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Stefan H. Faderl
Hagop M. Kantarjian • Elihu Estey
Editors
Acute Leukemias
Second Edition
Editors
Stefan H. Faderl Hagop M. Kantarjian
Reno Department of Leukemia
NV MD Anderson Cancer Center, University
USA of Texas
Houston, TX
Elihu Estey USA
Clinical Research Division
Fred Hutch
Seattle, WA
USA
ISSN 2197-9766 ISSN 2197-9774 (electronic)
Hematologic Malignancies
ISBN 978-3-030-53632-9 ISBN 978-3-030-53633-6 (eBook)
https://doi.org/10.1007/978-3-030-53633-6
© Springer Nature Switzerland AG 2021
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Contents
Part I Acute Myeloid Leukemia
1 Acute Myeloid Leukemia: Epidemiology and Etiology�������������������� 3
Kendra Sweet and Hannah Asghari
2 Clinical Presentation, Diagnosis, and Classification
of Acute Myeloid Leukemia�������������������������������������������������������������� 11
Ridas Juskevicius, Mary Ann Thompson, Aaron Shaver,
and David Head
3 Insights into the Pathobiology of Secondary AML ������������������������ 57
Tania Jain and Raajit K. Rampal
4 Selection of Patients for Individual Acute Myeloid
Leukemia Therapies�������������������������������������������������������������������������� 69
Roland B. Walter
5 Therapy of Newly Diagnosed Acute Myeloid Leukemia
(AML)�������������������������������������������������������������������������������������������������� 77
Anna B. Halpern and Elihu Estey
6 Management of Relapsed/Refractory Acute Myeloid
Leukemia�������������������������������������������������������������������������������������������� 89
Nadya Jammal, Serena Chew, Farhad Ravandi,
Hagop M. Kantarjian, and Elias Jabbour
7 The Role of Stem Cell Transplant in the Therapy
of Acute Myeloid Leukemia (AML) ���������������������������������������������� 111
David Sanford, Mahmoud Elsawy, and Florian Kuchenbauer
8 Novel and Investigational Therapies in Acute Myeloid
Leukemia������������������������������������������������������������������������������������������ 133
Yazan F. Madanat and Aziz Nazha
9 Immune-Based Approaches in AML���������������������������������������������� 145
Ahmad S. Alotaibi and Naval Daver
v
vi Contents
Part II Acute Lymphoblastic Leukemia
10 Acute Lymphoblastic Leukemia: Clinical Presentation,
Diagnosis, and Classification���������������������������������������������������������� 157
Sandeep Gurbuxani, Joseph P. Wynne, and Richard A. Larson
11 Frontline Therapy of Newly Diagnosed Acute Lymphoblastic
Leukemia������������������������������������������������������������������������������������������ 169
Melissa C. Mackey, Serena Chew, Hagop M. Kantarjian,
and Elias Jabbour
12 Acute Lymphoblastic Leukemia (ALL) in Children
and Adolescents�������������������������������������������������������������������������������� 185
Michael Rytting
13 Hematopoietic Cell Transplantation (HCT) for Acute
Lymphoblastic Leukemia (ALL)���������������������������������������������������� 193
Limei Michelle Poon and Partow Kebriaei
14 Minimal or Measurable Residual Disease in Acute
Lymphoblastic Leukemia���������������������������������������������������������������� 205
Shilpa Paul, Caitlin Rausch, Hagop M. Kantarjian,
and Elias Jabbour
15 Management of Philadelphia Chromosome-Positive Acute
Lymphoblastic Leukemia���������������������������������������������������������������� 219
Serena Chew, Nicholas J. Short, Hagop M. Kantarjian,
and Elias Jabbour
16 Ph-Like ALL: Diagnosis and Management ���������������������������������� 235
Emily K. Curran and Sarah K. Tasian
17 Adult Burkitt Leukemia/Lymphoma �������������������������������������������� 249
Pamela Abdayem, Jean-Marie Michot,
Valérie Camara-Clayette, Yegor Vassetsky, and Vincent Ribrag
18 Management of Relapsed and Refractory ALL���������������������������� 277
Ashwin Kishtagari and Anjali S. Advani
Part I
Acute Myeloid Leukemia
Acute Myeloid Leukemia:
Epidemiology and Etiology 1
Kendra Sweet and Hannah Asghari
1.1 Introduction 1.2 Epidemiology
Acute myeloid leukemia (AML) is a heteroge- 1.2.1 Prevalence
neous hematologic malignancy characterized by
abnormal differentiation of cells of the myeloid Acute myeloid leukemia comprises 1.1% of all
lineage, leading to clonal proliferation of leuke- new cancer diagnoses in the United States. It is
mic blast cells in the bone marrow, peripheral estimated that 19,520 new cases of AML were
blood, and potentially extramedullary tissue. diagnosed in the United States in 2018 [4, 5]. The
This in turn leads to decreased production of nor- overall incidence of acute myeloid leukemia in
mal hematopoietic cells and associated complica- the United States is 4.3 cases per 100,000 and is
tions related to ineffective hematopoiesis. higher in males, with an estimated 5.2 cases per
AML is the most common type of acute leu- 100,000 compared to 3.6 cases per 100,000 in
kemia diagnosed in adults and is associated females [4]. White individuals also have higher
with the lowest survival [1]. Although survival rates of AML compared to other ethnicities [4, 6].
remains poor overall, outcomes have improved The incidence of AML is generally higher in
over the past few decades with the advent of North America and Europe compared to other
new therapeutic approaches. With growing regions including countries in Asia and South
understanding of the molecular pathogenesis, America [1, 7].
multiple new therapies have been recently The incidence of AML increases with age and
approved for AML, and there is an ongoing is highest in adults aged 65 years and older
investigation of novel agents [2, 3]. (Fig. 1.1). The median age at diagnosis is
68 years. It is estimated that over half of new
cases of AML are diagnosed in individuals
65 years and older, with approximately one-third
of patients diagnosed at the age of 75 years or
older [4].
K. Sweet (*) Acute leukemia is the most common malig-
Department of Malignant Hematology, nancy in children, accounting for approximately
Moffitt Cancer Center, Tampa, FL, USA 30% of all pediatric cancers. AML is less common
e-mail: Kendra.Sweet@moffitt.org in children and adolescents compared to acute
H. Asghari lymphoblastic leukemia (ALL), c omprising
Department of Hematology/Oncology, Moffitt Cancer approximately 18% of childhood leukemias [8, 9].
Center/University of South Florida, Tampa, FL, USA
© Springer Nature Switzerland AG 2021 3
S. H. Faderl et al. (eds.), Acute Leukemias, Hematologic Malignancies,
https://doi.org/10.1007/978-3-030-53633-6_1
4 K. Sweet and H. Asghari
Fig. 1.1 Percent of new 40%
cases of AML by age
group from 2011 to
35%
2015. (Adapted from
originally published data
by SEER Cancer Stat 30%
Facts: Acute Myeloid
Percent of New Cases
Leukemia [4]) 25%
20%
15%
10%
5%
0%
<20 20-34 35-44 45-54 55-64 65-74 75-84 >84
Age
35
30
Percent Surviving
25
20
15
10
0
1975 1980 1985 1990 1995 2000 2005 2010 2015
Year
5-Year Survival
Fig. 1.2 Five-year relative survival from 1975 to 2010. (Reproduced from SEER Cancer Stat Facts: Acute Myeloid
Leukemia [4])
1.2.2 Mortality from 2001 to 2006 estimated the 5-year relative
survival rate for ages 15–24 years was 53% com-
The estimated overall 5-year survival rate of indi- pared to 13% for ages 60–69 years, and 3% for
viduals with AML is 27.4%, and in the United ages 70–79 years [11].
States, it is estimated that 10,670 patients died of
AML in 2018 [4, 5]. Overall survival has steadily
improved over the years (Fig. 1.2); however, sur- 1.3 Etiology
vival and outcomes of older adults remain poor,
and the estimated overall survival in AML The process of leukemogenesis is not entirely
decreases significantly with age [10]. A large understood; however, the pathogenesis of acute
population-based study in the United Kingdom myeloid leukemia involves oncogenic transfor-
1 Acute Myeloid Leukemia: Epidemiology and Etiology 5
mation of a hematopoietic stem cell or progenitor may later evolve to AML [17, 20]. One large
cell to a leukemic clone that is capable of self- study found that approximately 10% of individu-
proliferation [12]. AML is a highly heteroge- als over age 65 years have somatic mutations
neous disease. Most cases develop de novo and with associated clonal hematopoiesis, most com-
are associated with acquired genetic abnormali- monly with mutations in DNMT3A, ASXL1, and
ties, including cytogenetic changes and somatic TET2 [21]. In patients without a known hemato-
mutations. Secondary AML (s-AML) can arise in logic malignancy, this is referred to as clonal
the setting of clonal evolution from an antecedent hematopoiesis of indeterminate potential (CHIP)
hematologic disorder or from prior exposure to [22]. It has been demonstrated that the incidence
cytotoxic therapy (therapy-related AML or of somatic mutations involved in clonal hemato-
t-AML) and is overall associated with worse poiesis increases with age and is associated with
prognosis compared to de novo AML [13]. an increased risk of developing hematologic
Acquired chromosomal abnormalities are malignancies, cardiovascular disease, and all-
present in approximately 50–55% of cases of de cause mortality [23].
novo AML and have higher incidence in second- On average, patients with de novo disease
ary AML [14]. Cytogenetic abnormalities have have 13 genomic mutations, with an average of
been demonstrated to have prognostic signifi- five genes that are recurrently mutated in AML
cance in several studies and the European [24]. The most common recurrent mutations that
LeukemiaNet (ELN) classification incorporates play a role in the pathogenesis of AML (Fig. 1.3)
cytogenetic and molecular abnormalities in risk include genes involved in DNA methylation
stratification of AML [15–19]. (DNMT3A, TET2, IDH1, IDH2), tumor suppres-
Early somatic mutations are thought to confer sion (TP53, WT1, PHF6), spliceosome complex,
selective advantage for clonal hematopoiesis and modification of chromatin, cohesin complex, sig-
Chromatin modifiers (30.5%) Transcription factor fusions
MLL fusions, MLL PTD, Spliceosome (13.5%) (18%) PML-RARA,
NUP98-NSD1, ASXL1, EZ112, MYH11-CBFB, RUNX1-RUNX1T1,
KDM6A, other modifiers PICALM-MLLT10
Myeloid transcription
factors (22%) RUNX1, NPM1 (27%)
CEBPA, other myeloid
transcription factors
Tumor
suppressors (16.5%)
TP53, WT1, PHF6
DNA methylation (46%)
TET1, TET2, IDH1,
IDH2, DNMT3B, DNMT1,
Cohesin complex (13%)
DNMT3A
Activated signaling (59%)
FLT3, KIT, KRAS, NRAS, PTPs,
Ser/Thr kinases, other Tyr kinases
Fig. 1.3 Circos plot demonstrating functional categories of mutated genes involved in pathogenesis of AML.
(Reproduced from Chen et al. [25])
6 K. Sweet and H. Asghari
nal transduction (FLT3, KIT, KRAS/NRAS), in liferative neoplasms (MDS/MPN like CMML,
addition to nucleophosmin (NPM1), myeloid aCML) [29–33]. Paroxysmal nocturnal hemoglo-
transcription factors (RUNX1, CEBPA), and tran- binuria and aplastic anemia, which are non-
scription factor fusion genes [24, 26, 27]. malignant hematologic conditions, have also
Targeted mutational analysis in one study noted been associated with increased risk of developing
that the presence of certain somatic mutations AML [34, 35]. In a large population-based
(SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, Swedish study, AML from an antecedent hemato-
BCOR, or STAG2) was highly specific for sec- logic disease and therapy-related AML were both
ondary AML [28]. associated with worse overall survival and were
more likely to have high-risk cytogenetics and
lower rates of complete remission (CR) com-
1.3.1 Secondary AML pared to de novo AML [36]. Higher-risk AML is
also more common in older adults (Fig. 1.4).
AML can develop from antecedent hematologic AML with myelodysplasia-related changes
malignancies including myelodysplastic syn- (AML-MRC) can arise from an antecedent
drome, myeloproliferative neoplasms (i.e., poly- myelodysplastic syndrome or MDS/MPN and
cythemia vera, essential thrombocythemia, can be associated with MDS-related cytogenetic
myelofibrosis), and myelodysplastic/myelopro- abnormalities or multilineage dysplasia [13].
1000
26%
800
600 31%
21%
14%
N
24%
30%
400
34% 29%
17%
19% 31%
200
30%
29%
18% 13%
34%
0
<45 45-59 60-69 >=70
age class (years)
ELN low inter-1 inter-2 high
Fig. 1.4 Prevalence of AML in Germany and Austria as European LeukemiaNet (ELN) classification.
part of the AMLSG BiO registry. Prevalence stratified (Reproduced from Nagel et al. [37])
according to age and distribution of risk groups per 2010
1 Acute Myeloid Leukemia: Epidemiology and Etiology 7
AML-MRC is associated with worse overall sur- Individuals with Down syndrome (trisomy 21)
vival likely due to higher risk disease as affected have a significantly increased risk of AML (10-
individuals are more likely to be older and have to 20-fold increased risk), particularly the sub-
unfavorable cytogenetics [38]. type of acute megakaryocytic leukemia, and are
associated with somatic mutations of the GATA1
gene [46, 47].
1.3.2 Therapy-Related AML
Treatment with cytotoxic therapy for a preceding 1.3.4 Environmental Factors
primary malignancy is associated with predispo-
sition to developing therapy-related acute Exposure to environmental agents, including
myeloid leukemia (t-AML) [13]. Several agents radiation and certain chemicals, as well as life-
have been implicated, including prior treatment style factors can cause DNA damage and associ-
with alkylating agents, topoisomerase inhibitors, ated genetic changes which have been associated
and less commonly with exposure to other cyto- with increased risk of developing acute myeloid
toxic agents including taxanes or antimetabolites leukemia. It is important to note that most patients
[32, 39]. Alkylating agents can have longer with AML develop de novo disease without iden-
latency periods (5–7 years) prior to progression tifiable risk factors.
and can frequently be associated with myelodys- Historically, ionizing radiation was identified
plastic features as well as clonal cytogenetic as a risk factor for AML in survivors of atomic
abnormalities involving chromosome 5 and 7 bomb explosions in Japan [48]. Radiologists and
(del(5q) or −7/del(7q)). Inhibitors of topoisomer- technicians chronically exposed to high levels of
ase II can have a shorter latency period (2–3 years) radiation in the early twentieth century were also
prior to the development of therapy-related AML found to have increased risk of developing leuke-
and have been more commonly associated with mia [49]. The use of ionizing radiation for the
balanced cytogenetic translocations involving treatment of other primary malignancies have also
chromosome bands t(11q23.3) or t(21q22.1), as been implicated in potential development of AML
well as t(15;17) [29, 30, 40, 41]. [50, 51]. Increased risks have also been identified
with combined radiation and chemotherapy [52].
Occupational hazards may also play a contrib-
1.3.3 Inherited Syndromes uting factor, including prolonged exposure to cer-
tain chemicals including organic solvents and
There are also cases of inherited/familial syn- pesticides [53]. Exposure to benzene also appears
dromes associated with developing AML, includ- to be associated with increased risk of acute non-
ing inherited bone marrow failure syndromes lymphocytic leukemia [54]. Other factors includ-
(i.e., Fanconi anemia, Shwachman–Diamond ing cigarette smoking and obesity have also been
syndrome, dyskeratosis congenita) or telomere associated with increased risk of developing
syndromes (associated with mutations in TERT AML [55–58].
and TERC) [42, 43]. Other inherited disorders
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Clinical Presentation, Diagnosis,
and Classification of Acute 2
Myeloid Leukemia
Ridas Juskevicius, Mary Ann Thompson,
Aaron Shaver, and David Head
2.1 Introduction narios under the common heading of AML. The
WHO classification of AML is based on clinical,
The acute myeloid leukemias (AML) are a phenotypic, and molecular genetic features with
diverse set of phenotypically similar diseases an attempt to define biologically and prognosti-
characterized by increased myeloblasts replacing cally distinct entities which have uniform
the normal bone marrow, with variable involve- response to therapy. Although genetic heteroge-
ment of peripheral blood and occasional involve- neity of AML has been recognized for several
ment of extramedullary sites. In some cases, decades, enormous molecular heterogeneity has
proliferating blasts replace normal hematopoiesis become apparent only recently with the introduc-
resulting in failure of the marrow to produce nor- tion of new molecular diagnostic methodologies
mal peripheral blood cells, with tumor burden including next-generation sequencing (NGS)-
itself becoming life-threatening. In other cases, based assays. The massive amount of data gener-
while blasts are increased as a percentage of mar- ated utilizing these techniques is contributing to
row cells, the predominant problem is primary improved understanding of the biologic hetero-
marrow failure (resembling MDS) rather than geneity of AML. Incorporation of the data into
blast tumor burden. Classification of AML has the classification framework of AML is inevita-
undergone fundamental changes over the last two ble, but is still at its early stages, as we are only
decades, in part due to recognition of these vary- now beginning to understand the biologic and
ing scenarios [1]. Although not without areas of clinical implications of these newly discovered
controversy, the introduction of the World Health molecular alterations. In this chapter, we discuss
Organization (WHO) classification framework in the clinical presentation, diagnosis, and classifi-
2001, updated in 2008 and revised in 2016 [2], cation of AML, including appropriate diagnostic
represents the official international consensus laboratory studies necessary for diagnosis and
classification of AML, combining these two sce- subclassification of biologically and clinically
relevant types of disease. Understanding the basis
for the current WHO classification of AML
R. Juskevicius (*) · M. A. Thompson requires additional knowledge of the myelodys-
A. Shaver · D. Head plastic syndromes (MDS) and their relationship
Department of Pathology, Microbiology and
Immunology, Vanderbilt University Medical Center, to one subset of AML. Finally, we will address
Nashville, TN, USA monitoring AML minimal residual disease dur-
e-mail: ridas.juskevicius@vumc.org; ing and after treatment.
maryann.thompson.arildsen@vumc.org;
aaron.shaver@vumc.org; david.head@vumc.org
© Springer Nature Switzerland AG 2021 11
S. H. Faderl et al. (eds.), Acute Leukemias, Hematologic Malignancies,
https://doi.org/10.1007/978-3-030-53633-6_2
