Next Article in Journal
Omega-3 Fatty Acids in Modern Parenteral Nutrition: A Review of the Current Evidence
Previous Article in Journal
The Application of Genetic Risk Scores in Age-Related Macular Degeneration: A Review
Article Menu

Export Article

J. Clin. Med. 2016, 5(3), 33; https://doi.org/10.3390/jcm5030033

Review
Acute Myeloid Leukemia: A Concise Review
1
Medical Oncology/Hematology, Department of Internal Medicine, Starling-Loving Hall, Room M365, 320 W. 10th Ave., Columbus, OH 43210, USA
2
Division of Hematology, Department of Internal Medicine, 460 W 12th Ave, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Jeffrey E. Rubnitz
Received: 11 December 2015 / Accepted: 29 February 2016 / Published: 5 March 2016

Abstract

:
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by immature myeloid cell proliferation and bone marrow failure. Cytogenetics and mutation testing remain a critical prognostic tool for post induction treatment. Despite rapid advances in the field including new drug targets and increased understanding of the biology, AML treatment remains unchanged for the past three decades with the majority of patients eventually relapsing and dying of the disease. Allogenic transplant remains the best chance for cure for patients with intermediate or high risk disease. In this review, we discuss the landmark genetic studies that have improved outcome prediction and novel therapies.
Keywords:
AML; leukemia; review

1. Introduction

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by clonal expansion of myeloid progenitors (blasts) in the bone marrow and peripheral blood. Previously incurable, AML is now cured in approximately 35%–40% of patients younger than age 60 years old [1]. For those >60 years old, the prognosis is improving but remains grim. Recent studies have revealed that the disorder arises from a series of recurrent hematopoietic stem cell genetic alterations accumulated with age. Using deep sequencing techniques on primary and relapsed tumors, a phenomenon called clonal evolution has been characterized with both founding clones and novel subclones, impacting the therapeutic approach [2]. Despite an increased understanding of AML biology, our efforts to this point in changing treatment strategy have been disappointing. In this review, we discuss the current diagnostic and prognostic strategies, current treatment approaches and novel therapies critical to AML management.

2. Morphology

Morphologically, AML blasts vary in size from slightly larger than lymphocytes to the size of monocytes or larger. The nuclei are large in size, varied in shape and usually contain several nucleoli. AML blasts express antigens found also on healthy immature myeloid cells, including common differentiation (CD) markers CD13, CD33 and CD34 [3]. Other cells markers are expressed depending on the morphological subtype of AML and stage of differentiation block such as monocytic differentiation markers (CD4, CD14, CD11b), erythroid (CD36, CD71) and megakaryocytes markers (CD41a and CD61). On occasion, AML blasts also co-express antigens restricted to T or B cell lineages including Terminal deoxynucleotidyl transferase (TdT), Human leukocyte antigen-antigen D related (HLA-DR), CD7 and CD19. Rarely, the blasts can exhibit morphologic and immune-phenotypic features of both myeloid and lymphoid cells that make it difficult to classify them as either myeloid or lymphoid in origin. These cases are classified as mixed phenotypic leukemia and usually portend a worse overall survival [4]. Bone marrow aspirate and biopsy, including morphology, immune-phenotype, cytochemistry and genetics studies (conventional karyotype and molecular studies) remain essential for diagnosis, classification and risk stratification.

3. Classification

Over the years there have been several different classification systems for AML based on etiology, morphology, immune-phenotype and genetics. In the 1970s, AML was classified according to the French-American-British classification system using mainly morphology and immune-phenotype/cytochemical criteria to define eight major AML subtypes (FAB M0 to M7) [5]. The World Health Organization (WHO) classification of AML, replaced the old French-American-British classification system to become the essential modality for AML classification today. The WHO classification was updated in 2008 and identifies seven AML subtypes: (1) AML with recurrent genetic abnormalities (RUNX1-RUNX1T1 t(8;21)(q22;q22), CBFB-MYH11 Inv(16)(p13.1q22), t(16;16)(p13.1;q22), PML-RARA t(15,17)(q22;q12), MLL 11q23 abnormalities, etc.) and with gene mutations (Nucleophosmin 1 (NPM1) and CEBPA mutated gene); (2) AML with myelodysplasia-related changes; (3) Therapy related myeloid neoplasms; (4) AML not otherwise specified (NOS) (similar to FAB Classification M0–M7 with others such as acute megakaryoblastic leukemia, acute panmyelosis with myelofibrosis, and pure erythroleukemia); (5) Myeloid sarcoma; (6) Myeloid proliferations related to Down syndrome; and (7) Blastic plasmocytoid dendritic cell neoplasm [6]. Based on etiology alone, AML can also be subdivided into three distinct categories: (1) Secondary AML (s-AML) (associated with antecedent myelodysplastic syndrome (MDS) or other myeloid proliferative disorder (MPD)); (2) Therapy-related AML (t-AML) (associated with prior toxin/chemotherapy exposure) and (3) De novo AML [7].

4. Cytogenetics

Non-random chromosomal abnormalities (e.g., deletions, translocations) are identified in approximately 52% of all adult primary AML patients and have long been recognized as the genetic events that cause and promote this disease [8]. Certain cytogenetic abnormalities, including the t(8;21)(q22;q22), t(15;17)(q22;q12) and inv(16)(p13.1;q22) are associated with longer remission and survival, while alterations of chromosomes 5, 7, complex karyotype (described as >3 chromosomal abnormalities) and 11q23 are associated with poor response to therapy and shorter overall survival [1]. In contrast, about 40%–50% of all AML cases are cytogenetically normal (CN-AML) when assessed using conventional banding analysis [9]. Although, this group has an intermediate risk of relapse, a substantial heterogeneity is found in this population in terms of clinical outcome. Molecular screening of this AML category is critical for prognostic categorization and treatment strategy.

5. Molecular Abnormalities

During the last decade, several studies have shown that the presence or absence of specific gene mutations and/or changes in gene expression can further classify AML cases and have an effect on the patients’ prognosis [7,10,11]. As stated above, this is particularly relevant for patients with CN-AML. With the advent of next generation sequencing, the genetic landscape of CN-AML has been more defined with each case having an average of 13 mutations, eight of which are random “passenger” mutations and five of which are recurrent “driver” mutations [10]. Key molecular abnormalities have been identified and are now used to predict outcome and help guide treatment for AML patients. In the next sections we will describe the most relevant AML mutations discussed in relative order of frequency.

5.1. Nucleophosmin 1 (NPM1) Mutations

Nucleophosmin 1 (NPM1) mutations are the most frequent mutation in AML, occurring in 25%–30% of AML patients, with female predominance [12,13]. NPM1 mutations result in the aberrant expression of the NPM1 protein in the cytoplasm rather than the nucleus, stimulating myeloid proliferation and leukemia development [13,14,15]. Clinically, the mutation is associated with monocytic morphology and in the absence of FMS-like tyrosine kinase 3 or FLT3-ITD, predicts favorable overall survival (OS). The reason for improved survival remains unclear however it has been found that NPM1 mutations have been associated with chemosensitivity to intensive chemotherapy in both young and old patients, which may account for improved outcome [16]. NPM1 mutations are associated with other recurrent genetic abnormalities such as +8, DNMT3A mutations, FLT3-ITD (40% of the time), FLT3-TKD (10%–15%) and IDH mutations (25% of time) [11,17].

5.2. DNA Methyltansferase 3A (DNMT3A) Mutations

Mutations in the DNA methyltansferase 3A (DNMT3A) gene occurs in 18%–22% of all AML cases and in about 34% of CN-AML [18]. Missense mutations affecting arginine codon 882 (R882-DNMT3A) are more common than those affecting other codons (non-R882-DNMT3A) causing a defect in normal hematopoiesis and proper methylation [17]. Recently, DNMT3A mutations have been identified as pre-leukemic mutations, arising early in AML evolution and persisting in times of remission [19]. The prognostic significance of DNMT3A mutations is therefore thought to be adverse. Initial studies showed unfavorable impact on outcome in CN-AML [17]. However, these effects were age related. Younger patients with non-R882-DNMT3A mutations had shorter disease free survival (DFS) and overall survival (OS), whereas older patients with R882-DNMT3A mutations had shorter DFS and OS after adjustment for other clinical and molecular prognosticators [17]. A larger study involving more than 1700 AML cases found no significant impact of DNMT3A mutations on survival end points [20]. Recently, it was reported that patients with DNMT3A-mutated AML have an inferior survival when treated with standard-dose anthracycline induction therapy. Sehgal et al., concluded that this group should be considered for high-dose induction therapy [21]. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (p = 0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (p = 0.67) [22].

5.3. Fms-Like Tyrosine Kinase 3 (FLT3) Mutations

First described in 1991, FLT3 was found to be strongly expressed in hematopoietic stem cells with important roles in cell survival and proliferation [23,24]. Internal tandem duplications (ITD) in the juxta-membrane (JM) domain or mutations in the second tyrosine kinase domain (TKD) of the FLT3 gene have been found in 20% of all AML cases and 30% to 45% of CN-AML patients [1,25]. Both types of mutations constitutively activate FLT3 signaling, promoting blast proliferation [25,26]. Indeed patients with FLT3 mutations often present with extreme leukocytosis and characteristic prominent nuclear invagination often described as “cuplike” nucleus [25,27]. Furthermore, FLT3-ITD mutations have been associated with increased risk of relapse, while the prognostic relevance of FLT3-TKD mutations is controversial [28]. The degree to which FLT3-ITD is a biomarker associated with poor outcome is determined by the binding site and FLT3-ITD allelic burden [25,28,29]. Studies have shown that non-JM ITD are worse than JM domain ITD and higher mutant to wild-type allelic ratios were significantly associated with lower complete remission (CR) rates [28,29]. Currently, tyrosine kinase inhibitors (TKI) are being tested in FLT3 mutated AML patients. Unfortunately, when used alone, TKIs showed only a transient reduction of blasts, and even if initially effective, subsequent acquisition of secondary mutations induces resistance over time [30].

5.4. Isocitrate Dehydrogenase (IDH) Mutations

Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 gene are gain-of-function mutations which cause loss of the physiologic enzyme function and create a novel ability of the enzymes to convert α-ketoglutarate into 2-hydroxyglutarate. IDH mutations are oncogenic. Specifically recurrent mutations affecting the highly conserved arginine (R) residue at codon 132 (R132) of IDH1 and at codons R140 and R172 of IDH2 have been identified in 15%–20% of all AML and 25% to 30% of patients with CN-AML [11,22,31]. They are found more frequently in older patients [32]. IDH mutations, in particular IDH1, are associated with lower DFS and OS in CN-AML cases with NPM1 mutations and wild type FLT3 [31,32]. Orally available, selective, potent inhibitors of mutated IDH are currently being tested in Phase I and II studies in AML with promising results [33].

5.5. Ten–Eleven Translocation 2 (TET2) Mutations

The ten–eleven translocation oncogene family member 2 (TET2) is found mutated in about 9%–23% of AML patients [34]. TET1 is an enzyme involved in the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA, which is a process thought to play an important role in DNA demethylation [34]. In general, TET2 mutations are loss-of-function mutations. Overall, despite several studies their prognostic significance remains unclear. Metzeler et al., reported TET2 mutations as an adverse factor for CR and OS [35]. However Gaidzik et al., did not show a prognostic effect with TET2 mutations [36].

5.6. Runt-Related Transcription Factor (RUNX1) Mutations

Runt-related transcription factor (RUNX1) has been shown to be essential in normal hematopoiesis [37]. Also known as AML1 protein or core-binding factor subunit α-2 (CBFA2), RUNX1 is located at chromosome 21 and is frequently translocated with the ETO/MTG8/RUNX1T1 gene located on chromosome 8q22, creating a fusion protein AML-ETO or t(8;21)(q22;q22) AML [38]. In addition to chromosome translocations, RUNX1 mutations are found in 5%–13% of AML and are commonly associated with trisomy 13, trisomy 21, absence of NPM1 and older CN-AML [11]. In general, studies have shown RUNX1 mutations are associated with resistance to standard induction therapy with inferior overall survival for both younger and older patients [39].

5.7. CCAAT Enhancer Binding Protein α (CEBPA) Mutations

The differentiation-inducing transcription factor CCAAT enhancer binding protein α (CBPA) mutations are found in 6%–10% of all AML and 15%–19% of CN-AML, commonly in association with del(9q) [1,40]. CEBPA is a critical transcription factor that controls gene expression during hematopoiesis [41]. In AML, CEBPA mutations commonly harbor two mutations or double mutations, which frequently involve both a combination of an N-terminal and a bZIP gene mutation. Importantly, only bi allelic mutation, not single, CEBPA mutations predicted a higher complete response (CR) and favorable OS, occurring in 4%–5% of AML [42]. AML with a single CEBPA mutation is associated with survival similar to that of AML with wild-type CEBPA [11,43].

5.8. Additional Sex Comb-Like 1 (ASXL1) Mutations

Additional sex comb-like 1 (ASXL1) mutations are loss-of-function mutations that occur in 5%–11% of AML cases [44]. The function of ASXL1 protein is not fully understood, but it is suggested that it may be involved in epigenetic regulation (DNA and/or histone modifications) [36]. ASXL1 mutations are five times more common in older (≥60 years) patients (16.2%) than those younger than 60 years (3.2%; p < 0.001) [44]. Among older patients, ASXL1 mutations are associated with t(8;21), wild-type NPM1, absence of FLT3-ITD, mutated CEBPA, and overall inferior complete remission and overall survival [45,46].

5.9. Mixed Lineage Leukemia (MLL) Mutations

The mixed lineage leukemia (MLL) gene at chromosome 11q23 encodes for a protein that has histone methyltransferase activity that coordinates chromatin modification as part of a regulatory complex [47]. Translocations affecting the MLL gene lead to aggressive acute lymphoblastic and myeloid leukemia with poor prognosis that is characterized by HOX gene overexpression [37]. In addition to translocations, partial in tandem duplications (PTD) of the MLL gene (MLL-PTD) have been demonstrated most often in adult de novo CN-AML and in trisomy 11 AML cases [48,49]. In adult CN-AML, the frequency of MLL rearrangement is 11% with the presence of the MLL-PTD associated with a worse prognosis (i.e., shorter duration of remission) when compared with CN-AML without the MLL-PTD [50].

5.10. Tumor Protein p53 (TP53) Mutations

The tumor suppressor gene TP53 is found in 8%–14% of AML cases. These mutations and deletions are primarily associated in AML with complex karyotype (69%) and are rare in patient without chromosomal deletions. In general, TP53 mutations confer a very adverse prognosis with documented chemoresistance [51].

5.11. c-KIT Mutations

The KIT tyrosine kinase receptor is a 145 kDa transmembrane protein critical to normal hematopoiesis [52]. This mutation is rare in AML (<5%) however present approximately 22%–29% of the time in CBF mutations (i.e., AML harboring t(8;21)(q22;q22) or inv(16)(p13.1q22) or corresponding respective fusion genes RUNX1/RUNX1T1 and CBFB/MYH11). KIT mutations have been shown to confer higher relapse risk and lower OS. The KIT mutation in the codon D816 in particular has been associated with unfavorable DFS and OS, particularly in t(8;21)(q22;q22) patients [53]. Prospective studies later confirmed that patients with CBF AML harboring KIT mutations have shorter OS than patients with wild type KIT for t(8;21)(q22;q22) but not for patients with inv(16)(p13.1q22) [54]. Remarkably KIT could be targeted pharmacologically by using tyrosine kinase inhibitors, such as dasatinb [52]. Preliminary results were presented recently at the American Society of Hematology Annual Meeting from a phase II trial that combined the KIT inhibitor, dasatinib with standard chemotherapy for newly diagnosed patients with CBF AML. After a median follow-up of 21 months, patients with KIT mutations who received dasatinib with standard chemotherapy showed similar outcomes to that of wild type KIT patients [55]. Unfortunately, no survival benefit was found with maintenance dasatinib in a phase II study completed by Boissel et al., Interestingly, at relapse there was disappearance of the KIT subclone which is hypothesized to be dasatinib driven [56]. More studies are needed to evaluate the long term outcomes of KIT inhibitors in CBF AML.

5.12. Spilicing Factor Gene Mutations and Mutations in Cohesion Complex Members

Often considered founding mutations, spilicing factor gene mutations have been found to be associated with pre-leukemic conditions such as MDS. The most common genes reported include SF3B1, U2AF1, SRSF2 and ZRSR2 [7]. In newly diagnosed AML patients, splicesome mutations including SRSF2, F3B1, U2AF1, or ZRSR2 are now considered pathognomonic of secondary AML developing from precedent MDS [57]. Somatic cohesion complex mutations were identified in roughly 20% of patients with high-risk MDS and secondary AML. Relevant mutations include STAG2, TAD21 and SMC3 which are important in regulating gene expression and DNA-loop formation. Mutations in cohesion complex members are associated with poor overall survival [58].

6. Prognosis/Risk Stratification

Age and performance status in addition to chromosomal and molecular aberrations remain the most important tools for outcome prediction in AML. In 2010, the European LeukemiaNet (ELN) classification scheme was created in an effort to standardize risk stratification in adult AML patients by incorporating cytogenetic and known molecular abnormalities [59]. Patients are classified into one of four risk groups: favorable, intermediate 1, intermediate 2 and adverse (Table 1). Favorable prognosis is associated with acute promyelocytic leukemia (APL) t(15;17)(q22;q12), balanced abnormalities of t(8;21)(q22;q22), inv(16)(p13.1q22), t(16;16)(p13.1;q22), mutated NPM1 without FLT3-ITD and biallelic mutated CEBPA. Intermediate 1 includes mutated NPM1 with FLT3-ITD, wild-type NPM1 with or without FLT3-ITD. The intermediate -2 category includes t(9;11), MLLT3-MLL and cytogenetic abnormality neither favorable nor adverse. Complex karyotype, inv(3)(q21q26)/t(3;3)(q21;q26), RPN1-EVI1, DEK-NUP214 t(6,9)(p23;q34), t(6;11), −5 or del(5q), −7 or abnormal (17p) and monosomal karyotype are associated with poor prognosis [59,60]. Patients with monosomal karyotype (defined as having two of more distinct monosomies or one monosomy and another structural abnormality) have a very poor prognosis (less than 4% survival at four years) [61]. Studies have shown that age >60 is an independent predictor of poor outcomes regardless of the ELN classification [60].
APL is risk stratified according to the risk of relapse based on initial white blood count (WBC) and platelet count at diagnosis. The following patient categories are: (1) low-risk: presenting WBC count below or equal to 10 × 109/L and platelet count above 40 × 109/L; (2) intermediate-risk: presenting WBC and platelet counts below or equal to 10 × 109 and 40 × 109/L, respectively; and (3) high-risk group: presenting WBC greater than 10 × 109/L. Treatment strategy varies depending on risk stratification at diagnosis however, the inclusion of arsenic trioxide (ATO) in frontline therapy seems to benefit all-risk category APL patients [62].

7. Therapeutics

7.1. Induction Therapy

Since 1970, the backbone of intensive induction chemotherapy remains unchanged. For young adults (age < 60 years) and fit elderly patients (especially those harboring NPM1 mutations and CBF leukemia) the intensive anthracycline and cytarabine regimen, “7 + 3”, induction therapy is the standard of care. The typical dose and schedule includes either daunorubicin (60 or 90 mg/m2 on days 1, 2 and 3) or idarubicin (10–12 mg/m2 on days 1, 2 and 3) given with seven days of continuous cytarabine infusion (100 mg/m2/daily for one week (days 1 through 7). The goal of induction chemotherapy is to achieve morphologic complete remission (CR), which is defined as: (1) <5% blasts in bone marrow aspirate sample with marrow spicules and with a count of ≥200 nucleated cells (no blasts with Auer rods or persistence of extramedullary disease); (2) absolute neutrophil count (ANC) >1000/µL, and (3) platelets ≥ 100,000/µL [63]. Young, de novo, AML patients achieve CR in 65%–73% using standard induction with “7 + 3” while only 38%–62% of patients over 60 years of age with AML achieve CR [64,65,66]. Several trials have now shown that higher dose of anthracycline (90 versus 45 mg/m2) in both younger and older fit adults (from 60 to 65) results in higher CR rates and increases the duration of OS [65,66]. Concerns about toxicity of high-dose daunorubicin and the wide use of the 60-mg/m2 dose as a newer “standard,” led the United Kingdom (UK) National Cancer Research Council (NCRC) to conduct a prospective randomized trial with the goal to compare daunorubicin at 60 vs. 90 mg/m2 in the induction of 1206 AML patients [67]. In this study there was no benefit of using higher dosing (90 mg/m2) over 60 mg/m2 across all subgroups [67]. However there are some caveats to consider in this trial. In particular, the cumulative dose of anthracyclines in the low dose arm (60 mg/m2) was equivalent in the United Kingdom National Cancer Research Institute (UK NCRC) trial to the higher dose (90 mg/m2) of the other clinical trials due to multiple courses of anthracycline. In addition the UK NCRC trial has a shorter follow up [68]. Thus, it is clear that 45 mg/m2 of daunorubicin seems insufficient and 60 mg/m2 is not inferior to 90 mg/m2 with less associated toxicity. Patients found to have a FLT3 mutation should be treated with a FLT3 inhibitor (discussed in more detail below), such as midostaurin, added to standard induction therapy [69].
Characterizing fitness in the adult population is important when deciding treatment strategy. In particular, appropriate therapy in the elderly AML patient should be determined based on “patient-specific fitness” using geriatric assessments to determine fitness, vulnerable and frail status regardless of age [70]. In older adults, deemed not fit for intensive induction therapy especially harboring complex karyotype without NPM1 mutations, the use of hypomethylating agents including decitabine and azacitidine has shown to be beneficial [70,71,72]. Both agents, commonly used to treat myelodisplasia, have activity in AML as initial induction therapy and in the relapsed setting. Several phase II and III studies using azacitadine and decitabine have been conducted [71,72,73]. A study of 82 patients with AML, median age of 72 years, who received azacitidine as part of a compassionate use program showed CR/incomplete CR in 11 of the 35 untreated patients (31%). The median overall response duration was 13 months with the one-year and two-years overall survival rates of 58% and 24%, respectively [73]. Blum et al. showed an even higher complete remission rate of 47% and overall response rate of 64% with 10 days of low-dose decitabine at 20 mg/m2 intravenous over 1 h [72]. This treatment was well tolerated with CR achieved in 52% of subjects presenting with CN-AML and in 50% of those with complex karyotypes [72]. Older patients receiving induction decitabine usually require a median of two to four cycles of therapy to have an optimal response.
Patients with suspected acute promyelocytic leukemia (APL) should be treated with all-trans retinoic acid (ATRA) even before the diagnosis is confirmed. Early use of ATRA decreases the risk of APL induced coagulopathy, development of disseminated intravascular coagulation (DIC) and mortality. For patients with low-to-intermediate-risk APL (WBC ≤ 10 × 109/L) outcomes are excellent with the use of ATRA with arsenic (ATO) [74]. In this non-inferiority study, the ATO-ATRA combination showed CR rates in all 77 patients (100%) and in 75 of 79 patients (95%) in the ATRA-idarubicin group. The two-year event-free survival and OS rates were significantly improved (97% and 99%) in the ATO-ATRA arm than for those in the ATRA–chemotherapy arm (86% and 91%) [74]. For high-risk patients (WBC > 10 × 109/L), chemotherapy with idarubicin should be initiated once the diagnosis is confirmed in addition to ATO-ATRA for rapid control of leukocytosis. During induction treatment it is recommended that WBC, fibrinogen level, prothrombin time and partial thromboplastin time be monitored at least twice daily with aggressive transfusion support (platelet count ≥ 30 × 109/L and fibrinogen level ≥ 1.5 g/L). Prophylactic steroids are also recommended, in particular when using ATRA/ATO combination for induction in patients with high WBC count to prevent differentiation syndrome [74,75].

7.2. Consolidation Strategies

Consolidation or post-induction therapy is given to prevent relapse and eradicate minimal residual leukemia (MRD) in the bone marrow after induction as a bridge to transplant or to achieve cure. Assessment of minimal residual disease using real-time PCR or Next Generation Sequencing (NGS) is increasingly being used to help track treatment response and has been shown to be superior than morphology alone in predicting impending relapse [76,77]. Despite this powerful information, the heterogentiy of AML in general has made following mutational clones difficult to determine absolute risk of leukemia development as some clones can persist in patient in long-term remission following treatment, such as DNMT3A [19]. In general, there are two main strategies for consolidation; chemotherapy (including targeted agents) and hematopoietic stem cell transplantation [64]. Both strategies could be used alone or most commonly in combination depending on the type of leukemia, the fitness of the patient and the availability of a stem cell donor. Post induction chemotherapy using intermediate-dose cytarabine 1.5 g/m2 twice daily on days 1, 3 and 5 given in three to four cycles is an effective and established regimen to prolong remission and improve survival in favorable risk young adults (<60 year of age) [8]. These patients are usually treated with chemotherapy alone and transplantation is reserved only at relapse [64]. In 2013, Burnett et al. challenged this dose schedule for adults <60 year old and showed that higher dose (3 g/m2) as compared to lower dose (1.5 g/m2) cytarabine for three courses led to identical outcomes [78]. Thus, low dose cytarabine at 1.5 g/m2 became the standard of care. High-dose cytarabine is still used for patients with CBF AML [e.g., t(8:21); or inv(16)] and NPM1 mutated AML [8,78]. In elderly patients (>60 year of age) there was no benefit with high dose cytarabine with increased and sometimes irreversible neurotoxicity noted [79], therefore 500–1000 mg/m2 is standardly used [1].
For other prognostic groups, in particular fit patients with intermediate risk or high risk disease after achieving CR, allogeneic hematopoietic stem cell transplantation remains the most effective long term therapy for AML with cure in 50% to 60% of patients in first CR [80,81]. Despite this, several patients never become eligible for transplant given co-morbidities, failure to achieve CR or lack of suitable donor [80]. While waiting for transplant it is standard practice to give post induction chemotherapy to maintain CR and keep the leukemia burden low. Decisions regarding consolidation rather than moving straight to transplant should be individualized as consolidation therapy poses risk of morbidity and mortality, which may hinder eventual curative transplant. Recent evidence unanimously confirms that age should no longer be used as the sole criteria for transplant eligibility [80,82]. Rather eligibility should be decided upon based on pre-transplant performance status, co-morbidities and current remission. The most widely recognized and validated tool for assessing comorbidity includes the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) [82]. The higher the comorbidity index score, the worse the clinical outcome. Improvements in supportive care, increased donor options (haplo-identical donors and cord grafts) and reduced intensity preparation regimens for HCT have increased the success of transplant in all age groups. It is for this reason that we advocate for early patient discussion, risk assessment and tissue typing at diagnosis. Conditioning regimen should be decided based on patient fitness, transplant options and disease characteristics. Although risk of relapse is higher, long term outcomes of reduced-intensity allogeneic hematopoietic stem cell transplant in patients who were ineligible for myeloablative transplant are promising [81]. The results of a prospective multicenter phase II trial conduced by the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B) and the Blood and Marrow Transplant Clinical trial Network showed reduced intensity conditioning-based hematopoietic stem cell transplant (HSCT) to be an effective strategy for suitable older patients with an available matched donor with a disease-free survival and OS at two years after transplant of 42% and 48%, respectively [83]. Reduced intensity transplants are therefore becoming more common and clinically accepted.

7.3. Relapsed Disease

Of the patients who relapse, only a small fraction achieve successful second remission using salvage chemotherapy followed by allogeneic stem cell transplant with curative intent [64]. Studies examining clonal evolution of relapse show that relapse can occur from expansion of major or minor clones present at diagnosis or through newly acquired mutations over time [2]. Therefore, clinical trial is the preferred treatment approach especially in light of novel targeted therapies. Early relapse (occurring within the first six months after CR1) portends a poor overall survival. Salvage regimes include intermediate dose cytarabine (500–1500 mg/m2 intravenously every 12 h on days 1–3); MEC (Mitoxantrone 8 mg/m2 on days 1–5, Etoposide 100 mg/m2 on days 1–5, and Cytarabine 100 mg/m2 on days 1–5) or lastly, FLAG-IDA (Fludarabine 30 mg/m2, intravenously on days 1–5 (20 mg/m2 in patient >60 years old), Cytarabine 1500 mg/m2 (500–1000 mg/m2 in patients >60 year) intravenously, 4 h after fludarabine infusion, on days 1–5; Idarubicin 8 mg/m2, intravenously, on days 3–5; Granulocyte colony-stimulating factor 5 μg/kg, subcutaneously, from day 6 to white-cell count >1 g/L (FLAG-IDA) [1]. The likelihood of achieving a second CR is best in patients with a long first remission, younger age and in those with favorable cytogenetics [84]. In cases of APL, re-induction with ATO with or without ATRA remains the standard. CR rates with single agent ATO are good at roughly 85% [85].

8. Novel Targets

8.1. Fms-Like Tyrosine Kinase 3 (FLT3) Inhibitors

Several FLT3 small molecule inhibitors have been developed with mixed results. First generation drugs include multi-kinase inhibitors such as midostaurin, lestaurtinib, tandutinib sunitinib and sorafenib. When used as single agents they have limited anti-leukemia activity mostly showing only transient reduction of blood and bone marrow blasts and increased toxicity [86]. In a randomized trial of 224 patients with FLT3 mutated AML in first relapse lestaurtinib did not increase the response rate or prolong survival [87]. Single agent use with midostantrum, tandutinib and KW2449 in phase I/II trials were also not clinically effective [88,89,90]. Combination therapy using FLT3 inhibitors with chemotherapy have also been conducted. Serve et al. reported a randomized trial of 201 newly diagnosed older AML patients, using the addition of sorafenib to induction and consolidation therapy. Unfortunately, sorafenib did not improve outcomes and patients did worse in the sorafenib arm due to higher treatment-related mortality and lower CR rates [91]. A recent phase II study of sorafenib in combination with 5-azacitadine in relapsed/refractory FLT3-ITD mutant AML demonstrated a response rate of 46%, mostly consisting of CR or CR with incomplete count recovery [92]. Sunitinib added to induction and consolidation chemotherapy in older patients with AML and FLT3 activating mutations showed some effectiveness with CR rates 53% (8/15) and 71% (5/7) for patients with FLT3-ITD and FLT3-TKD mutations, respectively. The 13 patients who achieved CR went on to be consolidated with high dose cytarabine and 7/13 received sunitinib maintenance. The median overall survival in this study was 18.8 months [93]. The largest randomized, phase III clinical trial in FLT3-mutated AML conduced to date was recently presented at the 2015 American Society of Hematology (ASH) Plenary session showing the benefit of midostaurin added to induction chemotherapy (RATIFY trial) in which patients receiving midostaurin had significantly longer median OS than those receiving placebo: 74.7 versus 25.6 months (p = 0.0076) [94]. Second generation agents, promising to have better potency and less side effects include quizartinib and crenolanib are still undergoing clinical investigation. One trial, using quizartinib (AC220), did show better blast count clearance however also noted the development of secondary resistance. Drug resistance has since become the major challenge in treating patients with a single FLT3 inhibitor. The point mutations identified which lead to resistance include N676, F691, and D835 within the kinase domain of FLT3-ITD [95]. The novel FLT3 inhibitors, G-749 and ASP2215 (active against both FLT3 ITD and D835 mutations), have recently been shown to provide sustained inhibition of FLT3 phosphorylation and increased ability to overcome drug resistance in pre-clinical trials but further studies are needed to determine if it will have clinical efficacy [96,97].

8.2. Isocitrate Dehydrogenase (IDH) Inhibitors

The IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221 have demonstrated promising response rates in patients with AML in two separate phase I clinical trials [98,99]. Preliminary results were recently presented for both trials. The objective response rate (ORR) with AG-221 was 40% and 31% with AG-120 in relapsed/refractory AML patients. More interestingly the duration of the responses for AG-221 and AG-120 were more than 15 and 11 months at the analysis, and remained ongoing. Overall, 76% of responses lasted longer than six months. Based on these data, the Food and Drug Administration (FDA) have granted the medication an orphan drug designation for patients with AML.

8.3. Nuclear Exporter Inhibitors

The anti-leukemic efficacy of reversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1) has brought much excitement. CRM1 is a major nuclear exporter protein which mediates the export and inactivation of several tumor suppressors such as p53, p73, FOXO1, RB1 and p21 (CDKN1A) among others [100]. CRM1 has been shown to be upregulated in a range of solid tumors and hematological malignancies, including AML [101,102]. Preclinical studies indicate that treatment of AML cell lines, patient samples and AML xenografts with novel CRM1 inhibitors (Selinexor) induces strong anti-leukemic effects [103,104]. Based on these studies, Phase I/II clinical trials are currently ongoing to assess the safety, tolerability and activity of selinexor in AML patients.

8.4. Immune Therapies

Novel antibody therapies are revolutionary in the treatment leukemia and currently under development in AML. Monoclonal antibodies being explored include CD33 (Gemtuzumab ozogamicin) [105] and bispecific antibodies such as AMG 330 (anti-CD33 and CD3) [106]. Chimeric antigen receptor (CAR)-transduced T cells (CARTs) are T cells engineered to express a specific antigen receptor target designed against a specific cell-surface antigen. CD123 has been found to be expressed on the majority of AML blasts but also normal hematopoietic cells. Preclinical data shows that targeting CD123 via CARTs results in rejection of human AML and myeloablation in the mouse models [107].

9. Conclusions

AML is complex disease with a diverse genetic landscape. The field is rapidly expanding with increased understanding of the biology as well as potential new drug targets. Despite our best efforts at targeted therapy, it has become apparent that single drug options may be less likely to succeed over multiple drug targets. Relapse disease remains the highest cause of mortality after HCT. Immunotherapy is also an exciting new therapeutic approach which may offer long term cures for relapsed patients. We remain hopeful that the therapeutic options will continue to improve, with less toxicity and improved efficacy.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. Acute myeloid leukemia. N. Engl. J. Med. 2015, 373, 1136–1152. [Google Scholar] [PubMed]
  2. Ding, L.; Ley, T.J.; Larson, D.E.; Miller, C.A.; Koboldt, D.C.; Welch, J.S.; Ritchey, J.K.; Young, M.A.; Lamprecht, T.; McLellan, M.D.; et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012, 481, 506–510. [Google Scholar] [CrossRef] [PubMed]
  3. Campos, L.; Guyotat, D.; Archimbaud, E.; Devaux, Y.; Treille, D.; Larese, A.; Maupas, J.; Gentilhomme, O.; Ehrsam, A.; Fiere, D. Surface marker expression in adult myeloid leukemia: Correlations with initial characteristics, morphology and response to therapy. Br. J. Haematol. 1989, 72, 161–166. [Google Scholar] [CrossRef] [PubMed]
  4. Wolach, O.; Stone, R.M. How I treat mixed-phenotype acute leukemia. Blood 2015, 125, 2477–2485. [Google Scholar] [CrossRef] [PubMed]
  5. Bennett, J.M.; Catovsky, D.; Daniel, M.T.; Flandrin, G.; Galton, D.A.; Gralnick, H.R.; Sultan, C. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br. J. Haematol. 1976, 33, 451–458. [Google Scholar] [CrossRef] [PubMed]
  6. Vardiman, J.W.; Thiele, J.; Arber, D.A.; Brunning, R.D.; Borowitz, M.J.; Porwit, A.; Harris, N.L.; le Beau, M.M.; Hellstrom-Lindberg, E.; Tefferi, A.; et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 2009, 114, 937–951. [Google Scholar] [CrossRef] [PubMed]
  7. Lindsley, R.C.; Mar, B.G.; Mazzola, E.; Grauman, P.V.; Shareef, S.; Allen, S.L.; Pigneux, A.; Wetzler, M.; Stuart, R.K.; Erba, H.P.; et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015, 125, 1367–1376. [Google Scholar] [CrossRef] [PubMed]
  8. Byrd, J.C.; Mrózek, K.; Dodge, R.K.; Carroll, A.J.; Edwards, C.G.; Arthur, D.C.; Pettenati, M.J.; Patil, S.R.; Rao, K.W.; Watson, M.S.; et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002, 100, 4325–4336. [Google Scholar] [CrossRef] [PubMed]
  9. Gaidzik, V.; Dohner, K. Prognostic implications of gene mutations in acute myeloid leukemia with normal cytogenetics. Semin. Oncol. 2008, 35, 346–355. [Google Scholar] [CrossRef] [PubMed]
  10. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 2013, 368, 2059–2074. [Google Scholar]
  11. Marcucci, G.; Haferlach, T.; Dohner, H. Molecular genetic of adult acute myeloid leukemia: Prognostic and therapeutic implications. J. Clin. Oncol. 2011, 29, 475–486. [Google Scholar] [CrossRef] [PubMed]
  12. Schnittger, S.; Schoch, C.; Kern, W.; Mecucci, C.; Tschulik, C.; Martelli, M.F.; Haferlach, T.; Hiddemann, W.; Falini, B. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005, 106, 3733–3739. [Google Scholar] [CrossRef] [PubMed]
  13. Falini, B.; Nicoletti, I.; Martelli, M.F.; Mecucci, C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc + AML): Biologic and clinical features. Blood 2007, 109, 874–885. [Google Scholar] [CrossRef] [PubMed]
  14. Falini, B.; Bolli, N.; Shan, J.; Martelli, M.P.; Liso, A.; Pucciarini, A.; Bigerna, B.; Pasqualucci, L.; Mannucci, R.; Rosati, R.; et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc + AML. Blood 2006, 107, 4514–4523. [Google Scholar] [CrossRef] [PubMed]
  15. Cheng, K.; Sportoletti, P.; Ito, K.; Clohessy, J.G.; Teruya-Feldstein, J.; Kutok, J.L.; Pandolfi, P.P. The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model. Blood 2010, 115, 3341–3345. [Google Scholar] [CrossRef] [PubMed]
  16. Dohner, K.; Schlenk, R.F.; Habdank, M.; Scholl, C.; Rucker, F.G.; Corbacioglu, A.; Bullinger, L.; Frohling, S.; Dohner, H. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: Interaction with other gene mutations. Blood 2005, 106, 3740–3746. [Google Scholar] [CrossRef] [PubMed]
  17. Marcucci, G.; Metzeler, K.H.; Schwind, S.; Becker, H.; Maharry, K.; Mrozek, K.; Radmacher, M.D.; Kohlschmidt, J.; Nicolet, D.; Whitman, S.P.; et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J. Clin. Oncol. 2012, 30, 742–750. [Google Scholar] [CrossRef] [PubMed]
  18. Ley, T.J.; Ding, L.; Walter, M.J.; McLellan, M.D.; Lamprecht, T.; Larson, D.E.; Kandoth, C.; Payton, J.E.; Baty, J.; Welch, J.; et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 2010, 363, 2424–2433. [Google Scholar] [CrossRef] [PubMed]
  19. Shlush, L.I.; Zandi, S.; Mitchell, A.; Chen, W.C.; Brandwein, J.M.; Gupta, V.; Kennedy, J.A.; Schimmer, A.D.; Schuh, A.C.; Yee, K.; et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014, 506, 328–333. [Google Scholar] [CrossRef] [PubMed]
  20. Gaidzik, V.I.; Schlenk, R.F.; Paschka, P.; Stölzle, A.; Späth, D.; Kuendgen, A.; von Lilienfeld-Toal, M.; Brugger, W.; Derigs, H.G.; Kremer, S.; et al. Clinical impact of DNMT3A mutations in younger adult patient with acute myeloid leukemia: A comprehensive analysis of the AML study Group (AMLSG). Blood 2013, 121, 4769–4777. [Google Scholar] [CrossRef] [PubMed]
  21. Sehgal, A.R.; Gimotty, P.A.; Zhao, J.; Hsu, J.M.; Daber, R.; Morrissette, J.D.; Luger, S.; Loren, A.W.; Carroll, M. DNMT3A mutational status affects the results of dose-escalated induction therapy in acute myelogenous leukemia. Clin. Cancer Res. 2015, 21, 1614–1620. [Google Scholar] [CrossRef] [PubMed]
  22. Patel, J.P.; Gonen, M.; Figueroa, M.E.; Fernandez, H.; Sun, Z.; Racevskis, J. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 2012, 366, 1079–1089. [Google Scholar] [CrossRef] [PubMed]
  23. Maroc, N.; Rottapel, R.; Rosnet, O.; Marchetto, S.; Lavezzi, C.; Mannoni, P.; Birnbaum, D.; Dubreuil, P. Biochemical characterization and analysis of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase. Oncogene 1993, 8, 909–918. [Google Scholar] [PubMed]
  24. Gilliland, D.G.; Griffin, J.D. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002, 100, 1532–1542. [Google Scholar] [CrossRef] [PubMed]
  25. Kelly, L.M.; Liu, Q.; Kutok, J.L.; Williams, I.R.; Boulton, C.L.; Gilliland, D.G. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002, 99, 310–318. [Google Scholar] [CrossRef] [PubMed]
  26. Kayser, S.; Schlenk, R.F.; Londono, M.C.; Breitenbuecher, F.; Wittke, K.; Du, J.; Groner, S.; Späth, D.; Krauter, J. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 2009, 114, 2386–2392. [Google Scholar] [CrossRef] [PubMed]
  27. Kussick, S.J.; Stirewalt, D.L.; Yi, H.S.; Sheets, K.M.; Pogosova-Agadjanyan, E.; Braswell, S.; Norwood, T.H.; Radich, J.; Wood, B.L. A distinctive nuclear morphology in acute myeloid leukemia is strongly associated with loss of HLA-DR expression and FLT3 internal tandem duplication. Leukemia 2004, 18, 1591–1598. [Google Scholar] [CrossRef] [PubMed]
  28. Gale, R.E.; Green, C.; Allen, C.; Mead, A.J.; Burnett, A.K.; Hills, R.K.; Linch, D.C.; Medical Research Council Adult Leukaemia Working Party. The impact on FLT3 internal tandem duplication mutant level, number, size and interaction with NPM1 mutation in a large cohort of young adult patient with acute myeoid leukemia. Blood 2008, 111, 2776–2784. [Google Scholar] [CrossRef] [PubMed]
  29. Pratcorona, M.; Brunet, S.; Nomdedeu, J.; Ribera, J.M.; Tormo, M.; Duarte, R.; Escoda, L.; Guàrdia, R.; Queipo de Llano, M.P.; Salamero, O.; et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden LFT3-ITD mutation and concomitant NPM1 mutations: Relevance to post-remission therapy. Blood 2013, 121, 2734–2738. [Google Scholar] [CrossRef] [PubMed]
  30. Small, D. Targeting FLT3 for the treatment of leukemia. Semin. Hematol. 2008, 45, S17–S21. [Google Scholar] [CrossRef] [PubMed]
  31. Marcucci, G.; Maharry, K.; Wu, Y.Z.; Radmacher, M.D.; Mrózek, K.; Margeson, D.; Holland, K.B.; Whitman, S.P.; Becker, H.; Schwind, S.; et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: A cancer and leukemia group B study. J. Clin. Oncol. 2010, 28, 2348–2355. [Google Scholar] [CrossRef] [PubMed]
  32. Paschka, P.; Schlenk, R.F.; Gaidzik, V.I.; Habdank, M.; Krönke, J.; Bullinger, L.; Späth, D.; Kayser, S.; Zucknick, M.; Götze, K.; et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J. Clin. Oncol. 2010, 28, 3636–3643. [Google Scholar] [CrossRef] [PubMed]
  33. Fathi, A.T.; Wander, S.A.; Faramand, R.; Emadi, A. Biochemical, epigenetic, and metabolic approaches to target IDH mutations in acute myeloid leukemia. Semin. Hematol. 2015, 52, 165–171. [Google Scholar] [CrossRef] [PubMed]
  34. Chou, W.C.; Chou, S.C.; Liu, C.Y.; Chen, C.Y.; Hou, H.A.; Kuo, Y.Y.; Lee, M.C.; Ko, B.S.; Tang, J.L.; Yao, M.; et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 2011, 118, 3803–3810. [Google Scholar] [CrossRef] [PubMed]
  35. Metzeler, K.H.; Maharry, K.; Radmacher, M.D.; Mrozek, K.; Margeson, D.; Becker, H. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: A cancer and leukemia group B study. J. Clin. Oncol. 2011, 29, 1373–1381. [Google Scholar] [CrossRef] [PubMed]
  36. Gaidzik, V.I.; Paschka, P.; Spath, D.; Habdank, M.; Kohne, C.H.; Germing, U.; von Lilienfeld-Toal, M.; Held, G.; Horst, H.A.; Haase, D.; et al. TET2 mutations in acute myeloid leukemia (AML): Results from a comprehensive genetic and clinical analysis of the AML study group. J. Clin. Oncol. 2012, 30, 1350–1357. [Google Scholar] [CrossRef] [PubMed]
  37. Meyers, S.; Downing, J.R.; Hiebert, S.W. Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: The runt homology domain is required for DNA binding and protein-protein interactions. Mol. Cell Biol. 1993, 13, 6336–6345. [Google Scholar] [CrossRef] [PubMed]
  38. Tang, J.L.; Hou, H.A.; Chem, C.Y.; Liu, C.Y.; Chou, W.C.; Tseng, M.H. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: Prognostic implication and interaction with other gene alternations. Blood 2009, 114, 5352–5361. [Google Scholar] [CrossRef] [PubMed]
  39. Mendler, J.H.; Maharry, K.; Radmacher, M.D.; Mrozek, K.; Becker, H.; Metzeler, K.H. RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures. J. Clin. Oncol. 2012, 30, 3109–3118. [Google Scholar] [CrossRef] [PubMed]
  40. Mrózek, K.; Marcucci, G.; Paschka, P.; Whitman, S.P.; Bloomfield, C.D. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: Are we ready for a prognostically prioritized molecular classification? Blood 2007, 109, 431–448. [Google Scholar] [CrossRef] [PubMed]
  41. Koschmieder, S.; Halmos, B.; Levantini, E.; Tenen, D.G. Dysregulation of the C/EBPα differentiation pathway in human cancer. J. Clin. Oncol. 2009, 27, 619–628. [Google Scholar] [CrossRef] [PubMed]
  42. Fasan, A.; Haferlach, C.; Alpermann, T.; Jeromin, S.; Grossmann, V.; Eder, C.; Weissmann, S.; Dicker, F.; Kohlmann, A.; Schindela, S.; et al. The role of different genetic subtypes of CEBPA mutated AML. Leukemia 2014, 28, 794–803. [Google Scholar] [CrossRef] [PubMed]
  43. Wouters, B.J.; Lowenberg, B.; Erpelinck-Verschueren, C.A.; van Putten, W.L.; Valk, P.J.; Delwel, R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009, 113, 3088–3091. [Google Scholar] [CrossRef] [PubMed]
  44. Metzeler, K.H.; Becker, H.; Maharry, K.; Radmacher, M.D.; Kohlschmidt, J.; Mrózek, K.; Nicolet, D.; Whitman, S.P.; Wu, Y.Z.; Schwind, S.; et al. ASXL1 mutations identify a high risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood 2011, 118, 6920–6929. [Google Scholar] [CrossRef] [PubMed]
  45. Alpermann, T.; Haferlach, C.; Eder, C.; Nadarajah, N.; Meggendorfer, M.; Kern, W.; Haferlach, T.; Schnittger, S. AML with gain of chromosome 8 as the sole chromosomal abnormality (+8sole) is associated with a specific molecular mutation pattern including ASXL1 mutation in 46.8% of the patients. Leuk. Res. 2015, 39, 265–272. [Google Scholar] [CrossRef] [PubMed]
  46. Micol, J.B.; Duployez, N.; Boissel, N.; Petit, A.; Geffroy, S.; Nibourel, O.; Lacombe, C.; Lapillonne, H.; Etancelin, P.; Figeac, M.; et al. Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations. Blood 2014, 124, 1445–1449. [Google Scholar] [CrossRef] [PubMed]
  47. Ernest, P.; Wang, J.; Korsmeyer, S.J. The role of MLL in hematopoiesis and leukemia. Curr. Opin. Hematol. 2002, 9, 282–287. [Google Scholar] [CrossRef]
  48. Caligiuri, M.A.; Schichman, S.A.; Strout, M.P.; Mrózek, K.; Baer, M.R.; Frankel, S.R.; Barcos, M.; Herzig, G.P.; Croce, C.M.; Bloomfield, C.D. Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. Cancer Res. 1994, 54, 370–373. [Google Scholar] [PubMed]
  49. Caligiuri, M.A.; Strout, M.P.; Lawrence, D.; Arthur, D.C.; Baer, M.R.; Yu, F.; Knuutila, S.; Mrozek, K.; Oberkircher, A.R.; Marcucci, G.; et al. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res. 1998, 58, 55–59. [Google Scholar] [PubMed]
  50. Dohner, K.; Tobis, K.; Ulrich, R.; Frohling, S.; Benner, A.; Schlenk, R.F.; Dohner, H. Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: A study of the acute myeloid leukemia study group Ulm. J. Clin. Oncol. 2002, 20, 3254–3261. [Google Scholar] [CrossRef] [PubMed]
  51. Haferlach, C.; Dicker, F.; Herholz, H.; Schnittger, S.; Kern, W.; Haferlach, T. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia 2008, 22, 1539–1541. [Google Scholar] [CrossRef] [PubMed]
  52. Sattler, M.; Salgia, R. Targeting c-Kit mutations: Basic science to novel therapies. Leuk. Res. 2004, 28, S11–S20. [Google Scholar] [CrossRef] [PubMed]
  53. Paschka, P.; Marcucci, G.; Ruppert, A.S.; Mrozek, K.; Chen, H.; Kittles, R.A.; Vukosavljevic, T.; Perrotti, D.; Vardiman, J.W.; Carroll, A.J.; et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): A cancer and leukemia group B study. J. Clin. Oncol. 2006, 24, 3904–3911. [Google Scholar] [CrossRef] [PubMed]
  54. Boissel, N.; Leroy, H.; Brethon, B.; Philippe, N.; de Botton, S.; Auvrignon, A.; Raffoux, E.; Leblanc, T.; Thomas, X.; Hermine, O.; et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 2006, 20, 965–970. [Google Scholar] [CrossRef] [PubMed]
  55. Marcucci, G.; Geyer, S.; Zhao, W.; Caroll, A.J.; Bucci, D.; Uy, G.L.; Blum, W.; Pardee, T.; Wetzler, M.; Stock, W.; et al. Adding KIT inhibitor dasatinib (DAS) to chemotherapy overcomes the negative impact of KIT mutation/over-expression in core binding factor (CBF) acute myeloid leukemia (AML): Results from CLGB 10801 (Alliance). Blood 2014, 124, 8. [Google Scholar]
  56. Boissel, N.; Renneville, A.; Leguay, T.; Lefebvre, P.C.; Recher, C.; Lecerf, T.; Delabesse, E.; Berthon, C.; Blanchet, O.; Prebet, T.; et al. Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: A french acute myeloid leukemia intergroup trial. Haematologica 2015, 100, 780–785. [Google Scholar] [CrossRef] [PubMed]
  57. Cazzola, M.; Della Porta, M.G.; Malcovati, L. The genetic basis of myelodysplasia and its clinical relevance. Blood 2013, 122, 4021–4034. [Google Scholar] [CrossRef] [PubMed]
  58. Thota, S.; Viny, A.D.; Makishima, H.; Spitzer, B.; Radivoyevitch, T.; Przychodzen, B.; Sekeres, M.A.; Levine, R.L.; Maciejewski, J.P. Genetic alterations of the cohesin complex genes in myeloid malignancies. Blood 2014, 124, 1790–1798. [Google Scholar] [CrossRef] [PubMed]
  59. Dohner, H.; Estey, E.H.; Amadori, S.; Appelbaum, F.R.; Buchner, T.; Burnett, A.K.; Dombret, H.; Fenaux, P.; Grimwade, D.; Larson, R.A.; et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010, 115, 453–474. [Google Scholar] [CrossRef] [PubMed]
  60. Mrozek, K.; Marcucci, G.; Nicolet, D.; Maharry, K.S.; Becker, H.; Whitman, S.P.; Metzeler, K.H.; Schwind, S.; Wu, Y.Z.; Kohlschmidt, J.; et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J. Clin. Oncol. 2012, 30, 4515–4523. [Google Scholar] [CrossRef] [PubMed]
  61. Medeiros, B.C.; Othus, M.; Fang, M.; Roulston, D.; Appelbaum, F.R. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: The South-west Oncology Group (SWOG) experience. Blood 2010, 116, 2224–2228. [Google Scholar] [CrossRef] [PubMed]
  62. Sanz, M.A.; Lo Coco, F.; Martin, G.; Avvisati, G.; Rayon, C.; Barbui, T.; Diaz-Mediavilla, J.; Fioritoni, G.; Gonzalez, J.D.; Liso, V.; et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: A joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000, 96, 1247–1253. [Google Scholar] [PubMed]
  63. Cheson, B.D.; Bennett, J.M.; Kopecky, K.J.; Buchner, T.; Willman, C.L.; Estey, E.H.; Schiffer, C.A.; Doehner, H.; Tallman, M.S.; Lister, T.A.; et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J. Clin. Oncol. 2003, 21, 4642–4649. [Google Scholar] [CrossRef] [PubMed]
  64. Estey, E.; Döhner, H. Acute myeloid leukaemia. Lancet 2006, 368, 1894–1907. [Google Scholar] [CrossRef]
  65. Lowenberg, B.; Ossenkoppele, G.J.; van Putten, W.; Schouten, H.C.; Graux, C.; Ferrant, A.; Sonneveld, P.; Maertens, J.; Jongen-Lavrencic, M.; von Lilienfeld-Toal, M.; et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N. Engl. J. Med. 2009, 361, 1235–1248. [Google Scholar] [CrossRef] [PubMed]
  66. Fernandez, H.F.; Sun, Z.; Yao, X.; Litzow, M.R.; Luger, S.M.; Paietta, E.M.; Racevskis, J.; Dewald, G.W.; Ketterling, R.P.; Bennett, J.M.; et al. Anthracycline Dose Intensification in Acute Myeloid Leukemia. N. Engl. J. Med. 2009, 361, 1249–1259. [Google Scholar] [CrossRef] [PubMed]
  67. Burnett, A.K.; Russell, N.H.; Hills, R.K.; Kell, J.; Cavenagh, J.; Kjeldsen, L.; McMullin, M.; Cahalin, P.; Dennis, M.; Friis, L.; et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML Induction: Results from the UK NCRI AML17 Trial in 1206 Patients. Blood 2015, 125, 3878–3885. [Google Scholar] [CrossRef] [PubMed]
  68. Fernandez, H.F. Beyond the first glance: Anthracyclines in AML. Blood 2015, 125, 3828–3829. [Google Scholar] [CrossRef] [PubMed]
  69. Stone, R.M.; O’Donnell, M.R.; Sekeres, M.A. Acute myeloid leukemia. Hematol. Am. Soc. Hematol. Educ. Program 2004, 2004, 98–117. [Google Scholar] [CrossRef] [PubMed]
  70. Klepin, H. Geriatric perspective: How to assess fitness for chemotherapy in acute myeloid leukemia. Hematol. Am. Soc. Hematol. Educ. Program 2014, 2014, 8–13. [Google Scholar] [CrossRef] [PubMed]
  71. Quintas-Cardama, A.; Ravandi, F.; Liu-Dumlao, T.; Brandt, M.; Faderl, S.; Pierce, S.; Borthakur, G.; Garcia-Manero, G.; Cortes, J.; Kantarjian, H. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 2012, 120, 4840–4845. [Google Scholar] [CrossRef] [PubMed]
  72. Blum, W.; Garzon, R.; Klisovic, R.B.; Schwind, S.; Walker, A.; Geyer, S.; Liu, S.; Havelange, V.; Becker, H.; Schaaf, L.; et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc. Natl. Acad. Sci. USA 2010, 107, 7473–7478. [Google Scholar] [CrossRef] [PubMed]
  73. Maurillo, L.; Venditti, A.; Spagnoli, A.; Gaidano, G.; Ferrero, D.; Oliva, E.; Lunghi, M.; D'Arco, A.M.; Levis, A.; Pastore, D.; et al. Azacitidine for the treatment of patients with acute myeloid leukemia: Report of 82 patients enrolled in an Italian Compassionate Program. Cancer 2012, 118, 1014–1022. [Google Scholar] [CrossRef] [PubMed]
  74. Lo-Coco, F.; Avvisati, G.; Vignetti, M.; Thiede, C.; Orlando, S.M.; Iacobelli, S.; Ferrara, F.; Fazi, P.; Cicconi, L.; Di Bona, E.; et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 2013, 369, 111–121. [Google Scholar] [CrossRef] [PubMed]
  75. Mi, J.Q.; Li, J.M.; Shen, Z.X.; Chen, S.J.; Chen, Z. How to manage acute promyelocytic leukemia. Leukemia 2012, 26, 1743–1751. [Google Scholar] [CrossRef] [PubMed]
  76. Grimwade, D.; Freeman, S.D. Defining minimal residual disease in acute myeloid leukemia: Which platforms are ready for “prime time”? Blood 2014, 124, 3345–3355. [Google Scholar] [CrossRef] [PubMed]
  77. Kohlmann, A.; Nadarajah, N.; Alpermann, T.; Grossmann, V.; Schindela, S.; Dicker, F.; Roller, A.; Kern, W.; Haferlach, C.; Schnittger, S.; et al. Monitoring of residual disease by next-generation deep-sequencing of RUNX1 mutations can identify acute myeloid leukemia patients with resistant disease. Leukemia 2014, 28, 129–137. [Google Scholar] [CrossRef] [PubMed]
  78. Burnett, A.K.; Russell, N.H.; Hills, R.K.; Hunter, A.E.; Kjeldsen, L.; Yin, J.; Gibson, B.E.; Wheatley, K.; Milligan, D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: Results of the medical research council AML15 trial. J. Clin. Oncol. 2013, 31, 3360–3368. [Google Scholar] [CrossRef] [PubMed]
  79. Schiffer, C. Optimal dose and schedule of consolidation in AML: Is there a standard? Best Pract. Res. Clin. Haematol. 2014, 27, 259–264. [Google Scholar] [CrossRef] [PubMed]
  80. Appelbaum, F.R. The current status of hematopoietic cell transplantation. Annu. Rev. Med. 2003, 54, 491–512. [Google Scholar] [CrossRef] [PubMed]
  81. Popat, U.; de Lima, M.J.; Saliba, R.M.; Anderlini, P.; Andersson, B.S.; Alousi, A.M.; Hosing, C.; Nieto, Y.; Parmar, S.; Khouri, I.F.; et al. Long-term outcome of reduced-intensity allogeneic hematopoietic SCT in patients with AML in CR. Bone Marrow Transplant. 2012, 47, 212–216. [Google Scholar] [CrossRef] [PubMed]
  82. Sorror, M.L.; Maris, M.B.; Storb, R.; Baron, F.; Sandmaier, B.M.; Maloney, D.G.; Storer, B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: A new tool for risk assessment before allogeneic HCT. Blood 2005, 106, 2912–2919. [Google Scholar] [CrossRef] [PubMed]
  83. Devine, S.M.; Owzar, K.; Blum, W.; Mulkey, F.; Stone, R.M.; Hsu, J.W.; Champlin, R.E.; Chen, Y.B.; Vij, R.; Slack, J.; et al. Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J. Clin. Oncol. 2015, 33, 4167–4175. [Google Scholar] [PubMed]
  84. Breems, D.A.; Van Putten, W.L.; Huijgens, P.C.; Ossenkoppele, G.J.; Verhoef, G.E.; Verdonck, L.F.; Vellenga, E.; De Greef, G.E.; Jacky, E.; Van der Lelie, J.; et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J. Clin. Oncol. 2005, 23, 1969–1978. [Google Scholar] [CrossRef] [PubMed]
  85. Soignet, S.L.; Maslak, P.; Wang, Z.G.; Jhanwar, S.; Calleja, E.; Dardashti, L.J.; Corso, D.; DeBlasio, A.; Gabrilove, J.; Scheinberg, D.A.; et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N. Engl. J. Med. 1998, 339, 1341–1348. [Google Scholar] [CrossRef] [PubMed]
  86. Sudhindra, A.; Smith, C.C. FLT3 inhibitors in AML: Are we there yet? Curr. Hematol. Malig. Rep. 2014, 9, 174–185. [Google Scholar] [CrossRef] [PubMed]
  87. Levis, M.; Ravandi, F.; Wang, E.S.; Baer, M.R.; Perl, A.; Coutre, S.; Erba, H.; Stuart, R.K.; Baccarani, M.; Cripe, L.D.; et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 2011, 117, 3294–3301. [Google Scholar] [CrossRef] [PubMed]
  88. Stone, R.M.; DeAngelo, D.J.; Klimek, V.; Galinsky, I.; Estey, E.; Nimer, S.D.; Grandin, W.; Lebwohl, D.; Wang, Y.; Cohen, P.; 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. [Google Scholar] [CrossRef] [PubMed]
  89. Smith, B.D.; Levis, M.; Beran, M.; Giles, F.; Kantarjian, H.; Berg, K.; Murphy, K.M.; Dauses, T.; Allebach, J.; Small, D. 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. [Google Scholar] [CrossRef] [PubMed]
  90. Pratz, K.W.; Cortes, J.; Roboz, G.J.; Rao, N.; Arowojolu, O.; Stine, A.; Shiotsu, Y.; Shudo, A.; Akinaga, S.; Small, D.; et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 2009, 113, 3938–3946. [Google Scholar] [CrossRef] [PubMed]
  91. Serve, H.; Krug, U.; Wagner, R.; Sauerland, M.C.; Heinecke, A.; Brunnberg, U.; Schaich, M.; Ottmann, O.; Duyster, J.; Wandt, H.; 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. [Google Scholar] [CrossRef] [PubMed]
  92. Ravandi, F.; Alattar, M.L.; Grunwald, M.R.; Rudek, M.A.; Rajkhowa, T.; Richie, M.A.; Pierce, S.; Daver, N.; Garcia-Manero, G.; Faderl, S.; 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. [Google Scholar] [CrossRef] [PubMed]
  93. Fiedler, W.; Kayser, S.; Kebenko, M.; Krauter, J.; Salih, H.R.; Götze, K.; Späth, D.; Göhring, G.; Teleanu, V.; Döhner, K.; et al. Sunitinib and intensive chemotherapy in patients with acute myeloid leukemia and activating flt3 mutations: Results of the amlsg 10-07 study (clinicaltrials.Gov no. Nct00783653). In Procedings of the 56th ASH Annual Meeting and Exposition, Atlanta, GA, USA, 8–11 December 2012.
  94. Stone, R.M.; Mandrekar, S.; Sanford, B.L.; Geyer, S.; Bloomfield, C.D.; Dohner, K.; Thiede, C.; Marcucci, G.; Lo-CoCo, F.; Klisovic, R.B.; et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose c consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with FLT3 mutations (muts): An international prospective randomized (rand) p-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). In Proceedings of the American Society of Hematology Annual Meeting, Orlando, FL, USA, 5–8 December 2015.
  95. Smith, C.C.; Wang, Q.; Chin, C.S.; Salerno, S.; Damon, L.E.; Levis, M.J.; Perl, A.E.; Travers, K.J.; Wang, S.; Hunt, J.P.; et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukemia. Nature 2012, 485, 260–263. [Google Scholar] [CrossRef] [PubMed]
  96. Lee, H.K.; Kim, H.W.; Lee, I.Y.; Lee, J.; Lee, J.; Jung, D.S.; Lee, S.Y.; Park, S.H.; Hwang, H.; Choi, J.S.; et al. G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia. Blood 2014, 123, 2209–2219. [Google Scholar] [CrossRef] [PubMed]
  97. Altman, J.K.; Perl, A.E.; Cortes, J.E.; Levis, M.J.; Smith, C.S.; Litzow, M.R.; Baer, M.R.; Claxton, D.F.; Erba, H.P.; Gill, S.C.; et al. Antileukemic Activity and Tolerability of ASP2215 80mg and Greater in FLT3 Mutation-Positive Subjects with Relapsed or Refractory Acute Myeloid Leukemia: Results from a Phase 1/2, Open-Label, Dose-Escalation/Dose-Response Study. In Proceedings of the American Society of Hematology Annual Meeting, Orlando, FL, USA, 5–8 December 2015.
  98. Stein, E.M.; Altman, J.K.; Collins, R.; DeAngelo, D.J.; Fathi, A.T.; Flinn, I.; Frankel, A.; Levine, R.L.; Medeiros, B.C.; Patel, M.; et al. AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a Phase I Study in Patients with IDH2 Mutation Positive Advanced Hematologic Malignancies. In Procedings of 56th ASH Annual Meeting and Exposition, San Francisco, CA, USA, 6–9 December 2014; p. 115.
  99. Hansen, E.; Quivoron, C.; Straley, K.; Lemieux, R.M.; Popovici-Muller, J.; Sadrzadeh, H.; Fathi, A.T.; Gliser, C.; David, M.; Saada, V.; et al. AG-120, an Oral, Selective, First-in-Class, Potent Inhibitor of Mutant IDH1, Reduces Intracellular 2HG and Induces Cellular Differentiation in TF-1 R132H Cells and Primary Human IDH1 Mutant AML Patient Samples Treated Ex Vivo. In Procedings of 56th ASH Annual Meeting and Exposition, San Francisco, CA, USA, 6–9 December 2014; Volume 124, p. 3734.
  100. Fukuda, M.; Asano, S.; Nakamura, T.; Adachi, M.; Yoshida, M.; Yanagida, M.; Nishida, E. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 1997, 390, 308–311. [Google Scholar] [PubMed]
  101. Kojima, K.; Kornblau, S.M.; Ruvolo, V.; Dilip, A.; Duvvuri, S.; Davis, R.E.; Zhang, M.; Wang, Z.; Coombes, K.R.; Zhang, N.; et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood 2013, 121, 4166–4174. [Google Scholar] [CrossRef] [PubMed]
  102. Turner, J.G.; Sullivan, D.M. CRM1-mediated nuclear export of proteins and drug resistance in cancer. Curr. Med. Chem. 2008, 15, 2648–2655. [Google Scholar] [CrossRef] [PubMed]
  103. Ranganathan, P.; Yu, X.; Na, C.; Santhanam, R.; Shacham, S.; Kauffman, M.; Walker, A.; Klisovic, R.; Blum, W.; Caligiuri, M.; et al. Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood 2012, 120, 1765–1773. [Google Scholar] [CrossRef] [PubMed]
  104. Etchin, J.; Sun, Q.; Kentsis, A.; Farmer, A.; Zhang, Z.C.; Sanda, T.; Mansour, M.R.; Barcelo, C.; McCauley, D.; Kauffman, M.; et al. Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia 2013, 27, 66–74. [Google Scholar] [CrossRef] [PubMed]
  105. Castaigne, S.; Pautas, C.; Terré, C.; Raffoux, E.; Bordessoule, D.; Bastie, J.-N.; Legrand, O.; Thomas, X.; Turlure, P.; Reman, O.; 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. [Google Scholar] [CrossRef]
  106. Gasiorowski, R.E.; Clark, G.J.; Bradstock, K.; Hart, D.N.J. Antibody therapy for acute myeloid leukaemia. Br. J. Haematol. 2014, 164, 481–495. [Google Scholar] [CrossRef] [PubMed]
  107. Gill, S.; Tasian, S.K.; Ruella, M.; Shestova, O.; Li, Y.; Porter, D.L.; Carroll, M.; Danet-Desnoyers, G.; Scholler, J.; Grupp, S.A.; et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood 2014, 123, 2343–2354. [Google Scholar] [CrossRef] [PubMed]
Table 1. ELN risk stratification of molecular, genetic and cytogenetic alterations.
Table 1. ELN risk stratification of molecular, genetic and cytogenetic alterations.
Risk GroupSubsets
Favorablet(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD (normal karyotype)
Biallelic mutated CEBPA (normal karyotype)
Intermediate-IMutated NPM1 and FLT3-ITD (normal karyotype)
Wild-type NPM1 and FLT3-ITD (normal karyotype)
Wild-type NPM1 without FLT3-ITD (normal karyotype)
Intermediate-IIt(9;11)(p22;q23); MLLT3-KMT2A
Cytogenetic abnormalities not classified as favorable
or adverse
Adverseinv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA2-MECO (EVI1)
t(6;9)(p23;q34); DEK-NUP214
t(v;11)(v;q23); KMT2A rearranged
–5 or del(5q); –7; abnl(17p); complex karyotype *
Abbreviations: ITD, internal tandem duplication; * A complex karyotype is defined as three or more chromosome abnormalities; in the absence of one of the WHO designated recurring translocations; or inversions: t(8;21), inv(16) or t(16;16), t(15;17), t(9;11), t(v;11)(v;q23), t(6;9), inv(3) or t(3;3).
J. Clin. Med. EISSN 2077-0383 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top