`
`Genetic Abnormalities and Challenges in
`the Treatment of Acute Myeloid Leukemia
`
`Genes & Cancer
`2(2) 95 –107
`© The Author(s) 2011
`Reprints and permission:
`sagepub.com/journalsPermissions.nav
`DOI: 10.1177/1947601911408076
`http://ganc.sagepub.com
`
`C. Chandra Kumar
`
`Submitted 01-Feb-2011; accepted 17-Mar-2011
`
`Abstract
`Acute myeloid leukemia (AML) is a hematopoietic disorder in which there are too many immature blood-forming cells accumulating in the bone marrow
`and interfering with the production of normal blood cells. It has long been recognized that AML is a clinically heterogeneous disease characterized by a
`multitude of chromosomal abnormalities and gene mutations, which translate to marked differences in responses and survival following chemotherapy.
`The cytogenetic and molecular genetic aberrations associated with AML are not mutually exclusive and often coexist in the leukemic cells. AML is a
`disease of the elderly, with a mean age of diagnosis of 70 years. Adverse cytogenetic abnormalities increase with age, and within each cytogenetic group,
`prognosis with standard treatment worsens with age. In the past 20 years, there has been little improvement in chemotherapeutic regimens and hence
`the overall survival for patients with AML. A huge unmet need exists for efficacious targeted therapies for elderly patients that are less toxic than available
`chemotherapy regimens. The multitude of chromosomal and genetic abnormalities makes the treatment of AML a challenging prospect. A detailed
`understanding of the molecular changes associated with the chromosomal and genetic abnormalities in AML is likely to provide a rationale for therapy
`design and biomarker development. This review summarizes the variety of cytogenetic and genetic changes observed in AML and gives an overview of
`the clinical status of new drugs in development.
`
`Keywords
`acute myeloid leukemia, genetic abnormalities, new drugs
`
`Introduction
`
`Acute myeloid leukemia (AML) is a clonal hematopoietic
`disorder resulting from genetic alterations in normal hema-
`topoietic stem cells. These alterations disrupt normal dif-
`ferentiation and/or cause excessive proliferation of
`abnormal immature leukemic cells known as blasts. As the
`disease progresses, blast cells accumulate in the bone mar-
`row, blood, and organs and interfere with the production of
`normal blood cells. This leads to fatal infection, bleeding,
`or organ infiltration in the absence of treatment within
`1 year of diagnosis.1-3 AML is characterized by more than
`20% blasts in bone marrow. AML can arise de novo or sec-
`ondarily either due to the progression of other diseases or
`due to treatment with cytotoxic agents (referred to as
`therapy-related AML). Up to 10% to 15% of patients with
`AML develop the disorder after treatment with cytotoxic
`chemotherapy (usually for a solid cancer). There are 2 main
`types of therapy-related AML. The “classic” alkylating-
`agent type has a latency period of 5 to 7 years and is often
`associated with abnormalities of chromosomes 5 and/or 7.4
`Exposure to agents, such as etoposide and teniposide, that
`inhibit the DNA repair enzyme topoisomerase II is associated
`with secondary AML with a shorter latency period, usually 1
`to 3 years, with rearrangements at chromosome 11q23.5
`Drugs, such as chloramphenicol, phenylbutazone, chloro-
`quine, and methoxypsoralen, can induce marrow damage
`that may later evolve into AML. Secondary AML may also
`
`occur because of progression of myelodysplastic syndrome
`(MDS) or chronic bone marrow stem cell disorders, such as
`polycythemia vera, chronic myeloid leukemia, primary
`thrombocytosis, or paroxysmal nocturnal hemoglobin-
`uria.6,7 Secondary AML has a particularly poor prognosis
`and is not considered to be curable, with the exception of
`secondary acute promyelocytic leukemia (APL).8 This is
`largely due to the high percentage of secondary AML asso-
`ciated with multidrug resistance (MDR) mechanisms: up to
`70% of secondary AML patients show overexpression of
`P-glycoprotein (Pgp) or other MDR mechanisms.9
`The genetic changes in leukemic blasts make them inef-
`fective at generating mature red blood cells, neutrophils,
`monocytes, and platelets. In addition, these AML blasts
`also inhibit normal blasts from differentiating into mature
`progeny. Inhibition does not result from “crowding out” of
`normal blasts; rather, inhibition may be mediated by vari-
`ous chemokines produced by AML blasts.10 AML pro-
`gresses rapidly and is typically fatal within weeks or months
`if left untreated. The most common cause of death in AML
`is bone marrow failure, and the principal sign of marrow
`failure is infection. Potential fatal organ infiltration, most
`
`Onconova Therapeutics Inc., Pennington, NJ, USA
`
`Corresponding Author:
`C. Chandra Kumar, Onconova Therapeutics Inc., 73 Route 31 North,
`Pennington, NJ 08534
`Email: ckumar@onconova.us
`
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`Genes & Cancer / vol 2 no 2 (2011)
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`commonly involving the lung and the brain, becomes more
`likely as the disease progresses.
`AML is the most common acute leukemia affecting adults,
`and its incidence increases with age.1 Although the majority
`of patients under age 60 years achieve complete remission
`(CR) with traditional anthracycline- and cytarabine-based
`induction regimens, the long-term survival rates continue to
`be poor at approximately 30% to 40%.11-13 The prognosis is
`even poorer for those with high-risk AML, such as those
`who are older, those who had preceding MDS or myelopro-
`liferative disorders, or those with secondary AML from
`environmental exposures or prior chemotherapy. In such
`cases, CR is achieved in less than 40% of cases, with sur-
`vival rates of less than 10%.13 While 60% to 80% of younger
`patients achieve CR with standard therapy, only about 20%
`to 30% of the overall patient population has long-term dis-
`ease-free survival.3 Outcomes are worse for patients aged
`60 years or over, with CR rates in the range of 40% to 55%
`and poor long-term survival rates.3 Along with age, remis-
`sion rates and overall survival depend on a number of other
`factors, including cytogenetics, previous bone marrow dis-
`orders such as MDS, and comorbidities.3
`
`Epidemiology and Etiology of AML
`AML accounts for approximately 25% of all leukemias
`diagnosed in adults, and the median age at diagnosis is 67
`years.13,14 In the United States, 43,050 new cases of leuke-
`mia were reported in the year 2010, of which 12,330 were
`new cases of AML. There were 21,840 patients who died in
`the year 2010 because of leukemia, of which 8,950 were
`attributed to AML.15 The incidence of AML in the <65
`years’ age group is 1.8 cases per 100,000 patients, and the
`incidence in the >65 years’ age group is 17.9 cases per
`100,000 patients.15 The incidence of AML is expected to
`increase in the future in line with the aging population, and
`along with its precursor myelodysplasia, AML prevalence
`appears to be increasing, particularly in the population
`older than 60 years of age, and represents the most common
`type of acute leukemia in adults. Table 1 shows the inci-
`dence and prevalence of AML in the United States and
`other developed countries.
`Development of AML has been correlated with exposure
`to a variety of environmental agents, most likely due to
`links between exposure history and cytogenetic abnormali-
`ties. Radiation, benzene inhalation, alcohol use, smoking,
`dyes, and herbicide and pesticide exposure have all been
`implicated as potential risk factors for the development of
`AML.16,17 Survivors of the atomic bombs in Japan had an
`increased incidence of myeloid leukemias that peaked
`approximately 5 to 7 years following exposure.18 Therapeu-
`tic radiation also increases AML risk, particularly if given
`with alkylating agents such as cyclophosphamide, melpha-
`lan, and nitrogen mustard.
`
`Table 1. Number of Incidence and Prevalence Cases of Acute
`Myeloid Leukemia (AML) in the Major Pharmaceuticals Markets
`in 2010
`
`Markets
`
`US
`Europe
`Japan
`
`
`Incidence of
`new AML in 2010
`
`Prevalence of
`AML in 2010
`
`12,330
`12,923
`3,173
`28,426
`
`25,180
`22,790
`5,820
`53,790
`
`Note: Incident cases are the new cases diagnosed within a particular
`time frame; prevalent cases are all cases present at a particular time.
`Prevalence is thus a function of incident cases and duration of disease.
`
`Diagnosis and Classification of AML
`Demonstration of the accumulation of blasts resulting from
`the block in differentiation, characteristic of AML, is the
`essential requirement of diagnosis.19 The early signs of
`AML include fever, weakness and fatigue, loss of weight
`and appetite, and aches and pains in the bones or joints.
`Other signs of AML include tiny red spots in the skin, easy
`bruising and bleeding, frequent minor infections, and poor
`healing of minor cuts. The 2 systems commonly used in the
`classification of AML are the French-American-British
`(FAB) system and the World Health Organization (WHO)
`system. The FAB system is based on morphology and cyto-
`chemistry and recognizes 8 subtypes of AML, as shown in
`Table 2.20 In 1999, the WHO classification was introduced
`to include newer prognostic factors, such as molecular
`markers and chromosome translocations, and lowered the
`blast minimum criterion to 20%, thus including many cases
`classified as high-grade MDS in the FAB system.21 The
`WHO classification system identifies 4 AML subgroups: 1)
`AML with recurrent genetic abnormalities, 2) AML with
`multilineage dysplasia, 3) therapy-related AML and MDS,
`and 4) those that do not fall into any of these groups. This
`system created a minimum of 17 subclasses of AML, allow-
`ing physicians to identify subgroups of patients who might
`benefit from specific treatment strategies. Recently, a
`revised classification has been published as part of the
`fourth edition of the WHO monograph series.22 The aim of
`the revision was to incorporate new scientific and clinical
`information to refine diagnostic criteria for previously
`described neoplasms and to introduce newly recognized
`disease entities.
`
`Cytogenetic Abnormalities in AML
`AML is characterized by a high degree of heterogeneity
`with respect to chromosome abnormalities, gene muta-
`tions, and changes in expression of multiple genes and
`microRNAs. Cytogenetic abnormalities can be detected in
`approximately 50% to 60% of newly diagnosed AML
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`Table 2. French-American-British (FAB) Classification of Acute Myeloid Leukemia (AML)
`
`FAB subtype
`
`AML-M0
`AML-M1
`AML-M2
`AML-M3
`AML-M4
`AML-M4 eos
`AML-M5
`AML-M6
`AML-M7
`
`Morphological classification
`
`% of all AML cases
`
`Undifferentiated acute myeloblastic leukemia
`Acute myeloblastic leukemia with minimal maturation
`Acute myeloblastic leukemia with maturation
`Acute promyelocytic leukemia
`Acute myelomonocytic leukemia
`Acute myelomonocytic leukemia with eosinophilia
`Acute monocytic leukemia
`Acute erythroid leukemia
`Acute megakaryoblastic leukemia
`
`5
`15
`25
`10
`20
`5
`10
`5
`5
`
`patients.23 The majority of AML cases are associated with
`nonrandom chromosomal translocations that often result in
`gene arrangements. Cytogenetics is the most important
`prognostic factor for predicting remission rate, relapse, and
`overall survival.23 Several chromosomal abnormalities
`such as monosomies or deletions of part or all of chromo-
`somes 5 or 7 (–5/–7 AML) and trisomy 8 are common in
`AML.24 The chromosomal abnormalities also include the
`long arm of chromosome 11 (11q); balanced translocations
`between chromosomes 15 and 17 (t(15;17)); chromosomes
`8 and 21 (t(8;21)); others such as (q22;q22), (q31;q22), and
`t(9;11); and inversion such as inv(16).25 Table 3 shows
`the most frequent chromosomal aberrations and their cor-
`responding fusion genes in AML. The translocation in
`t(15;17) is always associated with APL and leads to the
`expression of PML-RARα oncofusion gene in hematopoi-
`etic myeloid cells.26 Generally, patients with APL t(15;17)
`phenotype represent a unique group characterized by dis-
`tinct biological features and good prognosis, particularly
`when all-trans retinoic acid (ATRA) is used as part of remis-
`sion induction.
`Many of the gene rearrangements involve a locus encod-
`ing a transcriptional activator, leading to expression of a
`fusion protein that retains the DNA-binding motifs of the
`wild-type protein. Moreover, in many instances, the fusion
`partner is a transcriptional protein that is capable of inter-
`acting with a corepressor complex.27 A commonly accepted
`paradigm is that through aberrant recruitment of a corepres-
`sor to a locus of active transcription, the fusion protein
`alters expression of target genes necessary for myeloid
`development, thus laying the groundwork for leukemic
`transformation.28 Potential targeting of this interaction has
`become a major focus for the development of novel thera-
`peutics. ATRA serves as a prototype: by altering corepres-
`sor interaction with the APL fusion protein, ATRA
`effectively induces remission and has become a mainstay of
`treatment of this previously fatal disease.8 However, to
`date, APL represents both the most curable and the best-
`studied subtype of AML, while molecular data on other
`fusion proteins are limited or absent. Still, the work on
`
`Table 3. Acute Myeloid Leukemia (AML)–Associated Oncofusion
`Proteins
`
`Translocations
`
`Oncofusion protein
`
`Frequency of
`occurrence(% of AML)
`
`t(8;21)
`t(15;17)
`inv(16)
`der(11q23)
`t(9;22)
`t(6;9)
`t(1;22)
`t(8;16)
`t(7;11)
`t(12;22)
`inv(3)
`t(16;21)
`
`AML1-ETO
`PML-RARα
`CBF□-MYH11
`MLL-fusions
`BCR-ABL1
`DEK-CAN
`OTT-MAL
`MOZ-CBP
`NUP98-HOXA9
`MN1-TEL
`RPN1-EVI1
`FUS-ERG
`
`10%
`10%
`5%
`4%
`2%
`<1%
`<1%
`<1%
`<1%
`<1%
`<1%
`<1%
`
`PML-RARα has inspired the molecular analysis of many
`other AML-associated oncofusion proteins, especially
`AML1-ETO, CBFβ-MYH11, and MLL fusions.
`
`Oncofusion Proteins Associated with AML
`A total of 749 chromosomal aberrations have been cata-
`logued in AML.29 The frequencies of the 4 most common
`translocations are between 3% and 10%, while for others,
`the prevalence is significantly smaller. The most frequent
`oncofusion proteins, PML-RARα, AML1-ETO, CBFβ-
`MYH11, and MLL fusions, are described below.
`
`t(15;17), PML-RARα
`
`The t(15;17) translocation is found in approximately 95%
`of APLs, a specific subtype of AML. The translocation
`results in the expression of the PML-RARα oncofusion
`gene in hematopoietic myeloid cells.8 The PML-RARα
`oncofusion protein acts as a transcriptional repressor that
`interferes with gene expression programs involved in differ-
`entiation, apoptosis, and self-renewal.8
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`t(8;21), AML1-ETO
`
`Class I Mutations
`
`Approximately 10% of AML cases carry the t(8;21) trans-
`location, which involves the AML1 (RUNX1) and ETO
`genes, and express the resulting AML1-ETO fusion pro-
`tein. AML1 is a DNA-binding transcription factor crucial
`for hematopoietic differentiation,30,31 while ETO is a pro-
`tein harboring transcriptional repressor activities.32 The
`fusion protein AML1-ETO is suggested to function as a
`transcriptional repressor that blocks AML1-dependent
`transactivation in various promoter reporter assays, sug-
`gesting it may function as a dominant-negative regulator of
`wild-type AML1.33,34
`
`inv(16), CBFβ-MYH11
`
`inv(16) is found in approximately 8% of AML cases.
`inv(16) fuses the first 165 amino acids of core binding fac-
`tor β (CBFβ) to the C-terminal coiled-coil region of a
`smooth muscle myosin heavy chain (MYH11). CBFβ-
`MYH11 fusion protein is suggested to cooperate with
`AML1 to repress transcription.35,36
`
`11q23, MLL Rearrangements
`
`Mixed lineage leukemia (MLL) is implicated in at least
`10% of acute leukemias of various types. In general, the
`prognosis is poor for patients harboring MLL transloca-
`tions.37 In these patients, the MLL protein fuses to 1 of >50
`identified partner genes, resulting in an MLL fusion protein
`that acts as a potent oncogene.38 The amino-terminal por-
`tion of MLL serves as a targeting unit to direct MLL onco-
`protein complexes to their target loci through DNA binding,
`whereas the fusion partner portion serves as an effecter unit
`that causes sustained transactivation.
`
`Gene Mutations in AML
`Approximately 40% to 50% of patients with AML have a
`normal karyotype and represent the largest subset of AML.39
`All such cases of cytogenetically normal AML are currently
`categorized in the intermediate-risk group; yet, this group is
`quite heterogeneous, and not all patients in this subset have
`the same response to treatment. This is likely a result of the
`large variability in gene mutations and gene expression in
`this population. These alterations appear to fall into 2
`broadly defined complementation groups. One group (class
`I) comprises mutations that activate signal transduction
`pathways and thereby increase the proliferation or survival,
`or both, of hematopoietic progenitor cells. The other com-
`plementation group (class II) comprises mutations that
`affect transcription factors or components of the cell cycle
`machinery and cause impaired differentiation.
`
`Mutations in KIT, FLT3, and NRAS fall into the class I
`mutations.
`
`KIT mutations. Although patients with AML and inv(16)
`and t(8;21) in general have a more favorable prognosis,
`there remains a significant failure rate, and the long-term
`disease-free survival rate is approximately 60%. Studies
`have shown that activating KIT mutations in approximately
`30% to 40% of patients with inv(16) are associated with
`higher incidence of relapse and significantly lower survival.
`In those with t(8;21), the incidence of KIT mutations
`appears to be variable.40
`
`FLT3 mutations. Fms-like tyrosine kinase 3 (FLT3) is a
`receptor tyrosine kinase that plays a key role in cell sur-
`vival, proliferation, and differentiation of hematopoietic
`stem cells.41,42 It is frequently overexpressed in acute leuke-
`mias. FLT3 mutations occur in approximately 30% of AML
`patients and confer a poor prognosis. The 2 major types of
`mutations that occur are internal tandem duplication (ITD)
`mutations of the juxtamembrane region and point mutations
`in the tyrosine kinase domain (TKD), which frequently
`involve aspartic acid 835 of the kinase domain. Both muta-
`tions result in constitutive activation of the receptor’s tyro-
`sine kinase activity in the absence of ligand.41 The incidence
`of FLT3 mutations also increases with age, but the FLT3
`ITD mutations have less prognostic impact in patients >60
`years of age possibly because other adverse prognostic fac-
`tors are more prevalent.
`
`RAS mutations. Mutations in NRAS and KRAS occur in
`approximately 10% and 5% of AML patients, respectively.
`IRASS mutations occur only rarely in conjunction with
`FLT3 mutations and do not appear to have a significant
`impact on AML survival.43
`
`Class II Mutations
`
`In addition, mutations in MLL, brain and acute leukemia
`gene (BAAL), Wilms tumor gene (WT-1), CCAAT/
`enhancer-binding protein α (CEBPα), and nucleoplasmin 1
`(NPM1) have also been observed in AML patients.44-46
`Recently, mutations in DNA methyltransferase gene
`DNMT3A have been identified in one third of patients with
`de novo AML with intermediate-risk cytogenetics.47
`DNMT3A represents 1 of 3 human genes that encodes DNA
`methyltransferase that catalyzes the addition of methyl
`groups to cytosine within CpG dinucleotide, resulting in
`repression of nearby genes. Genomes with DNMT3A muta-
`tions commonly harbored additional mutations in FLT3,
`NPM1, and IDH1. The presence of any DNMT3A mutation,
`
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`Table 4. Acute Myeloid Leukemia (AML) Cytogenetic Risk
`Groups
`
`Karyotype
`
`Frequency, %
`
`Complete
`remission, %
`
`Event-free
`survival, %
`
`Favorable
`t(8;21)
`inv(16)
`t(15;17)
`Intermediate
`Diploid, –Y
`Unfavorable
`−5/–7
`+8
`11q23, 20q-, other
`
`5-10
`5-10
`5-10
`
`40-50
`
`20-30
`10
`10-20
`
`90
`90
`80-90
`
`70-80
`
`50
`60
`60
`
`60-70
`60-70
`70
`
`30-40
`
`5-10
`10-20
`10
`
`either alone or in combination with FLT3 ITD mutation, is
`associated with significantly shorter overall survival (OS).47
`
`Prognostic Factors in AML
`Prognostic factors can be divided into those associated with
`treatment-related death occurring before response can be
`assessed and those associated with resistance to treatment.
`The predictor of treatment-related death is the patient’s per-
`formance status. Therapy-related AML or AML arising
`after MDS is usually more resistant to treatment than de
`novo AML.48 However, age and cytogenetics are the most
`important prognostic factors for predicting remission rate,
`relapse, and OS in AML. Risk stratification based on cyto-
`genetics divides patients into 3 main groups: patients with
`favorable, intermediate, and unfavorable cytogenetics
`depending on the presence or absence of specific chromo-
`somal abnormalities (Table 4). Studies have shown that the
`5-year survival rate was 55% for patients with favorable
`cytogenetics, 24% for patients with intermediate risk, and
`5% for patients with poor-risk cytogenetics.24 Adverse
`cytogenetic abnormalities increase with age, and within
`each cytogenetic group, prognosis with standard treatment
`worsens with age.3 A recent study demonstrated that the
`percentage of patients with unfavorable cytogenetics has
`been shown to increase from 35% in patients below 56
`years of age to 51% in patients over 75 years (Fig. 1).49
`
`Treatment of AML
`The primary objective of therapy for AML is to achieve and
`maintain CR. CR is defined as a marrow with less than 5%
`blasts, a neutrophil count greater than 1,000, and a platelet
`count greater than 100,000. CR is the only response that leads
`to a cure or at least an extension in survival. The probability of
`AML recurrence sharply declines to <10% after 3 years in
`CR.50 For the past 30 years, treatment of AML has consisted of
`the combination of an anthracycline, such as daunorubicin or
`
`Figure 1. Cytogenetic risk group by age group. Adapted with permission
`from Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid
`leukemia. Blood. 2006;107:3481-5.
`
`idarubicin, and cytarabine.51 Treatment of AML is divided into
`2 phases: 1) remission induction therapy (with possible postin-
`duction) and 2) postremission therapy.52 Generally, AML treat-
`ment includes at least one course of intensive induction
`chemotherapy followed by an additional course of intensive
`consolidation therapy and then maintenance therapy.
`
`Remission Induction Therapy
`In induction therapy, the goal is to achieve a marked reduc-
`tion in the number of malignant cells in order to establish
`normal hematopoiesis. A standard form of induction ther-
`apy consists of a standard dose of cytarabine (SDAraC,
`100-200 mg/m2), administered by continuous infusion for
`7 days and combined with an anthracycline administered
`intravenously for 3 days (referred to as 7 + 3 regimen).
`With standard induction regimens, remission is achieved in
`about 65% to 85% of younger patients but in less than 50%
`of patients over 60 years of age.2,53 This approach results in
`a long-term disease-free survival of approximately 30%,
`with treatment-related mortality of 5% to 10%. A number
`of studies have been conducted to improve the CR rate by
`use of alternative anthracyclines, incorporation of high-
`dose AraC (HDAraC), or addition of other agents such as
`etoposide, fludarabine, or cladribine. However, presently,
`there is no conclusive evidence to recommend one 7 + 3
`induction regimen over another. However, these studies
`clearly support the conclusion that further intensification
`of the induction regimen is not associated with an increased
`CR rate.
`In patients who fail to achieve CR following induction
`therapy, postinduction therapy is recommended. Postinduc-
`tion therapy with standard-dose cytarabine is recommended
`in patients who have received standard-dose cytarabine
`induction and have significant residual blasts.52 In other
`cases, postinduction therapy may consist of hematopoietic
`stem cell transplantation if a suitable donor can be found.
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`Postremission Therapy
`
`There are mainly 2 types of postremission therapy:
`
`1. Consolidation therapy is usually administered at
`doses approaching those used during induction.
`2. Maintenance therapy is usually defined as therapy
`less myelosuppressive than therapy used to pro-
`duce remission. Typically, patients receive the
`same regimen used during induction at approxi-
`mately monthly intervals for 4 to 12 months.
`
`Consolidation Therapy
`Although obtaining an initial remission is the first step in
`controlling the disease, it is important that patients continue
`with consolidation therapy to achieve a durable remission.
`Patients who do not receive consolidation therapy will
`relapse within 6 to 9 months.54,55 Consolidation therapy can
`consist of chemotherapy or hematopoietic stem cell trans-
`plantation (HSCT), and the choice of therapy is typically
`dependent on patient age, comorbidities, chance of recur-
`rence based on cytogenetics, and whether a patient has a
`suitable donor for HSCT.3 The use of HSCT is less common
`in patients aged over 60 years because of increased risks of
`transplant-related morbidity and mortality. Consolidation
`therapy comprises treatment with additional courses of
`intensive chemotherapy after the patient has achieved CR,
`usually with higher doses of the same drugs used during the
`induction period. High-dose AraC (2-3 g/m2) is now stan-
`dard consolidation therapy for patients aged <60 years of
`age. The median disease-free survival for patients who receive
`only the induction therapy is 4 to 8 months. However, 35%
`to 50% of adults aged <60 years who receive consolidation
`treatment survive 2 to 3 years.55 HSCT has a central role in
`the treatment of AML. However, because of the morbidity
`and mortality of the procedure, it tends to be used in patients
`who have a substantial risk of relapse.56 APL, a subtype of
`AML, is treated differently from other subtypes of AML;
`the vitamin A derivative ATRA (Vesanoid, Roche, Basel,
`Switzerland) can induce differentiation of leukemic promy-
`elocytes, resulting in high remission rates.8 Older patients
`are generally treated with lower intensity therapies such as
`subcutaneous cytarabine or hydroxyl urea in an attempt to
`minimize treatment-related mortality.
`
`Maintenance Therapy
`Maintenance therapy, which is considered less myelosuppres-
`sive than the induction and consolidation forms of treatment, is
`used in patients who have previously obtained CR. It is a strat-
`egy to further reduce the number of residual leukemic cells and
`prevent a relapse. Its role in the routine management of AML
`patients is controversial and depends mainly on the intensity of
`induction and consolidation therapies.52
`
`Genes & Cancer / vol 2 no 2 (2011)
`
`Table 5. Outcomes in Acute Myeloid Leukemia (AML) by Age
`Criteria
`
`Complete response, %
`Disease-free survival, %
`Early death, %
`Overall survival, %
`Median survival, mo
`
`Age <60 y
`
`Age >60 y
`
`70
`45
`10
`30
`24
`
`45
`20
`25
`10
`10
`
`Treatment of Relapsed and Refractory Disease
`
`Despite the substantial progress in the treatment of newly
`diagnosed AML, 20% to 40% of patients still do not achieve
`remission with standard induction chemotherapy, and 50% to
`70% of first CR patients are expected to relapse over 3 years.57
`The prognosis for patients with AML refractory to first-line
`treatment or in first or subsequent relapse is generally poor.
`The duration of first remission in relapsed patients is the most
`important prognostic factor correlating with the probability of
`second CR and survival.58 Patients who relapsed in less than 6
`months have a significantly poor prognosis compared to
`patients who relapsed after a first CR lasting >6 months.
`Treatment strategies for relapse are dependent on patient
`age.52 For patients less than 60 years old who have experi-
`enced an early (<6 months) relapse after induction chemo-
`therapy, the US National Comprehensive Cancer Network
`(NCCN) guidelines recommend participation in a clinical trial
`or HSCT.52 However, if patients have relapsed after a long
`(6 months or greater) remission, they can be retreated with a
`chemotherapy regimen or a development drug in the context
`of a clinical trial.52 The recommended option for patients aged
`60 years or older is participation in a clinical trial.52
`HSCT is the most commonly used treatment modality at
`relapse in patients aged below 60 years. In older patients,
`use of HSCT at relapse is rare, and single agents including
`azacitidine (Vidaza, Celgene, Summit, NJ), gemtuzumab
`ozogamicin (Mylotarg, Pfizer, New York City, NY), and
`hydroxyurea are most commonly used, although there is a
`lack of clear consensus over the optimum regimen.
`
`Age Is a Major Determinant of Survival
`Treatment recommendations for AML patients differ
`depending on whether patients are above or below 60
`years old.52 Table 5 shows the treatment outcomes based
`on age criteria. Survival in AML depends on age, with sig-
`nificantly lower survival rates reported for older adults.3
`Statistics from the Surveillance, Epidemiology and End
`Results (SEER) Program from 1996 to 2002 show 5-year
`survival rates of 34.4% for adults aged below 65 years and
`4.3% for those aged 65 years or older.54 While selected
`older patients can benefit from standard therapies, this
`group of patients experiences greater treatment-related
`
`Rigel Exhibit 1057
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`Genetic changes and new drugs in the pipeline for AML / Kumar
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`101
`
`Table 6. Therapeutic Strategies Being Investigated in the Treatment of Acute Myeloid Leukemia (AML)
`
`Therapeutic approach
`
`Epigenetic regulation
`
`Differentiation-inducing therapeutics
`
`Angiogenesis inhibition
`
`Inhibition of signaling pathways
`
`Modulation of drug resistance
`Modified traditional chemotherapeutics
`
`Immune therapy
`
`Examples
`
`Histone deacetylase inhibitors: vorinostat, panobinostat, belinostat
`DNA methyl transferase inhibitors: Vidaza, Dacogen
`Retinoid X receptor agonists
`Arsenic trioxide
`Inhibition of angiogenesis: Velcade
`Thalomid, Revlimid
`Tyrosine kinase inhibitors: midostaurin, lestaurtinib, sorafenib, KW-2449, AC220
`Cell cycle inhibitors: ON 01910.Na
`Farnesyl transferase inhibitors: Zarnestra, Sarasar
`mTOR inhibitors: Afinitor, PI-103, temsirolimus, GSK21110183
`PARP inhibitors: ABT-888
`MEK1/2 inhibitors: AZD6244, AS703026, PD98059, GSK1120212
`Bcl-2 inhibitors: oblimersen, obatoclax, ABT-263
`XIAP inhibitor: AEG-35156
`Aminopeptidase inhibitors (tosedostat)
`Valspodar, zosuquidar
`Nucleoside analogs: clofarabine, sapacitabine, elacytarabine
`Alkylating drugs: irofulven, Temodar, Onrigin
`Topoisomerase inhibitors: Hycamtin
`Antibodies: Mylotarg, lintuzumab, Avastin, T-cell targeted therapy
`
`toxicity, lower remission rates, shorter disease-free sur-
`vival, and shorter OS times.3 Older adults are less likely to
`achieve CR and to remain relapse free if they have
`achieved CR.3 In addition, these patients are more likely
`to experience treatment-related death, which is in the
`range of 15% to 30% in reported clinical trials.3 This is
`because patients over the age of 60 years are characterized
`by a higher prevalence of unfavorable cytogenetics and
`myelodysplasia, a greater incidence of MDR, and more
`frequent comorbidities that often make them unsuitable
`for intensive treatment.3
`
`Novel Agents in the Pipeline for AML
`Identification of specific gene mutations, chromosomal
`translocations, and alterations in signaling pathways and
`gene transcription in AML has led to the development of a
`number of targeted agents. A number of therapeutic
`approaches are being investigated in the treatment of AML
`(Table 6). These include histone deacetylase inhibitors,
`DNA methyl transferase inhibitors, retinoid X receptor
`agonists, proteosome inhibitors, antiangiogenesis inhibi-
`tors, FLT3 inhibitors, farnesyl transferase inhibitors,
`mTOR inhibitors, poly ADP-ribose polymerase (PARP)
`inhibitors, MEK1/2 inhibitors, modulators of drug resis-
`tance, and immune-modulating agents.59 In addition, a
`number of traditional chemotherapeutics in new formula-
`tions are also being investigated. Table 7 lists the mole-
`cules that are being investigated in late-stage clinical trials
`for AML. Clinical trial results of key drugs in AML are
`summarized below.
`
`Flt-3 Inhibitors
`Despite an exciting rationale for the use of FLT3 tyrosine
`kinase inhibitors (TKIs) in AML, the clinical results have
`so far been modest. Several FLT3 inhibitors are currently
`being developed suc