 28.5%, and 54.5% in the low-dose cytarabine, decitabine, and standard induction arms, respectively.²⁰ A separate phase II study designed to evaluate the combination of glasdegib given at 100 mg daily for 28 days with standard induction cytarabine and daunorubicin in patients over 55 years of age demonstrated a CR rate of 46.4%.²¹ The median survival in this older population was 14.9 months. In an important randomized phase II study of low-dose cytarabine 20 mg subcutaneously twice daily for 10 days with or without glasdegib 100 mg daily, the experimental arm demonstrated a statistically significant improved CR rates (15% versus 2.3%) and OS (8.3 months versus 4.3 months).²² Owing to the results of this phase II study, glasdegib was approved by the FDA in combination with low-dose cytarabine for unfit AML patients on 21 November 2018. Glasdegib is currently being studied in combination with standard induction therapy in fit patients, or with azacitidine in unfit patients (ClinicalTrials.gov identifier: NCT03416179). Given the high response rates seen with use of a hypomethylating agent plus venetoclax as described in the following, the common use of the glasdegib/low-dose cytarabine combination remains unclear.

Mutationally targeted inhibitors

FLT3

FLT3 is a transmembrane tyrosine kinase that has two mutational subtypes, an internal tandem duplication which results in the duplication of 3 to over 100 amino acids in the juxtamembrane region of the protein (ITD) or point mutations in the tyrosine kinase domain, that are present in approximately 30% of AML cases.²³ At least six different FLT3 inhibitors are currently in clinical development, including sorafenib, midostaurin, lestaurtinib, quizartinib, crenolanib, and gilteritinib. Midostaurin is the only FLT3 inhibitor that, to date, has demonstrated an overall survival benefit in combination with induction chemotherapy. In the RATIFY trial, 717 patients age 18–59 with FLT3 ITD or TKD mutations underwent randomization to receive standard induction chemotherapy or induction with midostaurin 50 mg orally bid given on days 8–22.²⁴ Patients in remission then received high-dose cytarabine consolidation ± midostaurin according to the original phase; the trial also included a maintenance phase where placebo or midostaurin was given for 12 28-day cycles. Whether or not to perform an allogeneic transplant was left to investigator discretion, but post-transplant midostaurin was not given. Though there was no statistically significant improvement in the CR rate as defined in the protocol, the primary endpoint of OS was met, with a median OS in the midostaurin group reaching 74.7 months versus 25.6 months in the placebo group (HR for event or death 0.78, one-sided p = 0.009 favoring the midostaurin arm). This pivotal data has led to its approval in the United States with induction and consolidation chemotherapy, and for induction, consolidation, and maintenance in Europe. A similarly designed trial of chemo ± the more specific FLT3 inhibitor quizartinib (does not inhibit the TKD mutation) has recently met accrual, but results are not available (ClinicalTrials.gov identifier: NCT02668653).

A phase III trial of induction chemotherapy ± sorafenib in older adults demonstrated that sorafenib was ineffective and was associated with increased toxicity in older adults;²⁵ however, a similarly designed trial in younger adults showed an improved event-free survival (EFS) but not OS with use of sorafenib; there was also substantial increased toxicity in the sorafenib arm.²⁶ A major concern is whether a FLT3 inhibitor more specific than midostaurin would be a better drug to combine with chemotherapy in the upfront setting. Ongoing trials of chemo+midostaruin versus gilteritinib and crenolanib (ClinicalTrials.gov identifier: NCT03258931) are either planned or underway.

Responses to the nonspecific FLT3 inhibitors midostaurin²⁷ and lestaurtinib in relapsed refractory patients have been modest.²⁸ However, two second-generation FLT3 inhibitors have demonstrated a survival benefit compared with chemotherapy in prospective randomized trials in relapsed refractory patients. Quizartinib was associated with an overall survival advantage compared with physician’s choice of 27 weeks (95% CI 23.1–31.3) versus 20 weeks (95% CI 17.3–23.7), and OS HR of quizartinib to physician’s choice was 0.76 (95% CI 0.58–0.98; stratified log-rank test, one-sided p = 0.0177).²⁹ In a similarly designed trial that also allowed patients with TKD mutations to enroll, gilteritinib demonstrated a 29% CR or CRi rate (ClinicalTrials.gov identifier: NCT02421939), leading to its approval in the relapsed setting by the FDA in late 2018, although full results of this trial are highly anticipated.

Sorafenib, approved in hepatocellar carcinoma and renal cancer owing to its vascular endothelial growth factor receptor (VEGFR) inhibitory activity, in combination with azacitidine in an older unfit or relapsed predominantly FLT-ITD population yielded an overall response rate of approximately 46%.³⁰ A recently presented randomized trial of sorafenib versus placebo in the post-allotransplant maintenance setting showed a marked improvement in 2-year relapse-free survival (85% versus 53.3%).³¹ A phase III study evaluating gilteritinib in the post-transplant setting is ongoing (ClinicalTrials.gov identifier: NCT02997202).

One possible reason for resistance to a FLT3 inhibitor in combination with chemotherapy is the increase in FLT3 ligand, which competes with the small-molecule inhibitor after exposure to cytotoxic stress.^32,33 Based on in vitro studies, both the AKT/FLT3-ITD dual inhibitor, A674563 and MDM2 inhibitors may overcome FL-mediated resistance.^34,35 Another potential mechanism for resistance is upregulation of fibroblast growth factor 2 (FGF2), which activates the mitogen-activated protein kinase (MAPK) pathway.³⁶

IDH2/IDH1

The isocitrate dehydrogenase (IDH) family of enzymes are involved in cellular energy generation in the oxidative decarboxylation cycle by catalyzing the conversion of isocitrate to α-ketoglutarate. While IDH1 is localized in peroxisomes in the cytosol and IDH2 resides in mitochondria.^37,38 Mutant IDH has become a viable target in AML treatment. Such mutations occur in blasts from approximately 20% of AML patients [IDH1 (8%) and IDH2 (12%)]. Somatic mutations in catalytically active arginine residues in these enzymes lead to the formation of alternative or ‘neomorphic’ product, 2-hydroxyglutate (instead of alpha-ketoglutarate the reaction product generated by the wild-type enzyme), which results in pro-leukemic epigenetic changes similar to those observed in cells with TET2 mutations. The oral agents ivosidenib and enasidenib, inhibitors of mutant IDH1 and IDH2, respectively, decrease cellular 2-hydroxyglutarate by more than 90%, thus reducing histone hypermethylation and reestablishing myeloid differentiation.³⁹ In a phase I/II study, IDH2 mutated relapse/refractory AML patients were treated with enasidenib at 100 mg daily resulting in an overall response rate of 40.3% with a median OS of 9.3 months; the 19.3% who achieved a CR had an OS of 19.7 months.⁴⁰ Similarly, the phase I/II study of ivosidenib in IDH1 relapsed/refractory mutant AML demonstrated a CR/CRi rate of 30.4% and overall response rate of 41.6%.⁴¹ These studies led to the approval of enasidenib and ivosidenib for relapsed AML. Further studies combining enasidenib with azacitidine in relapse (ClinicalTrials.gov identifier: NCT03683433) or ivosidenib with azacitidine in upfront AML patients (ClinicalTrials.gov identifier: NCT03173248) are ongoing. Preliminary results of a phase II study in which these inhibitors were tested in combination with standard induction chemotherapy in upfront patients with the appropriate mutation demonstrated a response rate of 93% in the ivosidenib arm and 73% in the enasidenib arm, with mutational clearance of 41% and 30% respectively.³¹ A randomized phase III trial comparing induction chemotherapy to chemotherapy plus the relevant inhibitor is currently being planned.

Pro-apoptotic agents

BCL-2 inhibition

B-cell leukemia/lymphoma-2 (BCL2) is an anti-apoptotic protein that promotes leukemic blast survival through regulation of the mitochondrial apoptotic pathway. Sensitizer BCL-2 homology 3 (BH3) proteins are antagonists of these antiapoptotic proteins and therefore promote apoptosis via mitochondrial outer membrane permeabilization.⁴² Venetoclax, an oral small-molecule BCL-2 inhibitor demonstrated on-target BCL-2 inhibition by BH3 profiling and an overall response rate of 19% in a single-agent trial in very advanced AML; patients with IDH mutations appeared to be more responsive (33%) to venetoclax.⁴³ In an effort to take advantage of the drug’s ability to help cells undergo apoptosis in the presence of cytotoxic stress, venetoclax was paired with either azacitidine or decitabine (institutional preference), in an elderly population of patients that were unfit for standard induction chemotherapy. The combinations were well tolerated, yielding a 61% CRi rate at the recommended phase II dose of 400 mg daily.⁴⁴ The phase II data revealed a CR+CRi rate of 73% and a median OS for the entire cohort of 17.5 months.⁴⁵ This combination of venetoclax with hypomethylating agents (HMA) may be becoming the new standard of care for patients who are elderly or unfit for standard induction chemotherapy. A second study evaluated venetoclax with low-dose cytarabine in a phase I/II trial in combination with low-dose cytarabine yielding CR/CRi rates of 35% for secondary AML and 71% for de novo AML.⁴⁶ Given these encouraging data, a plethora of studies have opened or proposed using venetoclax in combination with other agents, including combination with standard ‘3 + 7’ induction (ClinicalTrials.gov identifier: NCT03709758), although other ‘novel–novel’ combinations including but not limited to the multi-CDK inhibitor dinaciclib (ClinicalTrials.gov identifier: NCT03484520), gilteritinib (ClinicalTrials.gov identifier: NCT03625505), 10-day decitabine (ClinicalTrials.gov identifier: NCT03404193), and the mcl-1 inhibitor S64315 (ClinicalTrials.gov identifier: NCT03672695). A full list of the novel venetoclax trials can be found in Table 2.

Table 2.

AML-specific actively recruiting Venetoclax trials.

ClinicalTrials.gov identifier	AML population	Phase	Study
NCT03466294	TN elderly	II	Venetoclax + Azacitidine with venetoclax maintenance in MRD-negative patients
NCT03214562	r/r	Ib/II	Venetoclax with FLAG-IDA
NCT03484520	r/r	I	Venetoclax + Dinaciclib
NCT03625505	r/r	I	Venetoclax + Gilteritinib
NCT03441555	r/r	I	Venetoclax + Alvocidib
NCT03404193	TN elderly, r/r, or relapsed high-risk MDS	II	Venetoclax + 10-day decitabine
NCT03672695	TN or r/r	I	Venetoclax + S64315 (MCL-1 inhibitor)
NCT03471260	r/r	I/II	Venetoclax + Ivosidenib
NCT02670044	r/r, age ⩾60	I/II	Venetoclax + Cobimetinib or Idasanutlin
NCT02993523	TN elderly or unfit	III	Venetoclax + Azacitidine versus Azacitidine alone
NCT03069352	TN elderly or unfit	III	Venetoclax + LODAC versus LODAC alone
NCT03586609	TN	II	Venetoclax + cladrabine plus LODAC alternating with azacitidine
NCT03709758	Untreated, fit	I	Venetoclax + Daunarubicin/cytarabine
NCT03629171	TN or r/r	II	Venetoclax + liposomal encapsulated daunorubicin-cytarabine
NCT03214562	r/r	Ib/II	Venetoclax with FLAG-IDA
NCT03586609	TN, non-elderly	II	Venetoclax + Azacitidine

AML, acute myeloid leukemia; FLAG-IDA, fludarabine, cytarabine, GCSF, idarubicin; MRD, minimal residual disease; r/r, relapsed/refractory; TN, treatment naïve.

Myeloid cell leukemia-1 (MCL-1) inhibitors

MCL-1, like BCL-2, is capable of blocking pro-apoptotic proteins such as BAX and BAK, which do not interact with BCL-2, and upregulation may provide a resistance mechanism to venetoclax. MCL-1 inhibitors have been tested minimally in the clinic. MCL-1 inhibitory agents under investigation include AMG176 with venetoclax (in planning) or as a single agent (ClinicalTrials.gov identifier: NCT02675452), and AMG397 (ClinicalTrials.gov identifier: NCT03465540), S64315 with venetoclax (ClinicalTrials.gov identifier: NCT03672695) or single agent (ClinicalTrials.gov identifier: NCT02979366), and AZD5991 (ClinicalTrials.gov identifier: NCT03218683).⁴⁷

P53 reactivation

More than 50% of human cancers possess a p53 mutation, which is often a missense mutation that leads to protein unfolding and prevents this transcription factor from responding to cellular stress to elicit cell cycle arrest and apoptosis. p53 mutations are found in 18% of AML overall, in 70% of patients with complex karyotype, and is associated with very short median survival (5.4 months).^4,48,49 APR-246 is one of the first agents to specifically target mutated p53. The drug is given IV and is converted into a Michael acceptor, methylene quinuclidinone, which covalently binds to the p53 core domain promoting refolding, and the reinstitution of wild-type p53 function and, thus, cell cycle arrest and apoptosis may occur.⁵⁰ In an ongoing phase I/II clinical trial of MDS and AML with <30% blasts, APR-246 in combination with azacitidine induced an overall response of 100% (11 of 11 patients) with a CR rate of 82%. While the duration of remission is not yet known a phase III trial of aza±APR 246 in MDS is planned as is a similar trial in older adults with AML. A further study in an AML population is being planned.

Mouse double minute 2 inhibitors

Mouse double minute 2 (MDM2) is the primary regulator of p53 stability, activity in part by controlling p53 degradation. RG7112 was the first MDM2 inhibitor evaluated in a phase I trial for all leukemias. As expected p53 mutated patients failed to have durable responses. In the AML cohort, the overall response rate was 13%.⁵¹ A second-generation oral MDM2 inhibitor (RG7388, Idasanutlin) was evaluated in a phase I/Ib trial which demonstrated a 22% overall response rate, and in combination with cytarabine the CR+CRi rate was 24%.^52,53 These data have led to a phase III study of idasanutlin plus cytarabine versus cytarabine alone (ClinicalTrials.gov identifier: NCT02545283). Given preclinical data demonstrating potential synergy between idasanutlin and bcl-2 inhibition,⁵⁴ another ongoing trial combines venetoclax with idasanutlin for relapsed or refractory AML patients (ClinicalTrials.gov identifier: NCT02670044). Preliminary data presented in 2018 demonstrated an antileukemic response rate of 37% with a median time to response and duration of response of 1.8 and 8.1 months, respectively.⁵⁵

Two other inhibitors of this pathway have been evaluated. MK-8242, a human double minute 2 (HDM2) inhibitor was evaluated in a phase I trial for refractory/recurrent AML, but only 1 of 24 patients responded.⁵⁶ A second compound, HDM201 (Novartis) which selectively inhibits the HDM2-p53 interaction has been under evaluation in p53-wt AML at multiple dosing schedules and is ongoing. The preliminary results demonstrate as CR+CRi+PR rate of 20.6%.⁵⁷ A study evaluating HDM201 and chemotherapy in both a front-line and relapsed/refractory population is planned (ClinicalTrials.gov identifier: NCT03760445).

Microenvironment targeting

Uproleselan (GMI-1271)

E-selectin is a cell adhesion molecule involved in the migration of leukocytes along vascular endothelial cells and is highly expressed on leukemic blasts, especially those with advanced disease.⁵⁸ Uproleselan (GMI-1271) is an antagonist of E-selectin which enhances chemotherapy response while ameliorating chemotherapy toxicity in animal models. In the phase I/II trial combining Uproleselan with MEC chemotherapy in relapsed/refractory patients, the CR/CRi rate was 41%, with a 30- and 90-day mortality of 2% and 9% respectively, and a grade 3/4 mucositis rate of <4%.^59,60 Similarly, an elderly high-risk treatment-naïve AML population was treated with Uproleselan combined with standard induction; 68% (73% de novo, 64% sAML) achieved CR/CRi. The 30- and 90-day mortality was 8% and 12%, respectively, with no reports of grade 3/4 mucositis.^60,61 A phase III randomized trial is ongoing for r/r patients comparing Uproleselan with MEC versus MEC alone (ClinicalTrials.gov identifier: NCT03616470), and a separate phase II–III trial evaluating Uproleselan with induction versus induction alone was recently activated (ClinicalTrials.gov identifier: NCT03701308).

Cell cycle checkpoint inhibitors

Whereas AML is caused in part by dysregulation of cell proliferation, a series of targets involve the cell cycle regulation and DNA repair. One mechanism of chemotherapy resistance involves cell cycle regulators’ recognition of DNA damage which delays mitosis to allow repair to be initiated.⁶² Thus, inhibiting this pathway could have a synergistic effect with chemotherapy.

Aurora kinase inhibitors

Aurora kinases play an essential role in mitosis regulation, centrosome function, chromatid segregation, and bipolar spindle assembly.⁶³ Alisertib (MLN8273) is an oral Aurora A kinase inhibitor that increases efficacy of cytarabine.⁶⁴ A single-agent phase II trial dosing at 50 mg BID for 7 days every 21 days was associated a 17% overall response rate in unselected patients with advanced AML.⁶⁵ Given single-agent safety a phase I trial combined alisertib with 7 + 3 yielding a maximum-tolerated dose (MTD) of 30 mg bid.⁶⁶ In the phase II trial evaluating that alisertib dose plus ‘3 + 7’ in high-risk AML results included aCR+CRi rate of 64% with a 30-day and 60-day mortality rates of 8% and 13%, respectively, and a median OS of 12.2 months.⁶⁷ A phase III trial is under discussion.

Barasertib, an Aurora B kinase inhibitor delivered by IV continuous infusion, was also found to be active as a single agent and in combination with other chemotherapeutic agents.⁶⁸ A five patient single-agent phase I trial demonstrated safety with one patient achieving a CR, and a second phase I study combining barasertib with low-dose cytarabine (LODAC) demonstrated an overall response rate of 45% but at a cost of a 73% rate of significant infections.^69,70 The SPARK-AML1 trial was a 2:1 randomized phase II trial comparing barasertib with LODAC in elderly unfit patients, with the barasertib arm demonstrating a CR/CRi rate of 35.4% and an OS of 8.2 month. This compound can be given in a nanoparticle delivery system (AZD2811), which may achieve improved bioavailability and is currently under investigation as a phase I clinical trial (ClinicalTrials.gov identifier: NCT03217838).

Polo-like kinase-1 inhibitors

Polo-like kinase-1 (PLK1) plays an integral role in mitosis, DNA replication, and DNA repair. If PLK1 function is impaired, polo-arrest occurs, leading to cell cycle arrest in pro-metaphase.⁷¹ The initial PLK-1 inhibitor volasertib was studied in a randomized phase II trial low-dose cytarabine +/– the drug in untreated high-risk, older AML patients. CR+CRi rate for LODAC + volasertib was 31%.⁷² A second PLK-inhibitor, rigosertib, which also inhibits PI3-kinase and the RAS/MEK/ERK pathway, has been compared in a negative large phase III trial (ONTIME) to standard care in HMA-failed MDS. Rigosertib achieved a similar OS (8.2 months, 95% CI 6.1–10.1) compared with best supportive care (5.9 months, 95% CI 4.1–9.3) that did not reach statistical significance (HR 0.87, 95% CI 0.67–1.14; p = 0.33).⁷³ A phase I/II single-agent trial in patients with MDS or MDS progressed to AML showed only one responder of 13 AML patients.⁷⁴

Other cell cycle inhibitors

Cyclin-dependent kinases (CDK) are a group of proteins that promote transition through the cell cycle. Perturbation in the regulation of cell cycle flow between S phase and G2/M is thought to be essential for tumorigenicity in at least some settings.⁷⁵ Palbociclib is a CDK4/6 inhibitor approved in breast cancer and also is active against FLT3-ITD AML cells. A phase I trial of single-agent palbociclib in advanced AML was disappointing; however, this trial now includes cohorts of patient treated with palbociclib plus either dexamethasone, decitabine, or sorafenib (ClinicalTrials.gov identifier: NCT03132454).^76,77 A second single-agent trial limited to mixed lineage leukemia (MLL)-rearranged acute leukemias (ClinicalTrials.gov identifier: NCT02310243) is ongoing. Dinaciclib is a CDK9 inhibitor that also promotes apoptosis in MLL-rearranged AML, promoting studies in combination with venetoclax (ClinicalTrials.gov identifier: NCT03484520) and pembrolizumab (ClinicalTrials.gov identifier: NCT02684617) in this setting.⁷⁸

CHK1 is a multifunctional protein kinase and regulator of the DNA damage response.⁷⁹ In response to DNA damage, CHK1 mediates cell-cycle arrest to allow time for DNA repair, or if the damage is extensive, to trigger apoptosis. CHK1 is also essential for homologous recombination-mediated repair of double-strand DNA breaks, initiation of DNA replication origin firing, stabilization of replication forks, resolution of replication stress, and coordination of mitosis, even in the absence of exogenous DNA damage.⁸⁰ Analysis of AML patient samples has demonstrated that the CHEK1 gene is upregulated in AML with high expression associated with shorter responses and overall survival. Moreover, when these cells were treated with a CHK1 inhibitor in combination with cytarabine, DNA replication was reduced.⁸¹ Prexasertib (LY2606368) is an ATP-competitive inhibitor of CHK1 that causes double-stranded DNA breaks in S-phase cells leading to replication catastrophe.⁸² Two ongoing studies are evaluating prexasertib in the relapsed/refractory AML setting with either FLAG (ClinicalTrials.gov identifier: NCT02649764) or MEC (ClinicalTrials.gov identifier: NCT03735446).

Epigenetic regulators

Epigenetic dysregulation associated with mutations in genes such DNMT31, TET2, and ASXL1 which lead to aberrant methylation, demethylation, and acetylation contribute to myeloid leukemogenesis. Restoring the function of such mutations either directly or indirectly has remained an elusive but potentially interesting therapeutic strategy.

Disrupter of telomeric silencing 1-like

Rearrangements of the MLL gene (newly termed KMT2A) on chromosome 11q23 convey a poor prognosis in AML.⁸³ Mutant MLL proteins lead to high levels of histone 3 at lysine 79 (H3K79) and thereby directing disrupter of telomeric silencing 1-like (DOT1L) to aberrant targets. Inhibition of DOT1L disrupts leukemogenesis in mouse models, led to a single-agent phase I study with pinometostat (EPZ-5676), a small-molecule inhibitor of DOT1L, by continuous IV infusion.⁸⁴ Of the 51 patients with hematologic malignancies (84% AML, 82% of these with an MLL mutation) who were treated, pinometostat appeared safe; two patients, each of whom with t (11; 19) leukemia, achieved a CR. Evidence for target inhibition, based on reduction of H3K79 methylation in blasts, was also noted in all dose levels.⁸⁵ Further studies evaluating pinometostat with azacitidine (ClinicalTrials.gov identifier: NCT03701295) or with induction chemotherapy (ClinicalTrials.gov identifier: NCT03724084) in MLL mutated patients are planned.

Bromodomain and extraterminal protein family inhibitors

The bromodomain (BRD) and extraterminal (BET) protein family is integral for transcription through its association with enhancers and positive transcription factor b (P-TEFb), which promote the transition from RNA polymerase from the paused to the elongating state.^86,87 BET inhibitors have preclinical activity against MLL mutant cell lines; most MLL fusion partners are members of the super elongation complex (SEC), required for downstream transcription of the proleukemic genes such BCL2, C-MYC, and CDK6, which is blocked by displacement of BRD3/4 and the SEC components from chromatin.⁸⁸ Further preclinical studies also demonstrate promising activity against NPM1 and FLT3-ITD mutant AML.^89,90

Clinical studies with BET inhibitors have shown modest single-agent efficacy. In a phase I trial using the oral BET inhibitor OTX015, there were three patients with a CR among 36 AMLs treated across 6 dose levels. Dose-limiting toxicities (DLTs) included fatigue, rash, and gastrointestinal (GI) effects.⁹¹ Other BET inhibitors undergoing evaluation include TEN-010 (ClinicalTrials.gov identifier: NCT02308761) and GSK535762 (ClinicalTrials.gov identifier: NCT01943851). Like many of the other examples noted above, combinations of BET inhibitors in combination with other agents such as venetoclax or MCL inhibitors may be optimal based on preclinical data.⁹²

Immunotherapy

Allogenic stem-cell and donor lymphocyte infusions represent two forms of immunotherapy that have been effective in the therapy of AML.^93,94 Building on the benefit of novel agents such as monoclonal antibodies and chimeric antigen receptor (CAR) T cells seen in other diseases, multiple agents have been evaluated to take advantage of this native immune response.

Antibody-based therapy

Gemtuzumab ozogamicin

Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody conjugated to the antibiotic calicheamicin, which is toxic to leukemic cells. The drug was approved in 2001 for relapsed non-chemo-eligible relapsed AML based on trials using a dose of 9 mg/m² every 2 weeks yielding a 26% CR rate.⁹⁵ However, the increased hematologic and hepatic toxicity including high rates of veno-occlusive disease especially after allo SCT lead Pfizer to withdraw the drug from the US market in 2010. Further studies continued in Europe with the most prominent being the phase III ALFA-0701 study employing standard induction chemotherapy with or without a lower dose of GO. This study demonstrated significant improved 2-year event-free survival (40.8% versus 17.1%), relapse-free survival (50.3% versus 22.7%) and OS (53.2% versus 41.9%); the addition of gemtuzumab to chemotherapy appears especially beneficial in cytogenetically favorable risk AML.⁹⁶ Similarly, in a relapsed population, fractionated dosing of GO mitigated hematologic and hepatic toxicities, and demonstrated a CR rate of 26% and CRp of 6%.⁹⁷ Further evaluations are ongoing including use in the minimal residual disease (MRD) setting (ClinicalTrials.gov identifier: NCT03737955), and in combination with azacitidine,⁹⁸ cytarabine (ClinicalTrials.gov identifier: NCT02473146), decitabine (ClinicalTrials.gov identifier: NCT00882102), MRD (ClinicalTrials.gov identifier: NCT03737955) and multiple induction regimens.

Vadastuximab talirine (SGN-33A)

Vadastuximab talirine (VT) also targets CD33 but the cysteine residues of the antibody are conjugated to a DNA cross-linking agent pyrolobenzodiazepine (PBD) dimers via a cleavable maleimidocaproyl–valinealanine dipeptide linker. In the phase I study in advanced AML, a dose of 40 µg/kg was selected; the CR+CRi rate was 28%.⁹⁹ A second phase I trial combined VT with hypomethylating agents in an elderly population and demonstrated a CR+CRi rate of 70%, but significant myelosuppression was noted. Similar toxicity was noted in a study combining VT with 7 + 3 chemotherapy with dosing of 10–20 µg/kg on days 1 and 4.¹⁰⁰ This led to the phase III CASCADE trial, which was discontinued due to higher mortality in the VT arm.

Anti-CD123

CD123 is the interleukin 3 receptor alpha chain (IL-3α) and found to be overexpressed on myeloid blasts and leukemic stem cells. There have been multiple agents targeting this receptor. While the initial phase I study of the naked antibody CSL360 demonstrated minimal efficacy,¹⁰¹ anti-CD123 molecules are continually being explored. SGN-CD123A, an antibody using the same linker and warhead as Vadastuximab, demonstrated preclinical promise and is currently under investigation in AML (ClinicalTrials.gov identifier: NCT02848248).¹⁰² Similarly, the antibody–drug conjugate IMG632, a humanized anti-CD123 antibody conjugated to a mono-alkylating payload of the indolinobenzodiazepine pseudodimer (IGN) class, and is in phase I (ClinicalTrials.gov identifier: NCT03386513).¹⁰³

SL-401

SL-401 (Tagraxofusp) is a recombinant fusion protein combining human IL-3, the CD123 ligand, with a truncated diphtheria toxin that has demonstrated activity against CD34+CD123+ AML and MDS cells.¹⁰⁴ It is highly effective in blastic plasmacytoid dendritic cell neoplasm (BPDCN),¹⁰⁴ and has modest single-agent activity in AML.¹⁰⁵ Current studies are ongoing with combination therapy with azacitidine (ClinicalTrials.gov identifier: NCT03113643) and also as a single-agent consolidation for eradication of minimal residual disease (ClinicalTrials.gov identifier: NCT02270463).¹⁰⁶

Bispecific antibodies

Bispecific antibodies utilize two different variable regions, one binding to the T-cell subunit CD3 and the other to the tumor surface antigen to provide contact between the cells and create a T-cell activation against tumor cells. The success of blinatumomab, a bispecific antibody to CD19 and CD3, in acute lymphoblastic leukemia¹⁰⁷ has led to attempts to use this technology in AML. AMG330 is a bispecific antibody against CD3 and CD33 that demonstrates AML cell cytotoxicity, particularly in favorable-risk disease, and also has synergy with blockade of the PD-1/PD-L1 axis, thereby preventing immune exhaustion.^108,109 Owing to the intriguing preclinical data, phase I clinical trials are underway (ClinicalTrials.gov identifier: NCT02520427). Similarly, flotetuzumab (MGD006 or S80880) is a dual-affinity retargeting antibody (DART), which employs two independent polypeptides fusing the heavy-chain variable domain of one antibody to the light-chain variable domain of the other to connect CD3 and CD123. Preclinical studies demonstrated a dose-dependent killing of AML cells.¹¹⁰ Preliminary data of a phase I/II trial of flotetuzumab in advanced AML/MDS patients, with an acceptable safety profile, and demonstrated a CR/CRi rate of 31% (4/13 patients) with primary refractory disease, but no responses in relapsed patients (0/11). Another phase I trial in patients with a variety of hematologic malignancies is ongoing (ClinicalTrials.gov identifier: NCT03739606).¹¹¹

CAR-T-cell therapy

CAR-T-cell therapy hast had a dramatic effect on the management of lymphoid malignancies and thus while there is great interest in adapting this technology for AML, the lack of target that is ubiquitously expressed in AML yet dispensable has created challenges.^112–114 In a phase I study using CAR-T cells targeting the Lewis-Y antigen, three of four patients had evidence of an ephemeral biological response.¹¹⁵ A report described a CD33 directed CAR-T cell in one patient with relapsed/refractory AML; this patient had a dramatic cytokine release syndrome and experienced a decrease in blasts 2 weeks after treatment but then progression at 9 weeks.¹¹⁶ Budde et al. presented data on six patients who received anti-CD123 CAR-T cells, which demonstrated safety and activity with one morphologic leukemia-free state, two CR, and two reduction in blast counts.¹¹⁷ This trial is ongoing (ClinicalTrials.gov identifier: NCT02159495). NKG2DL has also been evaluated as a target for CAR-T cells. In a phase I trial in myeloma and AML, one patient had a transient response but otherwise no tumor responses were observed.¹¹⁸ A second phase I trial used CYAD-01, a similar product to that used in the aforementioned study but at a much higher dose of cells evaluated 8 r/r AML patients. The drug displayed promising efficacy as well as cytokine release syndrome that was successfully managed. An overall response rate of 42% was noted (ClinicalTrials.gov identifier: NCT03018405).¹¹⁹ There are currently other ongoing studies with variations of CAR-T cells from AML in both the United States and China, including UCART123 (ClinicalTrials.gov identifier: NCT03190278) which is an allogeneic or ‘off-the-shelf’ product and a novel CD33 CAR (ClinicalTrials.gov identifier: NCT03126864).

Checkpoint inhibitors

Anti-CTLA-4

Immune checkpoint inhibitors have been widely studied on solid tumors, and their migration to the hematologic malignancies has become more prominent since the success in Hodgkin’s Lymphoma,¹²⁰ and in the relapsed hematologic malignancy post-transplant setting.¹²¹ In the latter study using ipilimumab, an anti-CTLA-4 antibody, 5 of the 12 AML patients had responses, including four patients with extramedullary disease. While a phase Ib single agent ipilimumab trial demonstrated minimal effect as monotherapy after hypomethylating agent failure,¹²² further studies combining ipilimumab with decitabine (ClinicalTrials.gov identifier: NCT02890329) in the de novo and post-transplant setting are currently enrolling.

PD-1 blockade agents

Preclinically, PD-1 blockade demonstrated PD-L1 upregulation in murine AML cells in vivo with response to PD-L1 blocking antibodies.¹²³ Further studies have demonstrated the potential to enhance cytotoxicity in adoptive T-cell therapy by combining PD-1 with cytotoxic T-cell infusions.¹²⁴ A phase IB/II study combined nivolumab with azacitidine in 51 relapsed/refractory AML patients. Fourteen patients had grade 2 or higher immune-mediated toxicities with 12 responding to steroids; 6 of 25 evaluable patients achieved a CR, Cri, or hematologic improvement.¹²⁵ Another study in high-risk AML patients ineligible for stem cell transplant who were in CR received nivolumab every 2 weeks for 6 months, then every 4 weeks for 6 months, and every 3 months thereafter. In the 14 evaluable patients, the 12 and 18 month OS estimates were 86% and 67%, respectively (ClinicalTrials.gov identifier: NCT02532231).¹²⁶ Lastly, a phase II nonrandomized study was performed evaluating safety, efficacy, and biomarkers using azacitidine with either nivolumab or nivolumab + ipilimumab in relapsed/refractory AML. In the azacitidine/nivolumab arm, the CR/CRi rate was 22%, while the azacitidine/nivolumab + ipilimumab arm revealed a CR/CRp/CRi rate of 43%. Responders had a higher frequency of CD3+ and CD8+ cells in bone marrow by flow cytometry, making these potential predictive biomarkers for this regimen (ClinicalTrials.gov identifier: NCT02397720).¹²⁷

Nivolumab (every 2 weeks) has also been evaluated in an induction regimen containing idarubicin and cytarabine in AML or high-risk MDS (⩾10% blasts). Response rates were 77%, with responders again having higher frequency of CD3+ cells (ClinicalTrials.gov identifier: NCT02464657).¹²⁸ Further studies in relapsed/refractory AML utilizing nivolumab involve combinations with oral cyclophosphamide (ClinicalTrials.gov identifier: NCT03417154), and a phase I vaccine trial combining a novel vaccine with nivolumab and decitabine (ClinicalTrials.gov identifier: NCT03358719).

Pembrolizumab is another anti-PD-1 antibody researched for the treatment of AML. In a relapsed/refractory AML population, the group at University of North Carolina evaluated age-adjusted high-dose cytarabine followed by pembrolizumab, an anti-PD-1 antibody, on day 14, with responders receiving maintenance pembrolizumab every 3 weeks for up to 2 years (ClinicalTrials.gov identifier: NCT02768792). Preliminary data showed a CR/CRi rate of 40%; two patients went to maintenance with a median duration of CR 3.9 months.¹²⁹ Pembrolizumab was also combined with decitabine in a relapsed/refractory AML population, with 1 of 10 reported patients responding with a MRD-negative CR after 8 cycles.¹³⁰ A relapsed/refractory AML study using azacitidine and pembrolizumab in elderly patients is ongoing (ClinicalTrials.gov identifier: NCT02845297).

Vaccine therapy

Concepts being explored include vaccines to trigger an immune response to tumor-associated antigens by peptide vaccinations, or through fusion with dendritic cells that present antigen in the proper context may elicit a primary immune response.^131,132 A systematic review of the 9 Wilms’ Tumor-1 (WT-1) antigen trials demonstrated correlations between induction of T cells specific to WT-1 and response, and a moderate response rate (22 responses of 67 patients).¹³³ The most advanced of these vaccines is the multivalent WT1 peptide galinpepimut-S. In a phase II trial, the vaccine was administered 6 times over 10 weeks followed by 6 monthly doses in patients who achieved CR1. The vaccine was deemed well tolerated, with a median disease-free survival of 16.9 months and a relapse rate of 68%.¹³⁴ Another vaccine utilized OCV-501, an HLA class II restricted helper peptide derived from the WT1 protein. The phase II trial of this vaccine conducted in AML patients over 60 in CR1. A total of 133 patients were randomized to vaccine or placebo, and although well tolerated, there was no significant difference in disease-free survival.¹³⁵

Multiple dendritic cell-based vaccines have been evaluated for AML. DCP-001 is a vaccine developed from an AML cell line having epitopes for the disease but not patient specific. In a phase I trial in patients in CR or with smoldering disease, the treatment was well tolerated, and patient with no circulating blasts had an OS of 36 months.¹³⁶ An international phase II trial utilized dendritic cells electroporated with WT1 messenger RNA, and found an antileukemic response in 43% of patients.¹³⁷ A third trial developed a personalized vaccine fusing patient-derived AML cells with autologous dendritic cells. In 17 patients who achieved a remission to chemotherapy, 12 remained alive with a median follow up of 57 months at the time of publication (ClinicalTrials.gov identifier: NCT03679650).¹³⁸

Conclusion

In summary, the elucidation of pathways that promote proliferation, inhibiting apoptosis, targeting cause mitogenesis due to mutations in specific genes, and limit the native immune system have each provided a much-needed burst of novel agents for the treatment of AML over the past 2 years. New pharmacologic breakthroughs, such as venetoclax, or targeted therapies such as midostaurin or enasidenib have transformed the paradigm of AML treatment. The intense collaboration between benchwork and bedside has prompted a more rational approach compared with the sledgehammer of conventional chemotherapy; the ongoing BEAT AML trial and planned US cooperative group studies have acknowledged the heterogeneity of AML by assigning patients to therapies bases on their molecular subtype. The plethora of clinical trials using novel small-molecule inhibitors is intriguing: while history has taught that only a small fraction of these trials will be paradigm changing, the further development of some of these novel agents will surely build on these recent successes.

Footnotes

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement

ESW has served on advisory boards for Shionogi, Inc. and Pfizer and received research funding from Lilly. RMS has served on an advisory board/consulted for AbbVie, Actinium, Agios, Amgen, Arog, Astellas, AstraZeneca, Cellator/Jazz, Celgene, Cornerstone, Fujifilm, Juno, Macrogenics, Novartis, Ono/Theradex, Otzuka/Astex, Pfizer, Roche, and Sumitomo; served on a data safety monitoring board for Argenx, Celgene, and Takeda; and received research funding from AbbVie, Agios, Arog, and Novartis.

ORCID iD

Richard M. Stone

References

Siegel

Miller

Jemal

. Cancer statistics, 2018. CA Cancer J Clin 2018; 68: 7–30.

National Cancer Institute. SEER Cancer stat facts: acute myeloid leukemia (AML), https://seer.cancer.gov/statfacts/html/amyl.html/ (accessed 17 December 2018).

Rai

Holland

Glidewell

et al . Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood 1981; 58: 1203–1212.

Lindsley

Mar

Mazzola

et al . Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015; 125: 1367–1376.

Papaemmanuil

Gerstung

Bullinger

et al . Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016; 374: 2209–2221.

Döhner

Estey

Grimwade

et al . Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129: 424–447.

Hematology/Oncology (Cancer) Apporvals & Safety Notifications, https://www.fda.gov/drugs/informationondrugs/ucm279174.htm (accessed 17 December 18).

Lancet

Cortes

Hogge

et al . Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood 2014; 123: 3239–3246.

Lancet

Cortes

et al . CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol 2018; 36: 2684–2692.

10.

Ingham

McMahon

. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15: 3059–3087.

11.

Queiroz

KCS

Ruela-de-Sousa

Fuhler

et al . Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene 2010; 29: 6314.

12.

Zhao

Chen

Jamieson

et al . Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009; 458: 776.

13.

Dierks

Beigi

Guo

G-R

et al . Expansion of Bcr-Abl-Positive leukemic stem cells is dependent on hedgehog pathway activation. Cancer Cell 2008; 14: 238–249.

14.

Lim

Gondek

et al . Integration of hedgehog and mutant FLT3 signaling in myeloid leukemia. Sci Transl Med 2015; 7: 291ra296–291ra296.

15.

Irvine

Copland

. Targeting hedgehog in hematologic malignancy. Blood 2012; 119: 2196–2204.

16.

Munchhof

Shavnya

et al . Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened. ACS Med Chem Lett 2012; 3: 106–111.

17.

Sadarangani

Pineda

Lennon

et al . GLI2 inhibition abrogates human leukemia stem cell dormancy. J Transl Med 2015; 13: 98.

18.

Martinelli

Oehler

Papayannidis

et al . Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study. Lancet Haematol 2015; 2: e339–e346.

19.

Minami

Miyamoto

et al . Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci 2017; 108: 1628–1633.

20.

Savona

Pollyea

Stock

et al . Phase Ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. Clin Cancer Res 2018; 24: 2294–2303.

21.

Cortes

Douglas Smith

Wang

et al . Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: phase 2 study results. Am J Hematol 2018; 93: 1301–1310.

22.

Cortes

Heidel

Heuser

et al . A phase 2 randomized study of low dose Ara-C with or without glasdegib (PF-04449913) in untreated patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 2016; 128: 99.

23.

Stone

. What FLT3 inhibitor holds the greatest promise? Best Pract Res Clin Haematol 2018; 31: 401–404.

24.

Stone

Mandrekar

Sanford

et al . Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017; 377: 454–464.

25.

Serve

Krug

Wagner

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: 3110–3118.

26.

Röllig

Serve

Hüttmann

et al . 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: 1691–1699.

27.

Stone

DeAngelo

Klimek

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: 54–60.

28.

Smith

Levis

Beran

et al . Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 2004; 103: 3669–3676.

29.

Cortes

Khaled

Martinelli

et al . Quizartinib significantly prolongs overall survival in patients with FLT3-internal tandem duplication-mutation (mut) relapsed/refractory AML in the phase 3, randomized, controlled Quantum-R trial. In: 23rd Congress of the European Hematology Association, 14 June 2018, (Vol. 14, p. 17).

30.

Ravandi

Alattar

Grunwald

et al . Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 2013; 121: 4655–4662.

31.

Burchert

Bug

et al

Sorafenib As Maintenance Therapy Post Allogeneic Stem Cell Transplantation for FLT3-ITD Positive AML: results from the randomized, double-blind, placebo-controlled multicentre sormain trial. Blood 2018; 132: 661.

32.

Zheng

Bailey

Nguyen

et al . Further activation of FLT3 mutants by FLT3 ligand. Oncogene 2011; 30: 4004.

33.

Sato

Yang

Knapper

et al . FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 2011; 117: 3286–3293.

34.

Wang

Chen

et al . Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML. Oncotarget 2016; 7: 29131–29142.

35.

Seipel

Marques

MAT

Sidler

et al . MDM2- and FLT3-inhibitors in the treatment of FLT3-ITD acute myeloid leukemia, specificity and efficacy of NVP-HDM201 and midostaurin. Haematologica 2018; 103: 1862–1872.

36.

Traer

Martinez

Javidi-Sharifi

et al . FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia. Cancer Res 2016; 76: 6471–6482.

37.

Waitkus

Diplas

Yan

. Biological role and therapeutic potential of IDH mutations in Cancer. Cancer Cell 2018; 34: 186–195.

38.

Ragon

DiNardo

. Targeting IDH1 and IDH2 mutations in acute myeloid leukemia. Curr Hematol Malig Rep 2017; 12: 537–546.

39.

Stein

. IDH2 inhibition in AML: finally progress? Best Pract Res Clin Haematol 2015; 28: 112–115.

40.

Stein

DiNardo

Pollyea

et al . Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017; 130: 722–731.

41.

DiNardo

Stein

de Botton

et al . Durable remissions with ivosidenib in IDH1-Mutated relapsed or refractory AML. N Engl J Med 2018; 378: 2386–2398.

42.

Konopleva

Letai

. BCL-2 inhibition in AML - an unexpected bonus? Blood. Epub ahead of print 23 July 2018. DOI: 10.1182/blood-2018–03–828269.

43.

Konopleva

Pollyea

Potluri

et al . Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 2016; 6: 1106–1117.

44.

DiNardo

Pratz

Letai

et al . Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018; 19: 216–228.

45.

DiNardo

Pratz

Pullarkat

et al . Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019; 133: 7–17. DOI: 10.1182/blood-2018–08–868752.

46.

Wei

Strickland

Hou

et al . Venetoclax with low-dose cytarabine induces rapid, deep, and durable responses in previously untreated older adults with AML ineligible for intensive chemotherapy. Blood 2018; 132: 284.

47.

Luedtke

Niu

Pan

et al . Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Signal Transduct Target Ther 2017; 2: 17012.

48.

Kadia

Jain

Ravandi

et al . TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer. Epub ahead of print 26 July 2016. DOI: 10.1002/cncr.30203.

49.

Rücker

Schlenk

Bullinger

et al . TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012; 119: 2114–2121.

50.

Bykov

VJN

Zhang

et al . Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy. Front Oncol 2016; 6: 21.

51.

Andreeff

Kelly

Yee

et al . Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res 2016; 22: 868–876.

52.

Yee

Martinelli

Vey

et al . Phase 1/1b study of RG7388, a potent MDM2 antagonist, in acute myelogenous leukemia (AML) patients (Pts). Blood 2014; 124: 116.

53.

Reis

Jukofsky

Chen

et al . Acute myeloid leukemia patients’ clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts. Haematologica 2016; 101: e185–e188.

54.

Pan

Ruvolo

et al . Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell 2017; 32: 748–760.e746.

55.

Daver

Pollyea

Garcia

et al . Safety, efficacy, pharmacokinetic (PK) and biomarker analyses of BCL2 inhibitor venetoclax (Ven) plus MDM2 inhibitor idasanutlin (idasa) in patients (pts) with relapsed or refractory (R/R) AML: a phase Ib, non-randomized, open-label study. Blood 2018; 132: 767.

56.

Ravandi

Gojo

Patnaik

et al . A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Leuk Res 2016; 48: 92–100.

57.

Stein

Chromik

DeAngelo

et al . Abstract CT152: Phase I dose- and regimen-finding study of NVP-HDM201 in pts with advanced TP53wt acute leukemias. Cancer Res 2017; 77: CT152.

58.

Rashidi

. Targeting the microenvironment in acute myeloid leukemia. Curr Hematol Malig Rep 2015; 10: 126–131.

59.

DeAngelo

Liesveld

Jonas

et al . A phase I/II Study of GMI-1271, a novel E-selectin antagonist, in combination with induction chemotherapy in relapsed/refractory and elderly previously untreated acute myeloid leukemia; results to date. Blood 2016; 128: 4049.

60.

DeAngelo

Jonas

Liesveld

et al . GMI-1271 improves efficacy and safety of chemotherapy in R/R and newly diagnosed older patients with AML: results of a phase 1/2 study. Blood 2017; 130: 894.

61.

DeAngelo

Jonas

Becker

et al . GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML. J Clin Oncol 2017; 35: 2560.

62.

Aleem

Arceci

. Targeting cell cycle regulators in hematologic malignancies. Front Cell Dev Biol 2015; 3: 16.

63.

Durlacher

Chen

et al . An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor. Clin Exp Pharmacol Physiol 2016; 43: 585–601.

64.

Kelly

Nawrocki

Espitia

et al . Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism. Int J Cancer 2012; 131: 2693–2703.

65.

Goldberg

Fenaux

Craig

et al . An exploratory phase 2 study of investigational Aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes. Leuk Res Rep 2014; 3: 58–61.

66.

Fathi

Wander

Blonquist

et al . Phase I study of the Aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia. Haematologica 2017; 102: 719–727.

67.

Brunner

Blonquist

DeAngelo

et al . Phase II clinical trial of alisertib, an Aurora A kinase inhibitor, in combination with induction chemotherapy in high-risk, untreated patients with acute myeloid leukemia. Blood 2018; 132: 766.

68.

Yang

Ikezoe

Nishioka

et al . AZD1152, a novel and selective Aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 2007; 110: 2034–2040.

69.

Dennis

Davies

Oliver

et al . Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia. Cancer Chemother Pharmacol 2012; 70: 461–469.

70.

Kantarjian

Sekeres

Ribrag

et al . Phase I study assessing the safety and tolerability of barasertib (AZD1152) with low-dose cytosine arabinoside in elderly patients with AML. Clin Lymphoma Myeloma Leuk 2013; 13: 559–567.

71.

Hao

Kota

. Volasertib for AML: clinical use and patient consideration. Onco Targets Ther 2015; 8: 1761–1771.

72.

Döhner

Lübbert

Fiedler

et al . Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood 2014; 124: 1426–1433.

73.

Garcia-Manero

Fenaux

Al-Kali

et al . Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol 2016; 17: 496–508.

74.

Navada

Fruchtman

Odchimar-Reissig

et al . A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia. Leuk Res 2018; 64: 10–16.

75.

Asghar

Witkiewicz

Turner

et al . The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015; 14: 130.

76.

Uras

Walter

Scheicher

et al . Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood 2016; 127: 2890–2902.

77.

Kadia

Konopleva

Garcia-Manero

et al . Phase I study of palbociclib alone and in combination in patients with relapsed and refractory (R/R) leukemias. Blood 2018; 132: 4057.

78.

Baker

Gregory

Verbrugge

et al . The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia. Cancer Res 2016; 76: 1158–1169.

79.

Dai

Grant

. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res 2010; 16: 376–383.

80.

McNeely

Beckmann

Bence Lin

. CHEK again: revisiting the development of CHK1 inhibitors for cancer therapy. Pharmacol Ther 2014; 142: 1–10.

81.

David

Fernandez-Vidal

Bertoli

et al . CHK1 as a therapeutic target to bypass chemoresistance in AML. Sci Signal 2016; 9: ra90.

82.

Ghelli Luserna Di Rorà

Iacobucci

Imbrogno

et al . Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia. Oncotarget 2016; 7: 53377–53391.

83.

Schoch

Schnittger

Klaus

et al . AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 2003; 102: 2395–2402.

84.

Deshpande

Chen

Fazio

et al . Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. Blood 2013; 121: 2533–2541.

85.

Stein

Garcia-Manero

Rizzieri

et al . The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood 2018; 131: 2661–2669.

86.

Jang

Mochizuki

Zhou

et al . The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 2005; 19: 523–534.

87.

Yang

Yik

JHN

Chen

et al . Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 2005; 19: 535–545.

88.

Dawson

Prinjha

Dittmann

et al . Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011; 478: 529.

89.

Fiskus

Sharma

et al . BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Mol Cancer Ther 2014; 13: 2315–2327.

90.

Dawson

Gudgin

Horton

et al . Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia 2013; 28: 311.

91.

Berthon

Raffoux

Thomas

et al . Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol 2016; 3: e186–e195.

92.

Fiskus

Cai

DiNardo

et al . Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J 2019; 9: 4.

93.

Gale

Horowitz

Ash

et al . IDentical-twin bone marrow transplants for leukemia. Ann Intern Med 1994; 120: 646–652.

94.

Dietz

Wayne

. Cells to prevent/treat relapse following allogeneic stem cell transplantation. Hematology Am Soc Hematol Educ Program 2017; 2017: 708–715.

95.

Sievers

Larson

Stadtmauer

et al . Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001; 19: 3244–3254.

96.

Castaigne

Pautas

Terré

et al . Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012; 379: 1508–1516.

97.

Taksin

Legrand

Raffoux

et al . High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia 2006; 21: 66.

98.

Medeiros

Tanaka

Balaian

et al . A phase I/II trial of the combination of azacitidine and gemtuzumab ozogamicin for treatment of relapsed acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2018; 18: 346–352.e345.

99.

Stein

Walter

Erba

et al . A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood 2018; 131: 387–396.

100.

Erba

Levy

Vasu

et al . A phase 1b study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Blood 2016; 128: 211.

101.

Busfield

Ritchie

et al . A phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia. Leuk Lymphoma 2015; 56: 1406–1415.

102.

Sutherland

et al . Characterization of SGN-CD123A, a potent CD123-directed antibody–drug conjugate for acute myeloid leukemia. Mol Cancer Ther 2018; 17: 554–564.

103.

Kovtun

Jones

Adams

et al . A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. Blood Adv 2018; 2: 848–858.

104.

Mani

Goswami

Gopalakrishnan

et al . The interleukin-3 receptor CD123 targeted SL-401 mediates potent cytotoxic activity against CD34⁺CD123⁺ cells from acute myeloid leukemia/myelodysplastic syndrome patients and healthy donors. Haematologica 2018; 103: 1288–1297.

105.

Frankel

Konopleva

Hogge

et al . Activity and tolerability of SL-401, a targeted therapy directed to the interleukin-3 receptor on cancer stem cells and tumor bulk, as a single agent in patients with advanced hematologic malignancies. J Clin Oncol 2013; 31: 7029–7029.

106.

Lane

Sweet

Wang

et al . Results from ongoing phase 2 trial of SL-401 as consolidation therapy in patients with acute myeloid leukemia (AML) in remission with high relapse risk including minimal residual disease (MRD). Blood 2016; 128: 215.

107.

Kantarjian

Stein

Gökbuget

et al . Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 2017; 376: 836–847.

108.

Harrington

Gudgeon

Laszlo

et al . The broad anti-AML activity of the CD33/CD3 BiTE antibody construct, AMG 330, is impacted by disease stage and risk. PLoS One 2015; 10: e0135945.

109.

Krupka

Kufer

Kischel

et al . Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism. Leukemia 2015; 30: 484.

110.

Al-Hussaini

Rettig

Ritchey

et al . Targeting CD123 in acute myeloid leukemia using a T-cell–directed dual-affinity retargeting platform. Blood 2016; 127: 122–131.

111.

Rettig

Vey

et al . Phase 1 cohort expansion of flotetuzumab, a CD123×CD3 bispecific DART^® protein in patients with relapsed/refractory acute myeloid leukemia (AML). Blood 2018; 132: 764.

112.

Jacobson

. CD19 chimeric antigen receptor therapy for refractory aggressive B-cell lymphoma. J Clin Oncol. Epub ahead of print 13 December 2018. DOI: 10.1200/jco.18.01457.

113.

Maude

Frey

Shaw

et al . Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371: 1507–1517.

114.

Park

Rivière

Gonen

et al . Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 2018; 378: 449–459.

115.

Ritchie

Neeson

Khot

et al . Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther 2013; 21: 2122–2129.

116.

Wang

et al . Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther 2015; 23: 184–191.

117.

Budde

Song

Kim

et al . Remissions of acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm following treatment with CD123-specific CAR T cells: a first-in-human clinical trial. Blood 2017; 130: 811.

118.

Baumeister

Murad

Werner

et al . Phase 1 trial of autologous CAR T cells targeting NKG2D ligands in patients with AML/MDS and multiple myeloma. Cancer Immunol Res. Epub ahead of print 5 November 2018 DOI: 10.1158/2326–6066.cir-18–0307.

119.

Sallman

Kerre

Poire

et al . Remissions in relapse/refractory acute myeloid leukemia patients following treatment with NKG2D CAR-T therapy without a prior preconditioning chemotherapy. Blood 2018; 132: 902.

120.

Ansell

Lesokhin

Borrello

et al . PD-1 blockade with nivolumab in relapsed or refractory hodgkin’s lymphoma. N Engl J Med 2015; 372: 311–319.

121.

Davids

Kim

Bachireddy

et al . Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 2016; 375: 143–153.

122.

Zeidan

Knaus

Robinson

et al . A multi-center phase I trial of ipilimumab in patients with myelodysplastic syndromes following hypomethylating agent failure. Clin Cancer Res 2018; 24: 3519–3527.

123.

Zhang

Gajewski

Kline

. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 2009; 114: 1545–1552.

124.

Deng

Fan

et al . PD-1 blockade potentially enhances adoptive cytotoxic T cell potency in a human acute myeloid leukaemia animal model. Hematology 2018; 23: 740–746.

125.

Daver

Basu

Garcia-Manero

et al . Phase IB/II study of nivolumab in combination with azacytidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML). Blood 2016; 128: 763.

126.

Kadia

Cortes

Ghorab

et al . Nivolumab (Nivo) maintenance (maint) in high-risk (HR) acute myeloid leukemia (AML) patients. J Clin Oncol 2018; 36: 7014.

127.

Daver

Garcia-Manero

Basu

et al . Safety, efficacy, and biomarkers of response to azacitidine (AZA) with nivolumab (Nivo) and AZA with nivo and ipilimumab (Ipi) in relapsed/refractory acute myeloid leukemia: a non-randomized, phase 2 study. Blood 2018; 132: 906.

128.

Assi

Kantarjian

Daver

et al . Results of a phase 2, open-label study of idarubicin (I), cytarabine (A) and nivolumab (Nivo) in patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood 2018; 132: 905.

129.

Zeidner

Vincent

Ivanova

et al . Phase II study of high dose cytarabine followed by pembrolizumab in relapsed/refractory acute myeloid leukemia (AML). Blood 2017; 130: 1349.

130.

Lindblad

Thompson

Gui

et al . Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia. Blood 2018; 132: 1437.

131.

Weinstock

Rosenblatt

Avigan

. Dendritic cell therapies for hematologic malignancies. Mol Ther Methods Clin Dev 2017; 5: 66–75.

132.

Liu

Bewersdorf

Stahl

et al . Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: the dawn of a new era? Blood Rev. Epub ahead of print 5 December 2018. DOI: 10.1016/j.blre.2018.12.001.

133.

Di Stasi

Jimenez

Minagawa

et al . Review of the results of WT1 peptide vaccination strategies for myelodysplastic syndromes and acute myeloid leukemia from nine different studies. Front Immunol 2015; 6: 36.

134.

Maslak

Dao

Bernal

et al . Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia. Blood Adv 2018; 2: 224–234.

135.

Yamaguchi

Takezako

Kiguchi

et al . Phase II trial of a peptide vaccine, Ocv-501 in elderly patients with acute myeloid leukemia. Blood 2018; 132: 29.

136.

van de Loosdrecht

van Wetering

Santegoets

SJAM

et al . A novel allogeneic off-the-shelf dendritic cell vaccine for post-remission treatment of elderly patients with acute myeloid leukemia. Cancer Immunol Immunother 2018; 67: 1505–1518.

137.

Anguille

Van de Velde

Smits

et al . Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia. Blood 2017; 130: 1713–1721.

138.

Rosenblatt

Stone

Uhl

et al . Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions. Sci Transl Med 2016; 8: 368ra171.

Novel therapy in Acute myeloid leukemia (AML): moving toward targeted approaches

Abstract

Keywords

Conventional chemotherapy

Smoothened inhibition

Mutationally targeted inhibitors

FLT3

IDH2/IDH1

Pro-apoptotic agents

BCL-2 inhibition

Myeloid cell leukemia-1 (MCL-1) inhibitors

P53 reactivation

Mouse double minute 2 inhibitors

Microenvironment targeting

Uproleselan (GMI-1271)

Cell cycle checkpoint inhibitors

Aurora kinase inhibitors

Polo-like kinase-1 inhibitors

Other cell cycle inhibitors

Epigenetic regulators

Disrupter of telomeric silencing 1-like

Bromodomain and extraterminal protein family inhibitors

Immunotherapy

Antibody-based therapy

Gemtuzumab ozogamicin

Vadastuximab talirine (SGN-33A)

Anti-CD123

SL-401

Bispecific antibodies

CAR-T-cell therapy

Checkpoint inhibitors

Anti-CTLA-4

PD-1 blockade agents

Vaccine therapy

Conclusion

Footnotes

Funding

Conflict of interest statement

ORCID iD

References