Wolfgang Hiddemann

Editor

Handbook of
Acute Leukemia
Editor
Wolfgang Hiddemann

Handbook of
Acute Leukemia
Editor
Wolfgang Hiddemann, MD, PhD
Department of Medicine III
University of Munich
Munich, Germany

Handbook of
Acute Leukemia
Editor Contributors
Wolfgang Hiddemann, MD, PhD Michael Fiegl, MD
Department of Medicine III Wolfgang Hiddemann, MD, PhD
University of Munich Klaus Metzeler, MD
Munich Karsten Spiekermann, MD
Germany Marion Subklewe, MD

ISBN 978-3-319-26770-8 ISBN 978-3-319-26772-2 (eBook)

DOI 10.1007/978-3-319-26772-2

© Springer International Publishing Switzerland 2016

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 Contents
Editor and author biographies vii
Abbreviationsxi

1 Introduction1
Wolfgang Hiddemann
Reference2

2 Epidemiology, pathogenesis, and etiology

of acute leukemia 3
Michael Fiegl
Epidemiology and incidence 3
Biology and pathogenesis of acute leukemia 4
Etiology of acute leukemia 7
References11

3 Clinical manifestations and diagnosis 15

Klaus Metzeler
Clinical presentation of acute leukemia 15
Diagnostic testing and criteria  16
Differential diagnosis 20
Additional work-up for patients with acute leukemias 21
References22

4 Diagnostic criteria, classification, and prognosis

of acute leukemias 25
Klaus Metzeler
Diagnostic criteria and classification of acute myeloid leukemia 25
Diagnostic criteria and classification of lymphoblastic leukemias 30
Diagnostic criteria and classification of acute leukemias of
ambiguous lineage  33
Prognostic factors in acute myeloid leukemia  34
Prognostic factors in acute lymphoblastic leukemia 37
References38

v
v i • CO N TE NTS

5 Therapeutic management of acute myeloid leukemia 41

Michael Fiegl
Overview of treatment options 41
Treatment by phase 41
Resistant and relapsed leukemia 47
Treatment of the medically unfit and elderly patient 48
References  49

6 Therapeutic management of acute

promyelocytic leukemia 53
Karsten Spiekermann
Overview of treatment options 53
Treatment by risk group and phase  54
References63

7 Therapeutic management of acute

lymphoblastic leukemia 65
Karsten Spiekermann
General approach for management of acute lymphoblastic leukemia 65
Prognostic factors and risk-adapted therapy 65
Clinical trials supporting current treatment algorithms in first-line therapy 66
Overview of treatment options 69
Treatment by phase  72
References74

8 Future outlook for acute leukemias 77

Marion Subklewe
Emerging therapies in acute leukemias 77
Molecular-targeted therapies 77
Allogeneic hematopoietic stem cell transplantation  79
Antibody-based immunotherapy for acute leukemia 82
Chimeric-antigen receptor T cells 86
Checkpoint inhibitors in acute leukemia 89
Conclusions and future outlook 90
References90
Editor and author biographies
Wolfgang Hiddemann, MD, PhD, is Professor of Medicine and Director
of the Department of Internal Medicine III at the University of Munich,
Germany. Dr Hiddemann is best known for his research on the patho-
genesis of acute leukemias, and clinical trials in acute leukemias and
malignant lymphomas. He is head of the German AML Cooperative Group
(AMLCG), the German Low Grade Lymphoma Study Group (GLSG), and
founding chairman of the European Mantle-Cell-Lymphoma Network.
He is an active member of the editorial boards of several international
journals and has been a member of the Steering Committees for the
German Society of Hematology and Oncology and the German Cancer
Aid. Dr Hiddemann has published nearly 600 scientific articles address-
ing various aspects of research in malignant lymphomas and acute leu-
kemias. He has been awarded honorary memberships of the Hungarian
Society of Hematology and Oncology and of the South African Society for
Hematology. He also received the Honorary Medal of the Polish Society
for Internal Medicine. In 2003, he was awarded the Charles Burpbacher
Lectureship in Zürich, Switzerland, and in the same year the Emil Frei
Leukemia Lectureship, Harvard University, Boston. He has also received
the Jacqueline Seroussi Foundation Scientific Award.

Michael A Fiegl, MD, is a hematologist and oncologist in the Department

of Internal Medicine III at the Klinikum der Universität München,
Germany. After attending medical schools in Berlin and Munich, Germany,
he completed his clinical training at Munich under the supervision of
Prof Dr Wolfgang Hiddemann. He then extended his scientific experi-
ence during his postdoctoral fellowship at the UT MD Anderson Cancer
Center in Houston, TX, USA under Prof Dr Michael Andreeff. His work
has primarily focused on acute myeloid leukemia (AML) both clinically
and scientifically ever since; besides basic research on AML and the

v ii
v iii • ED I TO R A ND AU TH O R B IO GR AP H IE S

bone marrow microenvironment, he has collaborated on several large

multicenter trials on AML.

Klaus Metzeler, MD, is a senior physician in the Department of Internal

Medicine, Hematology and Oncology at the University of Munich,
Germany. He completed his clinical training at the University of Munich
and studied leukemia genetics as a research fellow at The Ohio State
Comprehensive Cancer Center, Columbus, OH, USA. As a clinician-
scientist, his research is focused on developing novel diagnostic tools,
prognostic and predictive biomarkers, and ultimately more effective
treatment approaches for patients with myeloid neoplasia. Dr Metzeler
has co-authored over 50 scientific publications on myeloid leukemias.

Karsten Spiekermann, MD, is a hematologist and oncologist in the

Department of Internal Medicine III at the Klinikum der Universität
München, Germany. After attending medical school in Hannover,
Germany, he completed his clinical training in Göttingen and Munich
under the supervision of Prof Dr Wolfgang Hiddemann. He received
his postdoc education at the Manx-Planck Institute for Biochemistry in
Martinsried (Germany) under the supervision of Prof Dr Axel Ullrich.
The focus of his work was the pathogenesis, diagnostics, and treatment
­optimization of acute and chronic leukemias.

Marion Subklewe, MD, is an attending physician and Professor of Medicine

with a focus on immunotherapy at the Department of Hematology/
Oncology at the Ludwig-Maximilians-University Munich, Germany. She
is head of the diagnostic flow cytometry unit within the Laboratory of
Leukemia Diagnostics within the Department of Hematology/Oncology
and head of the clinical cooperation group ‘Immunotherapy’, Helmholtz
Zentrum Munich. Prof Subklewe’s interests center on translational medi-
cine. Several preclinical immunotherapeutic approaches were successfully
translated into early clinical trials focusing on T-cell recruiting vaccines
and antibody concepts. She is active in several clinical studies, serving
as principal investigator for clinical trials in acute myeloid leukemia
(AML) and acute lymphoblastic leukemia (ALL), and as an investigator
 E D ITO R AN D AU T H OR BI OGR APHI E S • i x

and steering committee member of the AML Cooperative Group. Prof

Subklewe is involved in the Bavarian Immunotherapy Network, the
Helmholtz Alliance for Immunotherapy, the interdisciplinary CRC 1243
in Cancer Evolution, the German Consortium for Translational Cancer
Research (DKTK), the international Graduate School ‘Immunotargeting of
Cancer’ and the Else-Kröner Forschungskolleg ‘Cancer Immunotherapy’.
Abbreviations
ACT Adoptive cellular therapy
ADC Antibody drug conjugate
AIDA ATRA plus idarubicin
AIDS Acquired immune deficiency syndrome
ALL Acute lymphocytic leukemia
AML Acute myeloid leukemia
AML-MRC AML with myelodysplasia-related changes
ANC Absolute neutrophil count
APL Acute promelocytic leukemia
AraC Anthracycline
ATO Arsenic trioxide
ATRA All-trans retinoic acid
BCP-ALL B-cell precursor ALL
BID Twice daily
BiTE Bispecific T-cell engager
BM Bone marrow
CALGB Cancer and Leukemia Group B
CARTs Chimeric antigen receptor T cells
CBF Core binding factor
CCI Charlson Comorbidity index
CI Continuous infusion
CIR Cumulative incidence of relapse
CML Chronic myeloid leukemia
CML-BP CML in blast phase
CMML Chronic myelomonocytic leukemia
CNS Central nervous system
CR Complete response/remission
CSF Cerebrospinal fluid
CT Computed tomography
CTLA-4 Cytotoxic T lymphocyte-associated antigen 4
DA Daunorubicin
DART Dual affinity retargeting molecule
xI
xii • ABB R E V I ATI O N S

DFS Disease-free survival

DLT Dose limiting toxicity
DIC Disseminated intravascular coagulation
DIPPS Dynamic international prognostic scoring system
EBV Epstein-Barr virus
ECG Echocardiogram
ECOG Eastern Cooperative Oncology Group
EFS Event-free survival
EGIL European Group for the Immunological Characterization
of Leukemias
ELN European LeukemiaNet
EMA European Medicines Agency
ET Essential thrombocytopenia
ETP-ALL ‘Early’ T-cell ALL
EWALL European Working Group for Adult ALL
FBM Fludarabine, BCNU, and melphalane
FISH Fluorescence in situ hybridization
FLA Fludarabine and cytarabine
FLAG-Ida Fludarabine, cytarabine, idarubicin, and granulocyte-
colony stimulating factor
FLAMSA-RIC Fludarabine, Ara-C, and amsacrin
FLT3 Fms-like tyrosine kinase 3
F-SHAI Fludarabine, sequential high-dose cytarabine,
and idarubicin
G-CSF Granulocyte-colony stimulating factor
GIST Gastrointestinal stromal tumors
GMALL German Multicenter Study Group for ALL
HCT-CI Hematopoietic Cell Transplantation Comorbidity Index
HiDAC High-dose cytarabine
HIV-1 Human immunodeficiency virus 1
HLA-DR Human leukocyte antigen-DR
HSCT Hematpoietic stem cell transplant
HTLV-I Human T-lymphotropic virus type I
HU Hydroxyurea
iAMP21 Intrachromosomal amplification of chromosome 21
 ABBRE VIATIONS • x iii

ICE Ifosfamide, carboplatin, etopside

IDH Isocitrate dehydrogenase
IL-2 Interleukin 2
IPSS International prognostic scoring system
ITD Internal tandem duplication
IV Intravenous
LAA Leukemia-associated antigen
LBL Lymphoblastic lymphoma/leukemia
LIC Leukemia-initiating cells
MAC Mitoxantrone and cytarabine/myeloablative conditioning
MDACC MD Anderson Cancer Center
MDS Myelodysplastic syndrome
MFC Multiparameter flow cytometry
MLL Mixed lineage leukemia
MPAL Mixed phenotype acute leukemia
MPN Myeloproliferative neoplasm
MRC Medical Research Council
MRD Minimal residual disease
MRI Magnetic resonance imaging
mTOR Mechanistic target of rapamycin
MTX Methotrexate
MUD Matched unrelated donor
NCCN National Comprehensive Cancer Network
NK Natural killer
NOS Not otherwise specified
ORR Overall response rate
OS Overall survival
PB Peripheral blood
PCR Polymerase chain reaction
PD-1 Programmed cell death 1
PI3K Phosphoinositide 3 kinase
PMF Primary myelofibrosis
PML-RARα Promyelocytic leukemia–retinoic acid receptor α
PNH Paroxysmal nocturnal hemoglobinuria
PO Orally
xiv • AB B R E V I ATI O N S

PV Polycythemia vera
RAEB Refractory anemia with excess blasts
RAR Retinoic acid receptor
RIC Reduced intensity conditioning
r/r Relapsed/refractory
RT-PCR Reverse transcription polymerase chain reaction.
sAML Secondary AML
S-HAM Sequential high-dose cytarabine, mitoxantrone,
and pegfilgrastim
SKCC Sidney Kimmel Comprehensive Cancer Center
tAML Therapy-related AML
TAD-9 6-thioguanine, cytarabine, and daunorubicin
TCR T-cell receptor
TKI Tyrosine kinase inhibitor
TRM Transplant-related mortality
WBC White blood cell
WES Whole-exome sequencing
WGS Whole-genome sequencing
WHO World Health Organization
 Chapter 1

Introduction
Wolfgang Hiddemann

Acute leukemias are imminently life threatening disorders, which require

a quick and precise diagnostic work-up to select the most appropriate
therapeutic approach. Acute and chronic leukemias both arise from the
malignant transformation of hematopoietic stem cells. According to
the lineage from which this process originates myeloid and lymphoid
leukemias are discriminated. The discrimination between acute and
chronic leukemias is based on their clinical course and their biologic and
morphologic characteristics. While acute leukemias are highly prolifera-
tive disorders with a rapid progression and symptoms of hematopoietic
insufficiency, chronic leukemias have a more indolent clinical course
with a late onset of clinical symptoms and morphologically partially
maintained differentiation potential (Table 1.1).
The diagnostic work-up for the discrimination between the dif-
ferent types of leukemias is based on morphology, immunophenotyp-
ing, cytogenetics, and sometimes molecular analyses (for details see
Chapters 3 and 4). For acute myeloid leukemias in particular myelodys-
plastic syndromes and myeloproliferative disorders need to be considered
for differential diagnosis

Ó Springer International Publishing Switzerland 2016 1

W. Hiddemann (ed.), Handbook of Acute Leukemia,
DOI 10.1007/978-3-319-26772-2_1
2 • HAN D B O O K O F AC U TE LE U K E M IA

Acute Leukemias Chronic Leukemias

Proliferation High Low
Morphologic differentiation Lacking Partially maintained
Clinical course Rapidly progressive Indolent

Table 1.1 Basic characteristics of acute and chronic leukemias.

Reference
1 Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic
and Lymphoid Tissues. 4th edn. Lyon, France: IARC; 2008.
 Chapter 2

Epidemiology, pathogenesis,
and etiology of acute leukemia
Michael Fiegl

Epidemiology and incidence

Acute myeloid (AML) and acute lymphocytic leukemia (ALL) are rare
diseases, accounting for approximately 1.3% and 0.4% of all new cancer
cases in the US. While the overall incidence of leukemia has been stable
since 1975 (13 new cases/ 100,000 in 1975 and 14 new cases/ 100,000
in 2012) [1], the rates for new AML and ALL cases have been rising on
average by 2.2% and 0.6%, respectively over the last decade [2,3].

International and US statistics

The annual number of new cases/100,000 was 1.7 for ALL and 4.0 for
AML in the US [2,3], and similar rates are observed in other industrialized
countries such as Germany with 5.2 new AML cases and 1.6 ALL cases in
2010 [4], and UK with 4.5 AML cases and 1.0 ALL cases [5,6]. In other
words, in these three countries AML and ALL account for approximately
35,000 new cancer cases per year. With an estimated 5-year survival
rate of 25.9% for AML and 67.5% for ALL [2,3], these diseases were
responsible for approximately 12,000 deaths in 2015 in the US alone.

Ó Springer International Publishing Switzerland 2016 3

W. Hiddemann (ed.), Handbook of Acute Leukemia,
DOI 10.1007/978-3-319-26772-2_2
4 • HAN D B O O K O F AC U TE LE U K E M IA

Age, sex, and ethnicity-related differences

Both forms of acute leukemia are strongly related to age, but in an inverse
manner. While ALL has its peak in childhood, AML is more common in
the elderly (Figure 2.1). Accordingly, the median age at diagnosis for
AML is 67 years and 14 years for ALL [2,3].
There is a predilection for men with AML (4.8 versus 3.3 new cases)
while in ALL, there is no gender difference (1.9 new cases in men and
1.5 in women) [2,3]. Caucasians have the highest incidence of AML
while persons descending from native North Americans have the lowest
incidence. For ALL, people of Hispanic origin have the highest incidence
while the lowest is found in people of color [2,3].

Biology and pathogenesis of acute leukemia

Both myeloid and lymphocytic acute leukemia arise from genetic lesions in
hematopoietic progenitor cells. The lineage of the progenitor, in which the
lesion occurs, determines the type of leukemia (lymphoid versus myeloid),
but there is less security about the exact lineage-specific progenitor cells

60

50 ALL
Percentage of new cases

AML
40

30

20

10

0
<20 20–34 35–44 45–54 55–64 65–74 75–84 >84
Age

Figure 2.1 Age-related incidence of acute leukemias. Acute lymphocytic leukemia has its peak
incidence in childhood, while acute myeloid leukemia is a disease mainly of the older age. ALL, acute
lymphoblastic leukemia; AML, acute myeloid leukemia. Adapted from © National Cancer Institute,
2016. All rights reserved. National Cancer Institute, SEER [2,3].
 EPIDEMIOLOGY, PATHOGENESIS, AND E TIOLOGY OF ACUTE LEUKEMIA • 5

that are affected. Generally, these transformed cells are termed leukemia-
initiating cells (LIC) but they do not necessarily comprise hematopoietic
stem cells. These LICs represent a small minority within the whole leu-
kemic cell population; both have the ability of self-renewal and modest
differentiation (for example, as reviewed in reference [7]). They can be
identified by functional characteristics (ie, repopulating potential in mice)
and phenotyping of cell surface markers (for example, CD34, CD38, and
human leukocyte antigen-DR [HLA-DR]). The leukemic bulk instead,
forming the majority of tumor burden, does not have stem cell qualities
and hence has no ability to engraft in mice or cause relapse. However,
this bulk is responsible for the symptoms of the diseases: overgrowth of
the bone marrow with depletion of healthy progenitors and consecutive
hematopoietic insufficiency with (pan-)cytopenia and occasional hyper-
leukocytosis in the peripheral blood, resulting in organ ischemia due to
‘white clots’ comprising leukemic blasts and subsequently organ failure.
The genetic lesions that cause the malignant transformation are less
well understood. The identification and unraveling of the functional con-
sequences of the translocation (15;17) in acute promyelocytic leukemia
(APL) has sparked the hope that for other forms of acute leukemia, espe-
cially those with recurrent aberrations such as AML with t(8;21) or ALL
with t(9;22), similar genetic lesions could be identified that explain the
pathophysiology of the disease and may be targeted by specific therapies.
In APL, a balanced translocation between chromosomes 15 and 17 leads
to a fusion gene called promyelocytic leukemia–retinoic acid receptor α
(PML–RARα) gene [8]. The resulting protein comprises a transcription
factor that is fused to co-repressors of transcription. As a consequence,
affected cells are unable to differentiate into neutrophil granulocytes
and remain at the stage of promyelocytes. The systemic administration
of high doses of retinoic acid binds the RAR part of the fusion protein,
leading to conformational changes with dispensation of the co-repressors,
thus re-establishing transcription and differentiation [9].
However, for most cases of AML one single genetic defect is not suf-
ficient for leukemic progression; instead a series of genetic events is
required. These events target genes that are involved in different cellular
processes, for examples mutations in Fms-like tyrosine kinase 3 (FLT3),
6 • HAN D B O O K O F AC U TE LE U K E M IA

K-RAS, or c-kit [10], and are supposed to confer a proliferative advantage,

while other mutations, for example in CEBPA [11], impair hematopoietic
differentiation. However, further mutations have been identified that
affect genes involved in epigenetic regulation (IDH, DNMT3A, or ASXL1
in myelodysplastic syndrome [MDS]-related AML [12]). On average,
13 genes are mutated in AML, only 5 of which are recurrent and these
mutated genes can be allocated to one of 9 groups associated with certain
biological features (fusion genes, myeloid transcription factors, tumor
suppressors, spliceosome, DNA modification, NPM1, chromatin modi-
fiers, cohesins, and signal transduction) [13].
Similarly, in ALL genetic lesions can be found in the vast majority
of cases [14]. Best known is the translocation (9;22)(q34;q11.2), which
occurs in approximately 15–25% of patients (Ph+ ALL) [14]. This trans-
location results in the creation of the fusion gene BCR-ABL1 and confers
a bad prognosis. Recently another form of ALL has been identified, which
displays a gene expression profile similar to that of Ph+ ALL but without
the aforementioned translocation and hence without BCR-ABL1 [15,16].
This type of ALL is characterized by a bad prognosis similar to Ph+
ALL and was therefore named Ph-like ALL [16]. Genetic characteriza-
tion has identified deletions in transcription factors relevant for B-cell
development (eg, IKZF1, EBF1, and VPREB1) in more than 80% of cases,
but kinase-activating alterations were also regularly found, for example
involving, among others, ABL1, EPOR, CSF1R, or PDGFRB to name a few
(as reviewed in reference [17]). In general, these alterations result in, as
with BCR-ABL1, an activation of intracellular downstream signaling via
Janus kinases (JAK; further enhanced by occasional activating mutations
in JAK1 or 2), which in turn lead to cytokine-independent proliferation via
activation of signal transducer and activator of transcription 5 [STAT5].
In hypodiploid ALL, distinct genetic lesions have been identified that
differ with respect to the severity of aneuploidy [18]: while near-haploid
ALL (24–31 chromosomes) have aquired mutations in receptor tyrosine
kinases, Ras and IKZF3, low-hyplodiploid ALL (32–39 chromosomes) have
a high frequency of TP53 mutations. Both subtypes show a high activa-
tion of Ras and PI3K, which results in the activation of pro-survival and
anti-apoptotic pathways and offers targets for therapeutic intervention.
 EPIDEMIOLOGY, PATHOGENESIS, AND E TIOLOGY OF ACUTE LEUKEMIA• 7

Etiology of acute leukemia

Even though the exact genetic malfunctions in the hematopoietic stem
cells that result in malignant transformation are not exactly understood,
several risk factors for the development of acute leukemia have been
identified. However, the majority of patients with acute leukemia do not
meet any of these conditions.

Exposure to ionizing radiation

Ionizing radiation can result in DNA mutations, deletions or transloca-
tions by inducing double strand breaks in hematopoietic stem cells in a
dose-dependent manner. The leukemogenic effect of ionizing radiation
has long been identified, mainly because of the increased incidence of
both AML and ALL in atomic bomb survivors [19] and radiologists that
were exposed to high levels of radiation [20]. Similarly, radiation used in
the treatment of cancers has been made responsible for the ­development
of acute leukemia [21].

Exposure to benzene
Exposure to benzenes has been known to increase the risk for the devel-
opment of AML and MDS for several decades [22]. There seems to be a
dose dependency, with lower levels of benzene increasing the risk for
MDS but not for AML [23], but no definite threshold has been defined that
can be considered safe. There is also an association with development of
ALL [24], and in many countries, acute leukemia resulting after benzene
exposition during work has been recognized as an occupational disease.

Way of living
Besides exposure to chemicals, the way of living can affect the risk for the
development of AML and ALL. While the pathophysiological mechanisms
are unknown, it has been shown that being overweight [25] and also
smoking increases the risk for acute leukemia [26,27]. There is no clear
evidence for the role of alcohol intake in adult AML or ALL [28,29], but
parental alcohol consumption might increase the risk for the d
­ evelopment
of childhood leukemia [30,31].
7
8 • HAN D B O O K O F AC U TE LE U K E M IA

Genetic conditions
There are several genetic disorders that have predominantly systemic
manifestations but are also associated with the development of acute
leukemia such as Down syndrome [32] and Li Fraumeni syndrome [33].
In addition, inherited bone marrow failure syndromes such as Fanconi
anemia and Shwachman-Diamond syndrome pose a predisposition for
the development of myeloid neoplasias and acute leukemia [33]. Rare
forms of familial acute leukemia also exist, in which certain genes are
affected and the families display minor or sometimes no prior hemat-
opoietic abnormalities. In some of these cases, genes are involved that
have been associated with de novo AML (for example, RUNX1, CEBPA,
ETV6, and TERT) but there are also genes that predispose a person to
ALL (for example, SH2B3 and PAX5) [34].

Preceding blood and marrow disorders: secondary acute

myeloid leukemia
Malignant, but also several non-malignant, myeloid disorders increase the
risk for the development of AML, which is then called a secondary AML
(sAML). Best known is AML secondary to MDS, and the World Health
Organization (WHO) classification recognizes AML with myelodysplasia-
related changes as a distinct entity [35]. MDS is a highly diverse group
of diseases, and the risk of developing AML varies significantly between
the different subgroups. In general, the risk of MDS can be assessed by
the morphological subtype (where forms with an increase in blast counts
RAEB-1 (5–9%) and RAEB-2 (10–19%) have the lowest survival [36]),
but is more accurately reflected by the revised international prognos-
tic scoring system (IPSS-R [37]), which takes into account cytopenias,
blast count, and cytogenetics (Table 2.1). With this score, it is possible
to estimate the survival probability and to identify groups at a very
high risk for transformation into AML (for example, in the group of very
high risk patients 25% will develop AML within 0.7 years [37]). Other
myeloid neoplasias that pose a risk for transformation into AML include
essential thrombocytopenia (ET), polycythemia vera (PV), and primary
myelofibrosis (PMF). Chronic myeloid leukemia (CML) in blast crisis,
although resembling AML, represents a different entity. The risk for the
 EPIDEMIOLOGY, PATHOGENESIS, AND E TIOLOGY OF ACUTE LEUKEMIA • 9

Prognostic 0 0.5 1 1.5 2 3 4

variable
Cytogenetics Very Good Inter- Poor Very
good mediate poor
Bone marrow ≤2 >2–<5 5-10 >10
blasts (%)
Hemoglobin ≥10 8–<10 <8
Platelets ≥100 50–<100 <50
ANC ≥0.8 <0.8

Table 2.1 The International prognostic scoring system (IPSS-R) for assessment of individual
risk in patients with myelodysplastic syndromes. For each applicable feature, the appropriate
points are given, which add up the respective risk category (very low ≤1.5, low >1.5–3, intermediate
>3–4.5, high >4.5–6, and very high >6). ANC, absolute neutrophil count. Reproduced with
permission from © American Society of Hematology, 2012. All rights reserved. Greenberg et al [37].

development of AML in the aforementioned myeloproliferative diseases

is approximately 5% [38], but patients at risk cannot be adequately iden-
tified, as scoring systems (for example, the dynamic international prog-
nostic scoring system [DIPPS] in PMF) estimate survival in general [39].
Non-malignant diseases can increase the risk for the development of
acute leukemia, but the reasons for this are unclear. Among the most
common of such diseases are paroxysmal nocturnal hemoglobinuria (PNH
[40]) and severe aplastic anemia [41]. However, most patients with these
diseases suffer from complications other than the development of acute
leukemia but this might change with the advent of more potent treat-
ments (for example, eculizumab for PNH), which will increase survival
by the reduction of non-malignant complications (such as thrombosis)
but with an unknown effect on the development of sAML.

Prior chemotherapy
While there is no clear evidence that ALL may arise as a consequence
of preceding chemotherapy for other cancers, the risk of AML is clearly
increased in patients who received chemotherapeutic treatment, for
example for breast cancer [42] and Hodgkin lymphoma [43], usually
within 3–5 years. As such, cytotoxic agents commonly used in the treat-
ment of malignant diseases have been implicated with therapy-related
AML (t-AML), especially alkylating agents (for example, melphalan, busul-
fan, cyclophosphamide, and carbo- and cisplatin) and topoisomerase II
10 • HAN D B O O K O F AC U TE L E U K E M IA

inhibitors (for example, etoposide and doxorubicin) [44]. The majority

of t-AML represents with chromosomal abnormalities, which are often
unfavorable (for example, complex aberrant 26.9% versus 11.3% in de
novo AML [45]) and after topoisomerase II inhibitor treatment muta-
tions involving the MLL gene (11q23) are frequently observed [46]. This
later form usually develops much quicker (within 1–2 years after initial
­treatment). The WHO recognizes t-AML as a distinct entity [44].
Granulocyte colony-stimulating factor (G-CSF), given as an adjunct
in patients receiving chemotherapy or to stimulate expulsion of stem
cells into the peripheral blood for harvesting for either autologous or
allogeneic stem cell transplantation, may result in an increased risk
of AML and MDS. One large meta-analysis [47] found that in patients
treated with chemotherapy, the application of G-CSF increased the risk
of development of AML or MDS from 0.4% to 1.9%, however the general
mortality in this group declined by 3.4%.

Autoimmune conditions
Patients with autoimmune disorders (for example, rheumatoid arthritis)
receiving immunosuppressants have an increased risk for the development
of MDS or AML, similarly to t-AML. However, as doses of immunosup-
pressants including chemotherapy (methotrexate [MTX] and cyclophos-
phamide) are lower in these patients, the risk of therapy-related myeloid
neoplasias is also lower.

Viruses
For AML, there is no evidence for viral infection in the pathogenesis. In
certain subsets of acute lymphocytic leukemia, viral infections have been
associated with the pathogenesis, for example of adult T-cell leukemia-
lymphoma (caused by the human T-lymphotropic virus type I (HTLV-I)
[48]) and Burkitt lymphoma/leukemia, which is associated with Epstein-
Barr virus (EBV) but also with immunosuppression (for example, acquired
immune deficiency syndrome [AIDS]) and co-infection with malaria (see
review in reference [49]).
 EPIDEMIOLOGY, PATHOGENESIS, AND E TIOLOGY OF ACUTE LEUKEMIA • 11

References
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 Chapter 3

Clinical manifestations
and diagnosis
Klaus Metzeler

Clinical presentation of acute leukemia

Presenting symptoms in patients with acute leukemia are highly variable
(Table 3.1) but most are caused by hematopoietic insufficiency. Typically,
the onset of symptoms is acute, within weeks to a few months before
diagnosis, except in those patients who develop leukemia secondary to
a pre-existing hematologic disease such as myelodysplastic syndromes
(MDS) or myeloproliferative neoplasms. Infiltration of extramedullary
organs by leukemic blasts is found in 2.5–9% of acute myeloid leukemia
(AML) patients. Lymphadenopathy and/or hepatosplenomegaly are present
in up to 50% of patients with acute lymphoblastic leukemia (ALL), and
patients with T-lineage ALL frequently present with a mediastinal mass.
Involvement of the central nervous system (CNS), most commonly mani-
festing in the cerebrospinal fluid (CSF), is detectable in <5% of adults
with AML and in ~5% of adults with ALL at the time of initial diagnosis
[1]. Fever is one of the most common presenting symptoms in patients
with acute leukemias. Fever should always be interpreted as a sign of
infection, and should prompt a careful search for infectious foci. Rapid
initiation of empirical, broad-spectrum antibiotic coverage is usually
indicated in febrile patients. Fever as a direct manifestation of leukemia
without coexisting infection is rare.

Ó Springer International Publishing Switzerland 2016 15

W. Hiddemann (ed.), Handbook of Acute Leukemia,
DOI 10.1007/978-3-319-26772-2_3
16 • HAN D B O O K O F AC U TE L E U K E M IA

Diagnostic testing and criteria

Recommended diagnostic testing for patients with a suspected diagnosis
of acute leukemia is summarized in Table 3.2 [2–4].

Morphology
Microscopic evaluation of peripheral blood (PB) and bone marrow (BM)
smears remains the critical first step in the diagnostic work-up of patients
with suspected acute leukemia. A differential count of at least 500 BM
cells is recommended, and a diagnosis of AML is usually based on the
morphologic finding of ≥20% myeloid blasts (see page 25). In contrast,

Signs and symptoms of bone marrow infiltration and hematopoietic insufficiency

•• Neutropenia: fever, localized infection (eg, upper respiratory infection, pneumonia), sepsis
•• Anemia: fatigue, pallor, dyspnea on exertion, tachycardia
•• Thrombocytopenia: petechia, mucosal bleeding, spontaneous bruising, menorrhagia,
intracranial or intraocular bleeding
•• Bone pain (especially in childhood ALL)
Leukemic infiltration of extramedullary tissues
•• CNS: headache, somnolence, confusion, focal neurologic deficits
•• Testicular involvement (more common in ALL)
•• Hepatosplenomegaly (more common in ALL)
•• Lymphadenopathy (more common in ALL)
•• Mediastinal mass (T-ALL)
•• Gum hypertrophy (more common in AML M4, M5)
•• Leukemia cutis
•• Soft tissue infiltration
•• Arthralgias or arthritis
Symptoms due to hyperleukocytosis and leukostasis
•• CNS: lethargy, somnolence, confusion, ischemic stroke
•• Pulmonary involvement: pulmonary infiltrates, respiratory insufficiency
•• Myocardial ischemia
Constitutional symptoms
•• Fever
•• Night sweats
•• Weight loss
•• Fatigue
Coagulation abnormalities
•• Disseminated intravascular coagulation
Spontaneous tumor lysis syndrome (rare before initiation of therapy)
•• Hyperuricemia, renal failure
•• Hyperkalemia, hyperphosphatemia, hypocalcemia

Table 3.1 Presenting signs and symptoms in patients with acute leukemias. ALL, acute
lymphoblastic leukemia; AML, acute myeloid leukemia; CNS, central nervous system.
 CLINICAL MANIFESTATIONS AND DIAGNOSIS • 17

there is no strict threshold for the blast count in ALL, and the diagnosis
cannot be made based on morphology alone (see page 30).
If there is any degree of suspicion of APL based on cytomorphology
(such as the presence of Faggott cells) or clinical features (for example,
prominent coagulopathy or disseminated intravascular coagulation
[DIC]), patients should be immediately referred to a center capable of
rapid genetic testing using fluorescence in situ hybridization (FISH) or
Diagnostic test Recommendation
Complete blood count with differential count Mandatory
Bone marrow aspiration: Mandatory
•• Morphological evaluation of May-Grünwald-Giemsa-,
Wright-Giemsa- or Pappenheim-stained slides
•• Myeloperoxidase and non-specific esterase stains
•• Iron staining in cases with multilineage dysplasia
Bone marrow core biopsy: Recommended/mandatory in
•• Morphological evaluation (H&E stain) patients with a dry tap
•• Immunohistochemistry
Flow cytometry: Mandatory
•• Can be performed on bone marrow or blood
Cytogenetics: Mandatory
•• Karyotyping of G-banded metaphase chromosomes
Genetics (AML):
•• Rapid testing for PML-RARA by FISH or PCR Mandatory if APL suspected
•• Testing for NPM1, FLT3, and CEBPA gene mutations Mandatory in patients with normal
cytogenetics
•• Testing for KIT gene mutations Recommended in patients with
CBF leukemias
•• Other molecular markers Optional

Genetics (ALL):
•• Testing for BCR-ABL1 rearrangement by FISH and/or PCR Mandatory
•• Testing for clonal rearrangement of immunoglobulin Recommended for later MRD
or TCR genes monitoring
•• Assessment for hypo-/hyperdiploidy by flow cytometry Optional

Lumbar puncture ALL: Mandatory

AML: Optional / mandatory in
patients with clinical symptoms
suspicious of CNS involvement
Biobanking of pretreatment bone marrow and / or blood Recommended

Table 3.2 Recommended diagnostic tests for patients with acute leukemias. ALL, acute
lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; CBF,
core binding factor; CNS, central nervous system; FISH, fluorescence in situ hybridization; MRD,
minimal residual disease; PCR, polymerase chain reaction; TCR, T-cell receptor.
18 • HAN D B O O K O F AC U TE L E U K E M IA

polymerase chain reaction (PCR). All-trans retinoic acid (ATRA) treat-

ment should be initiated without delay and before genetic confirmation
is obtained. In patients with suspected APL who test negative for PML-
RARA, cryptic rearrangements that may be undetectable by standard
methods, as well as RARA fusions with other partner genes (ZBTB16-
RARA, NUMA1-RARA, NPM1-RARA, and others) need to be considered.
In these cases, ATRA therapy should be continued while awaiting the
results of cytogenetics and specialized molecular testing.

Immunophenotyping
Multiparameter flow cytometry (MFC) is a mandatory part of the diag-
nostic work-up for all acute leukemias. MFC analysis and interpretation
should follow standardized protocols such as those recommended by the
European LeukemiaNet [5]. Specifically, MFC is required to establish a
diagnosis of minimally differentiated (M0) AML, megakaryoblastic (M7)
AML, ALL, or acute leukemia of ambiguous lineage (see Chapter 4 for
diagnostic criteria). Leukemia-associated immunophenotypes (LAIPs)
identified at the time of initial diagnosis can be used for minimal residual
disease monitoring later on. Flow cytometry can contribute to the diag-
nosis of APL, which typically shows a CD33-bright, CD34-negative, and
HLA-DR-negative phenotype, and high side scatter, however MFC is only
an adjunct to morphology and genetic testing in this setting. The blast
percentage as determined by MFC should not be used as a substitute for
the morphological blast count, or to differentiate AML from MDS [2,3].

Cytogenetics and molecular testing

Cytogenetic evaluation is a mandatory component in the work-up of acute
leukemias. Specific cytogenetic alterations can establish a diagnosis of
AML or contribute to the sub-classification of AML, ALL, or ambiguous
lineage leukemias (see Chapter 4). Metaphase karyotyping allows the
detection of chromosomal alterations without prior knowledge of the
involved chromosomes or loci. At least 20 metaphases should be evalu-
ated. Metaphase karyotyping is labor intensive, requires high expertise
for specimen preparation and interpretation, and is unsuccessful in
5–10% of patients for various reasons [6]. Newer techniques for the
 CLINICAL MANIFESTATIONS AND DIAGNOSIS • 19

detection of larger chromosomal alterations based on microarrays or

whole-exome or whole-genome sequencing (WES/WGS) are used in a
research setting, but cannot replace standard metaphase cytogenetics
in clinical practice yet.
FISH can be used to detect specific numeric or structural chromo-
somal alterations. FISH is most commonly used to rapidly screen for
therapeutically relevant translocations such as PML-RARA in patients
with suspected APL and BCR-ABL1 in patients with ALL.
On the molecular scale, advances in genetics led to the discovery of
recurrent mutations in >100 different genes in AML [7]. At least one
genetic ‘driver’ event can now be identified in >99% of patients with
AML using WES or WGS, including transcription factor fusions (~18% of
patients) and mutations affecting NPM1 (27%), tumor suppressor genes
(16%), genes involved in DNA methylation (44%), growth factor signaling
(59%), chromatin modifiers (30%), myeloid transcription factors (22%),
the cohesin complex (13%), and the spliceosome complex (14%). These
new insights will change the approach to diagnosis and classification of
AML in the future [8]. However, only a relatively limited number of gene
mutations have been convincingly shown to be relevant for prognosis,
and even fewer mutations have been incorporated into widely accepted
and validated classification algorithms [9].
At the moment, testing for NPM1 mutations, Fms-like tyrosine kinase
3 (FLT3) internal tandem duplication (ITD), and biallelic CEBPA muta-
tions should be considered as the minimum requirement for molecular
genetic testing particularly in patients with normal cytogenetics, since
these markers are recognized in the European LeukemiaNet classification
[10]. For patients with FLT3-ITD, the mutant-to-wild type ratio should
be reported. In patients with core binding factor (CBF) leukemias, that
is, t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22), KIT muta-
tion testing is recommended because of its prognostic relevance. Testing
for additional gene mutations should be considered optional in current
routine practice, since the therapeutic implications of these markers are
unclear. This may change with the availability of novel, targeted treat-
ment approaches, such as inhibitors of the mutated IDH1 or IDH2 proteins
found in up to 30% of AML.
20 • HAN D B O O K O F AC U TE L E U K E M IA

Lumbar puncture
Cerebrospinal fluid (CSF) involvement is relatively rare in adult AML,
and therefore diagnostic lumbar puncture is generally recommended
only in patients presenting with neurologic symptoms such as lethargy,
confusion, or focal neurological defects. Imaging of the CNS should be
performed before lumbar puncture in these cases to rule out elevated
intracranial pressure. In contrast, CNS relapses are common in ALL even
in the absence of initial overt CSF involvement, unless CNS-directed
therapy is given. Therefore, lumbar puncture is considered mandatory
for ALL patients, with intrathecal chemotherapy applied according to
treatment protocols. In patients presenting with high peripheral blast
counts (for example, white blood cell [WBC] count >20,000/µl) without
CNS symptoms, it is prudent to delay lumbar puncture until the blast
count has declined. Evaluation of CSF by flow cytometry may increase
the sensitivity compared with morphology alone [11].

Differential diagnosis
The diagnosis of acute leukemia is rarely missed in patients presenting
with leukocytosis or unexplained cytopenias, if the previously mentioned
diagnostic tests are performed. However, in some cases, the differen-
tial diagnosis between acute leukemias and related disorders may be
challenging. Immunophenotyping is required to distinguish AML with
minimal differentiation (AML M0), megakaryoblastic (M7) AML, mixed
phenotype acute leukemia (MPAL), and acute lymphoblastic leukemia.
Some patients with MDS (refractory anemia with excess blasts [RAEB])
or chronic myelomonocytic leukemia (CMML) present with blast counts
close to 20% that place them on the borderline between these conditions
and AML. These cases can usually be classified by strict adherence to
the World Health Organization (WHO) criteria, although most of these
patients quickly progress to full-blown AML. The blast phase (BP) of
chronic myeloid leukemia (CML) is morphologically indistinguishable
from an acute leukemia. In patients without a known history of CML,
prominent splenomegaly may hint towards CML in blast phase (CML-BP).
Most CML-BP patients express the p210 BCR-ABL fusion transcript, but
there are also rare cases of de novo AML with this translocation [12].
 CLINICAL MANIFESTATIONS AND DIAGNOSIS • 21

In contrast, the p190 isoform occurs in about 50% of BCR-ABL-positive

ALL but is rare in CML including lymphoid BP.

Additional work-up for patients with acute

leukemias
Recommended pretreatment work-up
Once a diagnosis of acute leukemia has been established, additional
work-up is necessary to detect potential complications such as infections
and to assess coexisting conditions that may affect a patient’s fitness for
intensive chemotherapy (Table 3.3).

Medical history, physical exam, including:

•• Performance status (ECOG/Karnofsky Performance score)
•• Analysis of comorbidities
•• ALL patients: testicular exam
Laboratory work-up:
•• Chemistry: glucose, sodium, potassium, calcium, phosphate, creatinine, urea, uric
acid, lactate dehydrogenase, aspartate amino transferase, alanine amino transferase,
alkaline phosphatase, bilirubin, total protein, total cholesterol, total triglycerides, and
creatinine phosphokinase
•• Coagulation tests: d-dimer, fibrinogen, prothrombin time, and partial thromboplastin time
•• Urine analysis: pH, glucose, erythrocytes, leukocytes, protein, and nitrite
Human leukocyte antigen typing of patient and siblings:
•• Except for patients with a major permanent contraindication against hematopoietic cell
transplant. In high-risk patients, consider early alternative donor search
Active screen for infections, even in afebrile patients:
•• Clinical signs and symptoms of infection can be subtle in neutropenic patients
Hepatitis A, B, C; HIV-1 testing
Echocardiogram or cardiac scan:
•• Recommended in all patients, mandatory before therapy in patients with
preexisting cardiac disease, symptoms suggestive of cardiac dysfunction, or prior
anthracycline exposure
12-lead ECG, chest X-ray (recommended)
Consider counseling on fertility protection (eg, sperm or oocyte cryopreservation)
Premenopausal women: serum pregnancy test
Patients with neurological symptoms: CT/MRI of head
Patients with T-cell ALL: chest CT
Table 3.3 Recommended work-up for patients with newly diagnosed acute leukemia.
ALL, acute lymphoblastic leukemia; CT, computed tomography; ECG, echocardiogram; ECOG,
Eastern Cooperative Oncology Group; HIV-1, human immunodeficiency virus 1; MRI, magnetic
resonance imaging.
22 • HAN D B O O K O F AC U TE L E U K E M IA

Special considerations in older patients

The majority of AML patients are older than 65 years, and elderly patients
experience higher rates of complications from intensive chemotherapy,
higher treatment-related mortality, and shorter survival. However,
chronologic age alone is a poor surrogate for both disease-related and
patient-related risk factors. A thorough evaluation of the performance
status, by using the Eastern Cooperative Oncology Group (ECOG) scale
or the Karnofsky Performance Score, and an assessment of comorbidities
using a standardized tool, such as the Charlson Comorbidity index (CCI)
or the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI;
www.hctci.org), are strongly recommended [12]. A comprehensive geri-
atric assessment including physical, cognitive, and psycho-social factors
may be helpful for treatment decisions, yet a validated and generally
accepted approach is lacking.

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13 McGregor S, McNeer J, Gurbuxani S. Beyond the 2008 World Health Organization
classification: the role of the hematopathology laboratory in the diagnosis and management
of acute lymphoblastic leukemia. Semin Diagn Pathol. 2012;29:2-11.
 Chapter 4

Diagnostic criteria, classification,

and prognosis of acute leukemias
Klaus Metzeler

The currently accepted classification of acute leukemias was published in

2008 as part of the 4th edition of the World Health Organization (WHO)
classification of tumors of hematopoietic and lymphoid tissues [1]. A revi-
sion has recently been published [2]. The aim of the WHO classification
is to define distinct, non-overlapping, and reproducible entities based on
clinical features, morphology, immunophenotype, and genetic informa-
tion. It is important to note that the WHO system is aimed at assigning
mutually exclusive diagnostic categories, and not primarily intended for
risk stratification or treatment selection. Thus, additional classification
systems are useful in clinical practice.

Diagnostic criteria and classification of acute

myeloid leukemia
The diagnosis of acute myeloid leukemia (AML) is usually based on the
presence of ≥20% myeloid blasts in the blood or bone marrow. In rare
cases, the detection of specific chromosomal rearrangements allows a
diagnosis of AML in patients with lower blast counts. Table 4.1 ­summarizes
the 2016 revision of the WHO classification of AML [1,2].

Ó Springer International Publishing Switzerland 2016 25

W. Hiddemann (ed.), Handbook of Acute Leukemia,
DOI 10.1007/978-3-319-26772-2_4
26 • HAN D B O O K O F AC U TE L E U K E M IA

Acute myeloid leukemia with recurrent genetic changes

Detection of one of the balanced translocations included in this category
establishes a diagnosis of AML irrespective of the blast count in the
marrow or blood. NPM1 or CEBPA gene mutations alone are currently
not considered diagnostic for AML. Of note, patients with therapy-
related AML who have one of the recurrent genetic changes recognized
in this section should be categorized as therapy-related AML. Most

Category Frequency
Acute myeloid leukemia with recurrent genetic abnormalities:
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 7% (<60 years)
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 ~5% (<60 years)
AML with PML-RARA 5–10%
AML with t(9;11)(p22;q23); MLLT3-KMT2A ~3%
AML with t(6;9)(p23;q34); DEK-NUP214 ~1.5%
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA2, MECOM 1–2%
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 only in infants
AML with mutated NPM1 25–35%
AML with biallelic mutations of CEBPA 6–10%
Provisional entity: AML with BCR-ABL1
Provisional entity: AML with mutated RUNX1
Acute myeloid leukemia with myelodysplasia-related changes 25–35%
Therapy-related myeloid neoplasms 10–20%
Acute myeloid leukemia, not otherwise specified:
AML with minimal differentiation (FAB: AML M0) <5%
AML without maturation (FAB AMLM1) 5–10%
AML with maturation (FAB AML M2) ~10%
Acute myelomonocytic leukemia (FAB AML M4) 5–10%
Acute monocytic/monoblastic leukemia (FAB AML M5a/ M5b) <5%
Pure erythroid leukemia (FAB M6) <5%
Acute megakaryoblastic leukemia (FAB M7) <5%
Acute basophilic leukemia <1%
Acute panmyelosis with myelofibrosis <1%
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
Transient abnormal myelopoisesis
Myeloid leukemia associated with down syndrome

Table 4.1 World Health Organization classification of acute myeloid leukemia. Adapted from
© American Society of Hematology, 2016. All rights reserved. Arber et al [2].
 D IAGN OS T IC CR I T ER IA , CL A SSIFIC AT I O N, AND PRO GN OSIS O F ACU T E LEUK EMIA S • 27

of the balanced translocations recognized here also have prognostic

­relevance (see page 34).
Many of the recurrent genetic changes associate with specific morpho-
logic or immunophenotypic characteristics. Patients with RUNX1-RUNX1T1
rearrangement commonly have AML with maturation (FAB M2), Auer
rods, and show co-expression of CD19, and in some cases CD7 and CD56.
AML with CBFB-MYH11 fusion typically shows myelomonocytic morphol-
ogy with abnormal marrow eosinophils (FAB M4eo) and co-expression
of CD2. Patients with KMT2A (formerly mixed lineage leukemia [MLL])
rearrangement often have myelomonocytic differentiation (FAB M4/M5)
and express the proteoglycan antigen NG2 recognized by the 7.1 mono-
clonal antibody. The DEK-NUP214 fusion often associates with basophilia
and multi-lineage dysplasia in a hypocellular marrow, and two thirds of
patients have FLT3-ITD. AML with GATA2;MECOM rearrangement is
often characterized by dysplastic megakaryocytes and thrombocytosis.
In the 2016 WHO classification, AML with mutations in NPM1 or bial-
lelic CEBPA mutations are recognized as distinct entities, and AML with
BCR-ABL1 or RUNX1 mutations are introduced as new ‘provisional entities’
based on their frequency, clinical features, and prognostic significance
(see page 34). FLT3 mutations, although prognostically relevant, do not
define a separate category since they frequently occur alongside other
changes (for example, NPM1 mutations, PML-RARA, or DEK-NUP214).

Acute myeloid leukemia with myelodysplasia-related

changes
AML with myelodysplasia-related changes (AML-MRC) comprises
25–35% of adult AML patients. This type of leukemia is diagnosed in
patients with ≥20% blasts in the bone marrow or blood who fulfill ≥1
of the following criteria:
• History of previous myelodysplastic syndrome (MDS) or MDS/
myeloproliferative neoplasm (MPN)
• Presence of an MDS-associated cytogenetic abnormality (Table 4.2.)
• Multi-lineage dysplasia (dysplasia in ≥50% of the cells in
≥2 lineages)
28 • HAN D B O O K O F AC U TE L E U K E M IA

Patients with balanced translocations listed under ‘AML with recurrent

genetic abnormalities’, NPM1 mutations, or biallelic CEBPA mutations
should be classified as such, regardless of multi-lineage dysplasia or MDS
history. Patients with a history of cytotoxic therapy or irradiation for an
unrelated disease should be classified as ‘therapy-related AML’ (t-AML).
On average, patients with AML-MRC are older than de novo AML patients,
achieve lower remission rates, and have a shorter overall survival rate.
More specifically, MDS-related cytogenetic changes and/or a history of
MDS or MDS/MPN can be associated with an inferior prognosis, whereas
the presence of isolated multi-lineage dysplasia (without the other two
criteria) seems to have no independent prognostic significance [3].
Recent data suggest that AML-MRC may be genetically distinct from
other categories of AML [4].

Therapy-related myeloid neoplasms

A history of previous cytotoxic or radiation therapy is present in 7–10%
of AML patients in clinical trials, although this proportion may be
higher in the general population. The WHO classification combines
t-AML, t-MDS, and t-MDS/MPN into one category since most of these

Complex karyotype (≥3 unrelated abnormalities)

Unbalanced abnormalities •• -7/del(7q)
•• -5/del(5q)
•• del(11q)
•• del(12p)/t(12p)
•• -13/del(13q)
•• i(17q) or t(17p)
•• idic(X)(q13)
Balanced abnormalities •• t(11;16)(q23.3;p13.3)
•• t(3;21)(q26.2;q22.1)
•• t(1;3)(p36.3; q21.1)
•• t(2;11)(p21;q23.3)
•• t(5;12)(q32;p13.2)
•• t(5;7)(q32;q11.2)
•• t(5;17)(q32;p13.2)
•• t(5; 10)(q32;q21.2)
•• t(3;5)(q25.3;q35.1)

Table 4.2 Cytogenetic abnormalities diagnostic of acute myeloid leukemia with

myelodysplasia-related changes. Adapted from © American Society of Hematology, 2016.
All rights reserved. Arber et al [2].
 D IAGN OS T IC CR I T ER IA , CL A SSIFIC AT I O N, AND PRO GN OSIS O F ACU T E LEUK EMIA S • 29

patients have dysplastic features, and t-MDS frequently undergoes rapid

progression to t-AML.
All patients with previous cytotoxic therapy or radiotherapy for
prior neoplastic or non-neoplastic disorders are included in the therapy-
related myeloid neoplasm (t-MN) category, regardless of clinical features,
genetics, latency period, or proven causality. Due to the introduction of
classes of antineoplastic substances with novel mechanisms of action
(for example, tyrosine kinase inhibitors and immunomodulatory sub-
stances), the definition of t-MN has become blurred and will need to be
revised in the future. Overall, patients with t-MN have an unfavorable
prognosis, which is only partly explained by the high incidence of adverse
genetic features. Cumulative toxicity of previous threatment and AML
­chemotherapy may contribute to this observation [5].
Two subsets of t-MN are frequently described: t-MN following treat-
ment with irradiation or alkylating agents are characterized by a rela-
tively long latency (5–10 years), multi-lineage dysplasia, and frequent
unbalanced or complex chromosome abnormalities. In contrast, t-MN
after exposure to topoisomerase II inhibitors or anthracyclines occur
after a shorter latency (1–5 years) and frequently show balanced rear-
rangements of the KMT2A (MLL) gene. Core binding factor translocations
(RUNX1-RUNX1T1 and CBFB-MYH11) are also observed occasionally,
and associate with relatively favorable outcomes [6].

Acute myeloid leukemia, not otherwise specified

AML patients that do not fit into one of the previous categories are
categorized as AML, not otherwise specified (NOS), and sub-classified
according to their morphology, similar to the prior French-American-
British (FAB) classification. These morphological subcategories have no
independent prognostic relevance [7].

Rare entities
Myeloid sarcoma (granulocytic sarcoma, chloroma) is a rare extramed-
ullary tumor (<1% of AML) consisting of immature myeloid cells and
leading to destruction of the normal tissue architecture, without mor-
phological evidence of AML in the bone marrow. The most commonly
30 • HAN D B O O K O F AC U TE L E U K E M IA

affected organs are the skin (also known as leukemia cutis), lymph nodes,
mammary gland, testes, and spleen. Myeloid sarcoma is considered to
be an extramedullary presentation of a systemic disease, and without
treatment, progression to AML will occur almost invariably. A myeloid
sarcoma is evidence of relapse in a patient with previously treated
AML, and indicates evolution to AML in a patient with pre-existing
MDS, MDS/MPN, or MPN [8]. Standard AML chemotherapy is recom-
mended for myeloid sarcoma. Radiotherapy can achieve local disease
control but its effect on overall survival is unclear. Radiotherapy can
be considered if there is compression of vital organs or residual disease
after chemotherapy [9].
Blastic plasmacytoid dentritic cell neoplasm is a rare disease mainly
affecting older men (median age ~60 years), characterized by singular
or multiple cutaneous noduli with secondary generalization, or more
rarely by a primary leukemic course with or without skin involvement.
Case series suggest that the prognosis is very poor.

Outlook: the 2016 revision of the World Health

Organization classification
An updated version of the WHO classification is due to be released in
2016. With regard to AML, proposed changes include the recognition of
AML with NPM1 mutation and AML with biallelic (but not monoallelic)
CEBPA mutation as definite, rather than provisional entities. AML with
RUNX1 mutation and AML with BCR-ABL gene fusion are considered
as new provisional entities. Hereditary syndromes with a propensity
to develop AML or other myeloid neoplasms are proposed to form a
distinct category [2].

Diagnostic criteria and classification of

lymphoblastic leukemias
The diagnosis of the precursor lymphoid neoplasms, acute lymphoblastic
leukemia (ALL) and lymphoblastic lymphoma (LBL), is based on a com-
bination of morphology and immunophenotyping. Table 4.3 provides an
overview of the most important immunophenotypic markers used in the
diagnosis and subtyping of ALL. There is no generally accepted diagnostic
 D IAGN OS T IC CR I T ER IA , CL A SSIFIC AT I O N, AND PRO GN OSIS O F ACU T E LEUK EMIA S • 31

threshold for the percentage of bone marrow blasts required to make a

diagnosis of ALL. In fact, there is a continuum of clinical presentations
ranging from patients with extensive bone marrow and peripheral blood
involvement (ALL) to rarer patients who have nodal or extranodal mass
lesions with no or minimal bone marrow and peripheral blood involve-
ment (LBL). An arbitrary cut-off of ≥25% bone marrow blasts is often
used to separate ALL from LBL. The 2016 WHO classification of B- and
T-ALL is summarized in Table 4.4.

B-cell lymphoblastic leukemia/lymphoma with recurrent

genetic abnormalities
Within this category, B-cell precursor ALL (BCP-ALL) with BCR-ABL1
rearrangement needs to be recognized due to its prognostic and thera-
peutic relevance. BCR-ABL-positive ALL becomes more common with
increasing age, and often shows a characteristic immunophenotype
(CD19+, CD10+, CD25+ with co-expression of myeloid antigens). ALL
with KMT2A rearrangement most commonly occurs in the first year
of life or in adolescents and adults while the ETV6-RUNX1 fusion and
hyperdiploid ALL are frequent in children, but very rare in infants.
Patients with IL3-IGH rearrangement often have reactive eosinophilia
as the gene fusion leads to interleukin 3 (IL-3) overexpression. The bone
marrow blast count for patients with this rearrangement may be <20%
and blasts may be absent in the periphery.

B-lineage ALL CD10 CD19 cCD22 cCD79a TDT Ig PAX5

Early precursor – + + + + – +
(pro-B-ALL)
Common + + + + + – +
(cALL)
Pre-B-ALL +/– + + + + c-µ +
T-lineage ALL CD1a CD2 CD3 CD4 CD7 CD8 CD34
Pro-T – – c – + – +/–
Pre-T – + c – + – +/–
Cortical T + + c + + + –
Medullary T - + c, s +/– + +/– –

Table 4.3 Immunophenotypic markers in the diagnosis of acute lymphoblastic leukemia. ALL,
acute lymphoblastic leukemia; c, cytoplasmic; s, surface expression; c-µ, cytoplasmatic µ chains.
Reproduced with permission from © Elsevier, 2008. All rights reserved. McGregor et al [10].
32 • HAN D B O O K O F AC U TE L E U K E M IA

Category Frequency Frequency

(adults) (children)
B-lymphoblastic leukemia/lymphoma with recurrent
genetic abnormalities:
t(9;22)(q34.1;q11.2); BCR-ABL1 25% 2–4%
t(v;11q23.3); KMT2A (MLL)-rearranged 10% mainly in infants
t(12;21)(p13;q22); ETV6-RUNX1 (TEL-AML1) 2% 25%
hyperdiploidy (>50 chromosomes) 7% 25%
hypodiploidy (<46 chromosomes) 2–5% 1–5%
t(5;14)(q31;q32); IL3-IGH <1% <1%
t(1;19)(q23;p13.3); TCF3-PBX1 1–3% 6%
Provisional entity: B lymphoblastic leukemia/lymphoma,
BCR-ABL1-like
Provisional entity: B lymphoblastic leukemia/lymphoma with
intrachromosomal amplification of chromosome21 (iAMP21)
B-lymphoblastic leukemia/lymphoma, NOS
T-lymphoblastic leukemia/lymphoma
Provisional entity: Early T-cell precursor (ETP) lymphoblastic
leukemia

Table 4.4 World Health Organization classification of acute lymphoblastic leukemias. NOS, not
otherwise specified. Adapted from © American Society of Hematology, 2016. All rights reserved.
Arber et al [2].

Recent developments in acute lymphoblastic leukemia

Since the publication of the 4th edition of the WHO classification in
2008, novel subsets of ALL with potential clinical relevance have been
described [10]. These will be included as novel provisional entities in
the upcoming 2016 WHO classification.
• Ph-like ALL: A subgroup with BCR-ABL-negative B-cell progenitor
ALL have a gene expression profile similar to BCR-ABL-positive
patients. This BCR-ABL-like (or Ph-like) phenotype is most commonly
seen in adolescents and young adults, and associates with inferior
outcomes. Patients frequently have IKZF1 gene alterations, CRLF2
gene rearrangements, and mutations in signaling pathways that
might be targetable by tyrosine kinase inhibitors [11].
• iAMP21: Intrachromosomal amplification of chromosome 21
(iAMP21) is observed in approximately 2–5% of children with
B-precursor ALL and is also associated with poor outcomes.
 D IAGN OS T IC CR I T ER IA , CL A SSIFIC AT I O N, AND PRO GN OSIS O F ACU T E LEUK EMIA S • 33

• ETP-ALL: A subgroup of patients within the ‘early’ T-cell ALL/

lymphoblastic leukemia (LBL) category have a phenotype similar
to thymic early T-cell precursors (ETP) (CD1a negative, CD8
negative, CD5 negative/dim, and positive for one or more stem cell
or myeloid antigens). ETP ALL accounts for 11–12% of childhood
and ~7% of adult T-cell ALL/LBL and is associated with poorer
outcomes in children and adults.

Diagnostic criteria and classification of acute

leukemias of ambiguous lineage
The WHO category of ‘acute leukemias of ambiguous lineage’ (Table 4.5)
comprises acute undifferentiated leukemias (AUL) as well as mixed phe-
notype acute leukemias (MPAL). Leukemias of ambiguous lineage are rare
(<4% of acute leukemias). The diagnosis rests on immunophenotyping.
The MPAL group combines the older categories of bilineage (two dis-
tinct blast populations) and biphenotypic (co-expression of markers of
several lineages on a more or less homogenous cell population) acute
leukemias. AUL represents very rare cases of leukemias where no lineage
markers are present. Other rare entities such as basophilic or natural
killer (NK)-cell precursor neoplasms and blastic plasmacytoid dendritic
cell neoplasms as well as non-hematologic tumors need to be carefully
ruled out in such patients.
MPAL must be differentiated from AML or ALL with cross-lineage
antigen expression. The WHO adopted more stringent criteria to define
involvement of more than one lineage compared with the older European

Acute undifferentiated leukemia

Mixed phenotype acute leukemia
MPAL with t(9;22)(q34;q11.2); BCR-ABL1
MPAL with t(v;11q23); KMT2A (MLL)-rearranged
MPAL, B-myeloid, NOS
MPAL, T-myeloid, NOS
Provisional entity: natural killer (NK) cell lymphoblastic leukemia/lymphoma

Table 4.5 World Health Organization classification of acute leukemias of ambiguous

lineage. MLL, mixed lineage leukemia; MPAL, mixed phenotype acute leukemia; NOS, not
otherwise specified. Adapted from © American Society of Hematology, 2016. All rights reserved.
Arber et al [2].
34 • HAN D B O O K O F AC U TE L E U K E M IA

Group for the Immunological Characterization of Leukemias (EGIL) clas-

sification that is still in use [12]. According to the WHO, MPAL is defined
by expression of myeloperoxidase (by immunophenotyping or cytochem-
istry) or at least two monocyte markers (CD11c, CD14, CD64, lysozyme,
NSE). T-cell lineage is defined based on surface or strong cytoplasmic
CD3 expression, and B-cell lineage is defined by strong CD19 expres-
sion with strong expression of at least one other B-cell marker (CD79a,
cCD22, CD10), or weak expression of CD19 with strong expression of two
of the other markers. Of note, MPAL with BCR-ABL1 rearrangement is
recognized as a distinct entity. Patients with CML in blast phase can also
show an MPAL phenotype but should be categorized as CML.

Prognostic factors in acute myeloid leukemia

Prognosis in AML is determined by disease-related and patient-related
factors. Older age and the results of cytogenetic testing are commonly
regarded as the most important risk factors in AML, and gene mutations
have been increasingly recognized as additional risk markers. While the
relative frequency of unfavorable genetic features increases with age, this
fact alone does not fully explain the inferior outcomes of older patients.
Other factors such as comorbidities and poorer tolerability of intensive
chemotherapy may play a role here.

Medical Research Council classification

The most comprehensive study on the prognostic relevance of chromo-
somal alterations has been published by the British Medical Research
Council study group [13]. Based on an analysis of overall survival in
patients <60 years of age, the MRC classification delineates three prog-
nostic subgroups (Table 4.6). The prognostic relevance of some less
frequent alterations is uncertain in older patients.

European LeukemiaNet classification

An expert group on behalf of the European LeukemiaNet has pub-
lished a classification based on cytogenetics and gene mutations in
NPM1, FLT3 (internal tandem dupications, ITD), and CEBPA, which was
subsequently shown to delineate prognostically distinct subgroups in
 D IAGN OS T IC CR I T ER IA , CL A SSIFIC AT I O N, AND PRO GN OSIS O F ACU T E LEUK EMIA S • 35

younger (<60 years) and older (≥60 years), intensively treated patients
(Table 4.7) [14,15]. Of note, the European LeukemiaNet Intermediate-I
and Intermediate-II subgroups do not represent a prognostic grading.
In fact, younger patients in the Intermediate-II subgroups have better
outcomes than those with Intermediate-I genetics. While the European
LeukemiaNet guidelines included all cytogenetically normal patients
with mutated CEBPA in the ‘favorable’ group, it has now been shown
that only biallelic CEBPA mutations are prognostically favorable [16].

Gene mutations
Mutations in NPM1, biallelic CEBPA mutations, and FLT3-ITD are the most
well-established molecular risk markers in AML, and are included in the
European LeukemiaNet classification (page 34) [15]. Mutations in other
genes including TP53, RUNX1, DNMT3A, IDH1/IDH2, and ASXL1 have
been shown to be prognostic, but their role in clinical decision-making is
not yet well defined [17–19]. KIT gene mutations associate with shorter
relapse-free survival in the subgroup of patients with core binding factor

MRC prognostic group Alterations

Favorable* t(15;17)(q22;q21)
t(8;21)(q22;q22)
inv(16)(p13q22) or t(16;16)(p13;q22)
Intermediate Entities not classified as favorable or adverse,
including cytogenetically normal AML
Adverse abn(3q) [excluding t(3;5)(q21~25;q31~35)]
inv(3)(q21q26) or t(3;3)(q21;q26)
–5, add(5q), del(5q)
–7, add(7q), del(7q)
t(6;11)(q27;q23),
t(10;11)(p11~13;q23)
t(v;11q23) [excluding t(9;11)(p21~22;q23) and
t(11;19)(q23;p13)]
t(9;22)(q34;q11)
–17/abn(17p)
Complex (≥4 unrelated abnormalities)

Table 4.6 Medical Research Council classification. *Patients with these alterations are always
classified as favorable, irrespective of additional alterations listed in the adverse section. AML,
acute myeloid leukemia; MRC, Medical Research Council. Adapted from © American Society of
Hematology, 2010. All rights reserved. Grimwade et al [13].
36 • HAN D B O O K O F AC U TE L E U K E M IA

leukemias, particularly t(8;21)(q22;q22), less well ­established in patients

with inv(16)(p13.1q22) or t(16;16)(p13.1;q22).

Other risk factors and prognostic scoring systems

Besides age and genetic markers, a number of other risk markers have
been identified including comorbidities/performance status, therapy-
related AML, and a prior history of MDS. Various scoring systems have
been developed that integrate various risk factors and may contribute
to therapeutic decision-making, particularly in older patients [20]. For
example, a score based on seven clinical and laboratory parameters,
with or without information on cytogenetics and molecular markers,
can be used to predict the chance of response to induction therapy and
the risk of early death in patients ≥60 years (www.aml-score.org) [21].

ELN genetic group Alterations

Favorable t(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Cytogenetically normal AML, mutated NPM1 without FLT3-ITD
Cytogenetically normal AML, mutated CEBPA*
Intermediate-I Cytogenetically normal AML, mutated NPM1 and FLT3-ITD
Cytogenetically normal AML, wild-type NPM1 and FLT3-ITD
Cytogenetically normal AML, wild-type NPM1 without FLT3-ITD
Intermediate-II t(9;11)(p22;q23); MLLT3-KMT2A
Cytogenetic abnormalities not classified as favorable or adverse
Adverse inv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA2, MECOM
t(6;9)(p23;q34); DEK-NUP214
t(v;11)(v;q23); KMT2A (MLL)-rearranged [except t(9;11)(p22;q23)]
–5, del(5q)
–7
abnl(17p)
Complex [≥3 alterations, except patients with t(9;11), t(15;17), t(8;21),
inv(16) or t(16;16)]

Table 4.7 European LeukemiaNet classification. *While all CEBPA mutations in

cytogenetically normal AML are classified as ‘favorable’ according to the European LeukemiaNet
recommendations, it has now become clear that the favorable prognosis is restricted to those
patients with double (biallelic) mutations. AML, acute myeloid leukemia; ELN, European
LeukemiaNet. Adapted from © American Society of Hematology, 2010. All rights reserved.
Döhner et al [15].
 D IAGN OS T IC CR I T ER IA , CL A SSIFIC AT I O N, AND PRO GN OSIS O F ACU T E LEUK EMIA S • 37

Minimal residual disease

The detection of minimal residual disease (MRD) by sensitive molecular
assays for genetic alterations (gene mutations or fusion transcripts) or
by flow cytometry has been shown to associate with increased risk of
disease relapse [22]. In NPM1-mutated AML, MRD-positive status was
recently shown to be a stronger predictor of relapse or death than pre-
treatment genetic or clinical features [23]. It is currently unclear how
MRD measurements are best incorporated into treatment algorithms
and whether MRD-guided therapy will improve outcomes.

Prognostic factors in acute lymphoblastic leukemia

Various risk stratification systems have been proposed for adults with
ALL. The US National Comprehensive Cancer Network considers the
following genetic alterations as markers of high risk: hypodiploidy (<44
chromosomes); t(v;11q23) or MLL rearrangements; t(9;22) or BCR-ABL;
or a complex karyotype (≥5 chromosomal abnormalities). The absence
of all poor risk factors is considered standard risk. Elevated white blood
cell (WBC) count (≥30×109/L for B-cell ALL; ≥100×109/L for T-cell ALL)
may also be associated with poor outcomes. The risk grouping used in
clinical trials of the German Multicenter Acute Lymphoblastic Leukemia
Study Group (GMALL) is shown in Table 4.8.

Risk group B-precursor ALL T-ALL

Standard risk No pro-B-ALL Thymic T-ALL
and WBC <30×109/L
and no t(4;11)/MLL-AF4
and no t(9;22)/BCR-ABL1
And CR after first induction
course
High risk Pro-B-ALL Early/Mature T-ALL
or WBC ≥30×109/L
or t(4;11)/MLL-AF4
or CR after second induction
course
BCR-ABL-positive t(9;22)/BCR-ABL1 –

Table 4.8 Risk grouping of adult acute lymphoblastic leukemia according to the German
Multicenter Acute Lymphoblastic Leukemia study group. ALL, acute lymphoblastic leukemia.
38 • HAN D B O O K O F AC U TE L E U K E M IA

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cases reported in the literature 1974-2001. Leukemia. 2002;16:2366-2378.
7 Walter RB, Othus M, Burnett AK, et al. Significance of FAB subclassification of “acute myeloid
leukemia, NOS” in the 2008 WHO classification: analysis of 5848 newly diagnosed patients.
Blood. 2013;121:2424-2431.
8 Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization
(WHO) classification of myeloid neoplasms and acute leukemia: rationale and important
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12 Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classification of acute
leukemias. European Group for the Immunological Characterization of Leukemias (EGIL).
Leukemia. 1995;9:1783-1786.
13 Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute
myeloid leukemia: determination of prognostic significance of rare recurring chromosomal
abnormalities among 5876 younger adult patients treated in the United Kingdom Medical
Research Council trials. Blood. 2010;116:354-365.
14 Mrózek K, Marcucci G, Nicolet D, 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.
15 Döhner H, Estey EH, Amadori S, 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.
16 Dufour A, Schneider F, Metzeler K, et al. Acute myeloid leukemia with biallelic CEBPA gene
mutations and normal karyotype represents a distinct genetic entity associated with a
favorable clinical outcome. J Clin Oncol. 2010;28:570-577.
17 Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373:
1136-1152.
18 Roug AS, Hansen MC, Nederby L, Hokland P. Diagnosing and following adult patients with
acute myeloid leukaemia in the genomic age. Br J Haematol. 2014;167:162-176.
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19 Haferlach T. How does one work-up an acute myeloid leukemia patient in the molecular era?
http://learningcenter.ehaweb.org/eha/2015/20th/103570/torsten.haferlach.how.does.one.
work.up.an.aml.patient.in.the.molecular.era.html?f=m6t1576. Accessed August 12, 2016.
20 Klepin HD. Geriatric perspective: how to assess fitness for chemotherapy in acute myeloid
leukemia. Hematology Am Soc Hematol Educ Program. 2014;2014:8-13.
21 Krug U, Röllig C, Koschmieder A, et al. Complete remission and early death after intensive
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22 Grimwade D, Freeman SD. Defining minimal residual disease in acute myeloid leukemia:
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23 Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk
AML. N Engl J Med. 2016;374:422-433.
 Chapter 5

Therapeutic management of acute

myeloid leukemia
Michael Fiegl

Overview of treatment options

Acute myeloid leukemia (AML) is considered a curable disease and
hence the primary therapeutic intention in a patient with newly diag-
nosed AML should be to cure the patient with intensive chemotherapy.
However, there are two main reasons why clinicians should not follow
this approach: firstly, intensive chemotherapy cannot be administered
safely due to comorbidities (or patient refusal), and secondly, the patient
will not benefit from intensive chemotherapy because of high-risk AML,
which requires allogeneic stem cell transplantation that cannot be per-
formed because of advanced age, comorbidities, or patient refusal. Such
patients will receive palliative care as a cure is not achievable. Importantly,
advanced age alone is no reason for withholding intensive chemotherapy.

Treatment by phase
Intensive chemotherapy with curative intention is divided into two
stages: first, remission induction therapy, which is then followed by
post-remission therapy [1]. Post-remission therapy may comprise con-
ventional chemotherapy, namely consolidation therapy and sometimes
maintenance therapy, or allogeneic stem cell transplantation. While the
choice of induction chemotherapy is largely unaffected by the individual

Ó Springer International Publishing Switzerland 2016 41

W. Hiddemann (ed.), Handbook of Acute Leukemia,
DOI 10.1007/978-3-319-26772-2_5
42 • HAN D B O O K O F AC U TE L E U K E M IA

risk of the patient, post-remission therapy is determined mainly by the

genetic risk and the response to induction therapy. This chapter describes
treatment options that are considered ‘standard’ at the time of writing,
while novel options are described in detail in Chapter 8.

Remission induction
For over four decades, the backbone of AML induction chemotherapy
has been the antimetabolite cytarabine in combination with an anthra-
cycline. The ancestor of this combination is the so-called ‘7+3’, which
is still widely used and can be considered a worldwide standard. An
abundance of modifications of this regimen exist, with different dosages
of cytarabine, different anthracyclines with different dosages, and also
the addition of other antileukemic drugs.
Due to the strict correlation of cytarabine with leukemic cell killing
in vitro, one aim was to increase individual exposure of cytarabine. This
can be achieved by prolonged or continuous intravenous (IV) applications
versus applications twice daily, or by increasing the individual dosage
(<100 mg/m²: low-dose cytarabine; 100–200 mg/m²: standard-dose or
intermediate-dose cytarabine; and ≥500 mg/m² high-dose cytarabine
[HiDAC]), however cytarabine doses exceeding 1 g/m² (individual dose)
might increase toxicity without additional antileukemic effects [2].
While anthracyclines are a fundamental part of induction chemo-
therapy, there seems to be no relevant difference in terms of antileuke-
mic activity between different members of this group. Although earlier
trials suggested such a difference in favor of idarubicine, the dose of
the comparator daunorubicin was 45 mg/m² and thus too low [3,4].
Adequate dosage of daunorubicin is however paramount and even older
patients profit from daunorobicin without increase in relevant toxicities
[5]. Current evidence suggests however that doses >60 mg daunorubicin
do not further improve the overall outcome [6].
The addition of a third antileukemic drug has not convincingly
improved the efficacy of induction chemotherapy, may it be a cytotoxic
drug (for example, etoposide [7]) or a differentiating agent (for example,
all trans retinoic acid [ATRA] [8]). The role of biologicals is unclear to date
and the addition of these drugs to induction chemotherapy has yielded
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E M Y E LO I D L EU K E M I A • 43

unequivocal results for example, the addition of tyrosine kinase inhibi-

tor (TKI) sorafenib to induction chemotherapy did not improve clinical
outcome in elderly patients [9], but prolonged relapse free-survival in
younger patients without affecting survival [10]. While promising, no
general recommendation for the use of any of these drugs during induc-
tion chemotherapy can be given. Whether this might differ in certain
subgroups or for novel TKIs is subject to investigation.
Usually, two cycles of chemotherapy are applied within 21 days,
resulting in the so-called ‘double induction’. A bone marrow aspirate
is usually performed between the two, and while some experts recom-
mend omitting the second cycle if less than 5–10% blasts are detected
in this control (a so-called ‘adequate blast clearance’), others do so only
in elderly patients (≥60–65 years). A dose-dense approach, where the
second cycle of induction chemotherapy is given shortly after the first
(‘S-HAM’) has been shown to be of benefit due to shortened cytopenia

Regimen Drugs and dosage

7+3 [12] Cytarabine 100 mg/m² CI days 1–7
Daunorubicin 60 mg/m² IV days 3–5
modified 7+3 [5] Cytarabine 200 mg/m² CI days 1–7
Daunorubicin 90 mg/m² IV days 1–3
TAD-9 [13] Thioguanine 100 mg/m² PO days 3–9
Cytarabine 100 mg/m² CI days 1–2
Cytarabine 2 x 100 mg/m² IV days 3–8
Daunorubicin 60 mg/m² IV days 3–5
HAM [13] Cytarabin 2 x 1000 mg/m² IV days 1–3
Mitoxantron 10 mg/m² IV days 3–5
S-HAM* [11] Cytarabine 2 x 1000 mg/m² IV days 1–2 and days 8–9
Mitoxantrone 10 mg/m² IV days 3–4 and days 10–11
ICE [8] Idarubicin 12 mg/m² IV days 1+3
Cytarabine 100 mg/m² CI days 1–5
Etoposide 100 mg IV days 1+3

Table 5.1 Induction chemotherapy for acute myeloid leukemia. A second cycle (similar or
different from the first one) may be applied 3 weeks after initiation of the first cycle with the
exception of S-HAM, where both cycles are given within 11 days. *G-CSF recommended in patients
with adequate blast clearance in post-reatment aplasia. CI, continuous infusion; G-CSF, granulocyte-
colony stimulating factor; ICE, ifosfamide, carboplatin, etopside; IV, intravenous; PO, orally;
S-HAM, sequential high-dose cytarabine, mitoxantrone, and pegfilgrastim; TAD-9, 6-thioguanine,
cytarabine, and daunorubicin.
44 • HAN D B O O K O F AC U TE L E U K E M IA

[11]. Different examples of regimens for intensive induction chemother-

apy are listed in Table 5.1. While most of these regimens have not been
tested head-to-head, clinical evidence suggests that none of the applied
regimens yields better results than the conventional ‘7+3’ in terms of
complete remission (CR) rates and survival parameters [12].
Based on these results, the minimal requirements for induction chemo-
therapy in AML are the combination of cytarabine with an anthracycline
and the application of two cycles of chemotherapy (at least if residual blasts
are detected in the control bone marrow aspiration 1 week after the first
cycle). At least one cycle should contain HiDAC (possibly not exceeding
1 g/m² per individual dose); if two intermediate doses of cytarabine are
given, then HiDAC should be scheduled for consolidation. Anthracyclines
need to be administered in an appropriate dose, for example, ≥60 mg/m²
for daunorubicin (also in older patients).

Supportive therapy
For patients who initially present with (hyper-)leukocytosis, it may be neces-
sary to carry out therapeutic leukapheresis. There is no clear threshold for
the leukocyte count, which requires leukapheresis but it should be consid-
ered in patients with a peripheral leukocyte count >100 G/L and/or who
show signs of organ ischemia (for example, increased lactate or troponine
levels in serum, respiratory insufficiency, and renal failure). In patients
who have hyperleukocytosis but do not require leukapheresis, a pre-phase
with cytarabine 100 mg/m² continuous infusion (CI) or hydroxyurea 1 g/
m² orally (PO) twice daily (BID) can be administered prior to induction
chemotherapy; leukocytes should drop below 30 G/L to avoid or dimin-
ish the risk for tumor lysis syndrome. In case tumor lysis is imminent or
present, rasburicase 3–7.5 mg intravenously (IV) is recommended.
During and after the application of induction chemotherapy, the patient
faces severe bone marrow aplasia for approximately 6–8 weeks. While
anemia and thrombocytopenia are treated with transfusions of erythro-
cytes and thrombocytes, routine administration of granulocyte-colony
stimulating factor (G-CSF) is not recommended, as it has no impact on
overall survival despite diminishing severity and duration of infections
[14,15]. There is no clear recommendation for prophylactic antibiotics
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E M Y E LO I D L EU K E M I A • 45

during aplasia, however antimykotic prophylaxis with oral posaconazole

has been shown to reduce the incidence of invasive aspergillosis [16] and
its use is recommended in this setting.
Routine examination of cerebral spinal fluid and chemotherapeutic
prophylaxis for meningeosis leukemica is usually not necessary, but can be
reasonable in patients with chloroma or AML with monocytic ­differentiation
or neurological symptoms.

Post-remission therapy
After achievement of CR, post-remission therapy is warranted. The prin-
cipal choice of conventional chemotherapy versus allogeneic stem cell
transplantation is made by the individual risk of the patient. In general,
patients with a low risk of relapse (favorable genetic alterations) should
receive conventional chemotherapy, while patients with a high risk of
relapse require allogeneic stem cell transplantation. For patients with an
intermediate risk profile, the role of allogeneic stem cell ­transplantation
is less clear.

Consolidation and maintenance

Usually, one to three cycles of chemotherapy are given as consolidation 4–6
weeks after the patient has achieved CR following induction chemotherapy.
If high-dose cytarabine has not been given during induction, usually one
to three cycles of HiDAC (with or without an anthracycline) are given
as consolidation within a 6–8 week span. Table 5.2 lists some examples.

Regimen Drugs and dosage

HiDAC [17] Cytarabine 2x3 g/m² over 3 hours days 1, 3, 5
TAD-9 [13] Thioguanine 100 mg/m² PO days 3–9
Cytarabine 100 mg/m² CI days 1–2
Cytarabine 2x100 mg/m² IV days 3–8
Daunorubicine 60 mg/m² IV days 3–5
MAC [18] Cytarabine 2 x 1 g/m² IV days 1–6
Mitoxantrone 10 mg/m² IV days 4–6

Table 5.2 Consolidation chemotherapy for acute myeloid leukemia. Usually, one to three cycles
of consolidation are given. In the case of TAD-9, one cycle of consolidation is followed by prolonged
maintenance chemotherapy. CI, continuous infusion; HiDAC, high-dose cytarabine; IV, intravenous;
MAC, mitoxantrone and cytarabine; TAD-9, 6-thioguanine, cytarabine, and daunorubicin.
46 • HAN D B O O K O F AC U TE L E U K E M IA

While the original publication by the Cancer and Leukemia Group B

(CALGB) [19], which defined the benefit of HiDAC during consolidation
also included four additional cycles of monthly maintenance therapy, this
modality is rarely used in AML today despite evidence for the benefit of
such an approach [13]. Similarly, autologous stem cell transplantation,
which was popular in the 1990s, has lost its importance in consolidation
of AML although it might be beneficial in certain AML subsets [20].
Although chemotherapeutic maintenance is not considered as stand-
ard therapy, immune-modulating therapy comprising of interleukin 2
(IL-2) and histamine dihydrochloride (10 cycles for a total of 1.5 years
after achievement of CR) has been approved in the European Union and
can be considered especially in younger patients [21] with a monocytic
differentiated AML [22].

Stem cell transplantation

Patients with an unfavorable risk profile are clear candidates for allogeneic
stem cell transplantation in first complete remission (CR1). In the large
cohort of patients with a genetic intermediate risk profile the role of allo-
geneic stem cell transplantation is less clear. While for the whole group no
clear evidence exist that these patients benefit from allogeneic stem cell
transplantation in CR1, there are certain subgroups that most certainly
will. In general, patients with an FLT3-ITD mutation (and especially those
with a high FTL3/FLT3-ITD ratio [23]) should be considered high-risk and
be allocated to allogeneic stem cell transplantation whenever feasible.
Similarly, patients with chromosomal alterations that are neither favorable
nor unfavorable seem to benefit from allogeneic stem cell transplantation
while those with normal karyotype may not [24]. Patients that display
inadequate blast clearance in the bone marrow during aplasia should also
be considered as candidates for allogeneic stem cell transplantation as they
have an inferior outcome [25]. Ultimately, the decision to perform alloge-
neic stem cell transplantation in these patients remains an individual one.
Both HLA-identical related and unrelated stem cell donors can be
chosen but due to quicker availability and less costs the primary choice
will be a sibling donor. Both peripheral stem cells and bone marrow can be
used as source with equal outcome [26]. If no HLA-identical or compatible
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E M Y E LO I D L EU K E M I A • 47

donor (for example, ≥8 out of 10 matches) is available, alternative stem

cell sources can be used such as cord blood or a haploidentical donor.
The latter seems to equal HLA-identical allogeneic stem cell transplan-
tation in terms of overall survival despite increased relapse rates (and a
lower incidence of graft versus host-disease), but less treatment-related
mortality [27]. Nowadays, reduced intensity conditioning (RIC) is the
treatment of choice, due to equal effectiveness and less toxicity as com-
pared with myeloablative conditioning (MAC). Possible conditioning
regimens with reduced conditioning include fludarabine, Ara-C, and
amsacrin (FLAMSA-RIC) [28], fludarabine, BCNU, and melphalane (FBM)
[29], and 8 Gy total-body irradiation [30]. The increasing use of these
regimens has resulted in an increase of the age threshold to above 60–65
years and in selected patients this can even be above 70 years of age.

Resistant and relapsed leukemia

Resistant disease is generally defined as either persistent disease after
intensive chemotherapy or reappearance of AML after achievement of CR
within 6 months after initiation of intensive chemotherapy, while reap-
pearance of the disease at a later time point is called relapse. While the
duration of CR is generally related to prognosis (the longer, the better),
relapse itself is prognostically unfavorable.
The only curative option for relapsed/refractory (r/r) leukemia patients
is allogeneic stem cell transplantation. While a second CR (CR2) can be
achieved in a certain proportion of patients, remission rates are lower than
at primary diagnosis and short lived. In the salvage situation anthracy-
clines cannot be re-applied in the majority of cases due to exhaustion of
the cumulative anthracycline dose [31]. Therefore, alternative approaches
are applied such as higher doses of cytarabine with its chemomodula-
tion by fludarabine or cladribine or by a sequential dose-dense design.
Table 5.3 lists some examples. The relevance of achieving a CR2 prior
to allogeneic stem cell transplantation is not clear; therefore if the pro-
cedure can be organized quickly, a bridging concept with cytoreductive
therapy (for example, low-dose cytarabine or 5-azacitidine) instead of
intensive re-induction is feasible.
48 • HAN D B O O K O F AC U TE L E U K E M IA

If the r/r patient is not a candidate for allogeneic stem cell trans-
plantation then the approach from this point is palliative therapy and
resembles the one described in following paragraph.

Treatment of the medically unfit and elderly patient

In medically unfit patients, intensive induction and consolidation chemo-
therapy is not superior to palliative chemotherapy [36]. Hence, while inten-
sive chemotherapy can be applied in certain cases on an individual basis,
palliative chemotherapy is recommended in adjunction to best supportive
care (BSC). This comprises mild cytoreduction with low-dose cytarabine
or hydroxyurea, antibiotics, and transfusions. While mild chemotherapy
can induce CRs in a small proportion of these patients, this is usually
not possible in patients with cytogenetically unfavorable AML for whom
cytarabine was not superior to BSC [37]. Different treatment options are
given in Table 5.4. The main treatment goal is to improve quality of life by
reducing cytopenias (and hence infections, transfusions, and hospitaliza-
tion) and to a lesser degree achievement of CR and prolonging of life for
the patient. In the course of such a treatment, resistant disease or relapse
will eventually arise. In these cases, one of the mentioned regimens might
be given, or treatment can be merely supportive.
Regimen Drugs and dosage
FLA [32] Fludarabine 30 mg/m² IV days 1–5
Cytarabine* (1–)2 g/m² IV days 1–5
FLAG-Ida [33] Fludarabine 30 mg/m² IV days 1–5, 4 hours prior to
Cytarabine 1-2 g/m² IV days 1–5
Idarubicine 10 mg/m² days 1–3
G-CSF 300 µg/m² days -1–5 (+day 7 until leukocyte recovery)
F-SHAI [34] Fludarabine 15 mg/m² IV days 1–2 and 8–9, 4 hours prior to
Cytarabine* 2x(1–)3 g/m² IV days 1–2 and 8–9
Idarubicine 10 mg/m² IV days 3–4 and 10–11
S-HAM [35] Cytarabine* 2 x (1–)3 g/m² IV days 1–2 and 8–9
Mitoxantrone 10 mg/m² IV days 3–4 and 10–11

Table 5.3 Intensive re-induction chemotherapy for relapsed/refractory acute myeloid leukemia.
Intensive re-induction chemotherapy in relapsed/refractory acute myeloid leukemia is usually only
warranted in patients that will proceed to allogeneic stem cell transplantation. *Patients ≥60 years
received 1 g/m². FLA, fludarabine and cytarabine; FLAG-Ida, fludarabine, cytarabine, idarubicin, and
granulocyte-colony stimulating factor; F-SHAI, fludarabine, sequential high-dose cytarabine, and
idarubicin; IV, intravenous; S-HAM, sequential high-dose cytarabine, mitoxantrone, and pegfilgrastim.
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E M Y E LO I D L EU K E M I A • 49

Regimen CR rates (%) Median overall survival

Hydroxyurea [37] 1 <6 months
1–2 g PO daily
Low-dose cytarabine [37] 18 <6 months
2 x 20 mg SC for 10 days
5-Azacitidine [38] 18 24.5 months*
75 mg/m² SC (or IV) for (5–)7 days Improvement over standard: 1.5-fold
Decitabine [39] 18 7.7 months§
g/m² IV for 5 days Improvement over standard: 1.5-fold

Table 5.4 Palliative chemotherapy in acute myeloid leukemia. Both hypomethylating agents
(5-Aza and decitabine) have been shown to be superior to standard treatment comprising
cytarabine and hydroxyurea (+BSC), but the latter are still reasonable alternatives in selected
cases. Effectiveness of the treatment with these agents should not be evaluated before four to six
cycles have been administered. *OS for standard arm: 16 months. Only acute myeloid leukemia
with ≤30% bone marrow blasts were included. §OS for standard arm: 5.0 months. IV, intravenous;
OS, overall survival; PO, orally; SC, subcutaneous.

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chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation,
and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and
myelodysplastic syndrome. J Clin Oncol. 2005;23:5675-5687.
29 Marks R, Potthoff K, Hahn J, et al. Reduced-toxicity conditioning with fludarabine, BCNU,
and melphalan in allogeneic hematopoietic cell transplantation: particular activity against
advanced hematologic malignancies. Blood. 2008;112:415-425.
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E M Y E LO I D L EU K E M I A • 51

30 Bornhaüser M, Kienast J, Trenschel R, et al. Reduced-intensity conditioning versus standard

conditioning before allogeneic haemopoietic cell transplantation in patients with acute
myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3
trial. Lancet Oncol. 2012;13:1035-1044.
31 Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia.
2000;14:476-479.
32 Milligan DW, Wheatley K, Littlewood T, et al. Fludarabine and cytosine are less effective than
standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and
ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood. 2006;107:
4614-4622.
33 Parker JE, Pagliuca A, Mijovic A, et al. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA)
for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J
Haematol. 1997;99:939-944.
34 Fiegl M, Unterhalt M, Kern W, et al. Chemomodulation of sequential high-dose cytarabine
by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the
AMLCG. Leukemia. 2014;28:1001-1007.
35 Kern W, Schleyer E, Unterhalt M, Wörmann B, Büchner T, Hiddemann W. High antileukemic
activity of sequential high dose cytosine arabinoside and mitoxantrone in patients with
refractory acute leukemias. Results of a clinical phase II study. Cancer. 1997;79:59-68.
36 Quintas-Cardama A, Ravandi F, Liu-Dumlao T, et al. 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.
37 Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and
hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk
myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer.
2007;109:1114-1124.
38 Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared
with conventional care regimens in elderly patients with low bone marrow blast count acute
myeloid leukemia. J Clin Oncol. 2010;28:562-569.
39 Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase
III trial of decitabine versus patient choice, with physician advice, of either supportive care or
low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid
leukemia. J Clin Oncol. 2012;30:2670-2677.
 Chapter 6

Therapeutic management of acute

promyelocytic leukemia
Karsten Spiekermann

Overview of treatment options

Appropriate treatment of acute promyelocytic leukemia (APL) requires
genetic confirmation of the diagnosis by fluorescence in situ hybridiza-
tion (FISH) or polymerase chain reaction (PCR) (promyelocytic leuke-
mia/retinoic acid receptor [PML-RAR+]) and should be performed in
specialized centers with experience in APL treatment. The high cure rate
of APL can only be realized when therapy is initiated as soon as possible
and therefore diagnosis must also be made as early as possible. As pan-
cytopenia can occur in APL, additional coagulation abnormalities such
as hyperfibrinolysis should lead to immediate bone marrow diagnostics.
When the marrow is packed, smears have to be carefully examined for
the presence of Fagott cells. The less frequent hypogranular variant
(M3v) has a characteristic cytomorphology and may not be overlooked
(see diagnosis information in Chapters 3 and 4).
Once the diagnosis of APL has been established it is mandatory
to distinguish high versus non-high risk group patients according to
the classification of Sanz [1], which guides first-line therapy. Therapy
recommendations according to the German Acute Myeloid Leukemia
(AML)-Intergroup are shown in Figure 6.1.

Ó Springer International Publishing Switzerland 2016 53

W. Hiddemann (ed.), Handbook of Acute Leukemia,
DOI 10.1007/978-3-319-26772-2_6
54 • HAN D B O O K O F AC U TE L E U K E M IA

Treatment by risk group and phase

The combination of all trans retinoic acid (ATRA) with chemotherapy has
been used since the 1990s when the benefit over anthracycline (Ara-C)-
based induction therapy was shown [2,3]. ATRA induces differentiation

APL - Diagnosis

WBC

Non-high-risk High-risk
≤ 10GPI/l > 10GPI/l

ATO/ATRA AIDA AIDA

Induction therapy: Induction therapy: Induction therapy:
ATO ATO/ATRA ATRA Idarubicin ATRA Idarubicin

4x Consolidation Consolidation therapy: Consolidation therapy:

therapy:
ATO ATRA 1st Cons. 2nd Cons. 3rd Cons. 1st Cons. 2nd Cons. 3rd Cons.

ATRA ATRA ATRA ATRA ATRA ATRA

Idarubicin Mitoxantrone Idarubicin Idarubicin Mitoxantrone Idarubicin

AraC AraC

RT-PCR- RT-PCR- RT-PCR- RT-PCR-

negative negative negative positive

No maintenance Maintenance Maintenance Salvage

therapy therapy: therapy: therapy:
Figure 6.2
6-mercaptopurine 6-mercaptopurine
Methotrexate Methotrexate

ATRA ATRA

Figure 6.1 Treatment algorithm for first-line therapy of acute promyelocytic leukemia.
Specific anti-leukemic treatment has to be accompanied by immediate supportive management,
which differs from non-acute promyelocytic leukemia acute myeloid leukemia therapy (see
'Supportive management' on page 61). Data from [18]. ATO, arsenic trioxide; APL, acute
promyelocytic leukemia; ATRA, all trans retinoic acid; Cons, consolidation; RT-PCR, reverse
transcription polymerase chain reaction.
 THER APEUTIC MANAGEMENT OF ACUTE PROMYELOC Y TIC LEUKEMIA • 55

of APL blasts, improves coagulopathy, and as a monotherapy can induce

remissions in up to 90% of patients.
The European APL group showed that simultaneous ATRA and chemo-
therapy during induction was superior to sequential ATRA and chemo-
therapy [4]. One European and US study also demonstrated the benefit
of adding maintenance therapy to ATRA [3,4]. Further optimization of
induction chemotherapy resulted in the omission of cytarabine during
induction therapy by the GIMEMA and PETHEMA groups and established
the ATRA plus idarubicin (AIDA) protocol as a widely adapted standard.
Further dose reduction in consolidation for low/intermediate risk patients
established the current standard of risk-adapted ATRA/chemotherapy,
the AIDA2000 protocol (Tables 6.1 and 6.2) [5]. Two randomized trials
have established arsenic trioxide (ATO) plus ATRA as an efficient regimen

Group Year N CR (%) D(E)FS (%) Strategy

European APL 4 1999 99 94 84 ATRA/DA
GIMEMA [6] 1997 240 95 79 ATRA/idarubicin
North American 3 1997 172 72 75 Maintenance
PETHEMA [7] 1999 123 89 92 No Ara-C
AMLCG [8] 2000 51 92 88 High-dose Ara-C
(high risk)

Table 6.1 Early clinical trials comparing ATRA+/– CT and ATRA with modified chemotherapy
in the first-line treatment of acute promyelocytic leukemia. Ara-C, cytarabine; ATRA+/–,
all trans retinoic acid; CR, complete remission; DA, daunorubicin; D(E)FS, disease- (event-) free
survival. Adapted from © American Society of Hematology, 2009. All rights reserved. Tallman,
Altman [9].

Group N Type of chemotherapy CR rate (%)

European APL 4 413 Daunorubicin+Ara-C 90–94
French-Belgian-Swiss [10] 340 Daunorubicin+Ara-C 94–99
MRC [11] 120 Daunorubicin+Ara-C+ other 87
GIMEMA AIDA493 [5] 642 Idarubicin (AIDA) 94.3
GIMEMA AIDA 2000 [5] 453 Idarubicin (AIDA) 94.4
PETHEMA LPA96 [12] 175 Idarubicin (AIDA) 90.7
PETHEMA LPA99 [12] 251 Idarubicin (AIDA) 91.1
PETHEMA/HOVON LPA2005 [13] 402 Idarubicin (AIDA) 92.5

Table 6.2 Larger studies using ATRA+CT first-line treatment of acute promyelocytic
leukemia. AIDA, ATRA + idaruibin; ATRA, all-trans retinoic acid; CR, complete remission; CT,
chemotherapy. Adapted from © American Society of Clinical Oncology, 2011. All rights reserved.
Sanz et al [14].
56 • HAN D B O O K O F AC U TE L E U K E M IA

in the first line treatment of APL. The APL0406 [15] and MRC17 [16]
trial randomized patients to receive either the ATRA/chemotherapy or a
chemotherapy-free regimen consisting of ATO/ATRA. Both trials consist-
ently showed that the ATO/ATRA combination is at least as effective as
the ATRA/chemotherapy arm and represents another standard therapy
of first line non-high risk APL (Table 6.3).

European LeukemiaNet recommendations

Based on the above mentioned studies therapy recommendations from the
European LeukemiaNet [17] were established in 2009 and further ­developed
by national groups for example, the German Intergroup guidelines.

Induction therapy
Induction therapy should consist of the administration of concomitant
ATRA and anthracycline-based chemotherapy. Standard induction
therapy should not be modified based on the presence of additional
leukemia cell characteristics for example, secondary chromosomal
abnormalities, Fms-like tyrosine kinase 3 (FLT3) mutations, CD56
expression, and BCR3 PML-RARA isoform. ATO should be used as stand-
ard therapy in countries where locally produced arsenic compounds
provide a more affordable treatment approach than ATRA plus chemo-
therapy if these compounds are produced under good quality control.
Treatment with ATRA should be continued until terminal differentiation

Study Patients Median Treatment CR EFS OS CIR DFS Median

(n) age (years; (%) (%) (%) (%) (%) follow-up
range)
APL 0406 276 45 ATRA+ATO 100 98 99.1 1.1 98 36 months
[15] (18.7–70.2) versus 97 84.9 94.4 9.4 7.9 (1–75)
ATRA+CHT
AML 17 235 47 ATRA+ATO 94 91 93 1 NR 30.5
[16] (16–77) versus 89 70 89 18 months
ATRA+CHT (3–41.2)
Table 6.3 Randomized clinical trials using ATO/ATRA in the first-line treatment of acute
promyelocytic leukemia. AML, acute myeloid leukemia; APL, acute promyelocytic leukemia;
ATO, arsenic trioxide; ATRA all-trans retinoic acid; CHT, chemotherapy; CIR, cumulative incidence
of relapse; CR, complete remission; DFS, disease-free survival; EFS, event-free survival; NR, not
reported; OS, overall survival.
 THER APEUTIC MANAGEMENT OF ACUTE PROMYELOC Y TIC LEUKEMIA • 57

of blasts and achievement of CR, which occurs in virtually all patients

after conventional ATRA anthracycline induction schedules. Clinicians
should refrain from making therapeutic modifications on the basis of
incomplete blast maturation (differentiation) detected up to 50 days
or more after the start of t­ reatment by morphology, cytogenetics, or
molecular assessment.

Consolidation therapy
Two or three courses of anthracycline-based chemotherapy are consid-
ered the standard approach for consolidation therapy, and the addition
of ATRA to chemotherapy in consolidation seems to provide a clinical
benefit. Consolidation therapy for high-risk patients younger than 60
years of age with white blood cell (WBC) counts higher than 10G/L
should include at least one cycle of intermediate- or high-dose cyta-
rabine. The use of ATO in consolidation represents an alternative in
patients that have received ATRA/ATO as induction therapy. Molecular
remission in the bone marrow should also be assessed at completion of
consolidation therapy by RT-PCR assay affording a sensitivity of at least
1 in 10,000. Patients with confirmed molecular persistence should then
be considered for allogeneic hematpoietic stem cell transplant (HSCT).
However, for patients with molecular persistence who are not candidates
for allogeneic HSCT, therapy with ATO or gemtuzumab ozogamicin
may be considered.

Management after consolidation

Maintenance therapy should be used for patients who have received a
chemotherapy-based induction and consolidation treatment regimen
wherein maintenance has shown a clinical benefit, but not for patients after
ATRA/ATO based induction/consolidation therapy. Because early treat-
ment intervention in patients with evidence of minimal residual disease
(MRD) affords a better outcome than treatment in full-blown relapse,
every 3 months MRD monitoring of bone marrow should be offered to all
patients for up to 3 years after completion of consolidation. Bone marrow
generally allows greater sensitivity for detection of MRD than blood and
therefore is the sample type of choice for MRD monitoring. For patients
58 • HAN D B O O K O F AC U TE L E U K E M IA

testing PCR-positive at any stage after completion of consolidation treat-

ment, it is recommended that a bone marrow aspiration should be repeated
for MRD assessment within 2 weeks and samples should be sent to the
local laboratory, as well as to a reference laboratory for independent con-
firmation. Finally, central nervous system (CNS) prophylaxis should only
be considered for patients with hyperleukocytosis.

Treatment of low/intermediate risk patients according to

the APL0406 study
Patients are considered to be low/intermediate risk patients if their WBC
measures <10G/L at diagnosis. The recommendations as follows are
aimed at treating this population in accordance with results from the
APL0406 study (Table 6.5) [15].

Treatment of high risk patients (WBC >10G/L at diagnosis)

according to AIDA
Patients are considered to be high risk if their WBC measures >10G/L
at diagnosis. The recommendations as follows are aimed at treating this
population in accordance with AIDA (Table 6.6).

Therapy Dosage recommendations

Induction •• ATRA 45 mg/m2 po in two single doses daily until CR, max 60 days
•• Idarubicin 12 mg/m2 iv day 2, 4, 6, 8 (only 3 days in elderly and
comorbid patients)
Consolidation I •• ATRA 45 mg/m2 po in two single doses days 1–15
•• Idarubicin 5 mg/m2 iv day 1, 2, 3, 4
Consolidation II •• ATRA 45 mg/m2 po in two single doses days 1–15
•• Mitoxantrone 10 mg/m2 iv day 1, 2, 3, 4, 5
Consolidation III •• ATRA 45 mg/m2 po in two single doses days 1–15
•• Idarubicin 12 mg/m2 iv day 1
Maintenance •• 6‐mercaptopurine 50 mg/m2 po daily (day 1–91) followed by 15 days
of rest for 7 cycles
•• Methotrexate 15 mg/m2 im/po once weekly for 91 days followed by
15 days of rest for 7 cycles
•• ATRA 45 mg/m2 po in two single doses daily for 15 days (prior to day
1 or after day 91) every 3 month for a total of 6 cycles; during ATRA
therapy treatment break of 6‐MP and MTX

Table 6.4 Therapy of non-high-risk APL with ATRA+ chemotherapy according to AIDA.
AIDA, ATRA plus idarubicin; APL, acute promyelocytic leukemia; ATRA, all trans retinoic acid; CR,
complete response; MTX, methotrexate; iv, intravenous; po, orally. Data from [18].
 THER APEUTIC MANAGEMENT OF ACUTE PROMYELOC Y TIC LEUKEMIA • 59

Relapse treatment options

Experts from the European LeukemiaNet and the German Intergroup
[18] have developed recommendations for salvage therapy of relapsed
APL (Figure 6.2), which are available on the European LeukemiaNet

Therapy Dosage recommendations

Induction •• ATO 0.15 mg/kg iv over 2 h daily starting on day 1; until CR, max 60 days
•• ATRA 45 mg/m2 po in two single doses daily starting on day 1; until
CR, max 60 days
•• Prophylaxis of APL differentiation syndrome with prednisone 0.5
mg/kg day po from day 1 of ATO application to the end of induction
therapy and possibly hydroxyurea (see 'Supportive management',
p61) when WBC >10 G/L
Consolidation •• ATO/ATRA‐based induction therapy is followed by 4 courses of ATO/
ATRA‐based consolidation
•• ATO 0.15 mg/kg iv over 2 h daily for 5 days a week; treatment break
on day 6 and 7
•• 4 weeks on 4 weeks off for a total of 4 courses; last cycles will be
administered on week 25–28
•• ATRA 45 mg/m2 po in two single doses daily 14 days on, 14 days off
for a total of 7 courses

Table 6.5 Therapy of non-high-risk APL with ATO/ATRA according to APL0406. APL, acute
promyelocytic leukemia; ATO, aarsenic trioxide; CR, complete response; iv, intravenous; po, orally;
WBC, white blood cell. Data from [18].

Therapy Dosage recommendations

Induction •• ATRA 45 mg/m2 po in two single doses daily until CR, max 60 days
•• Idarubicin 12 mg/m2 iv day 1, 3, 5, 7 (only 3 days in elderly and
comorbid patients)
Consolidation I •• ATRA 45 mg/m2 po in two single doses days 1–15
•• Id arubicin 5 mg/m2 iv day 1, 2, 3, 4 prior to Ara-C administration
•• Ara-C 1000 mg/m2 iv over 3 hr day 1, 2, 3, 4 after the end of idarubicin
Consolidation II •• ATRA 45 mg/m2 po in two single doses days 1–15
•• Mitoxantrone 10 mg/m2 iv day 1, 2, 3, 4, 5
Consolidation III •• ATRA 45 mg/m2 po in two single doses days 1–15
•• Idarubicin 12 mg/m2 iv day 1 prior to Ara-C administration
•• Ara-C 150 mg/m2/8h iv day 1, 2, 3, 4, 5
Maintenance •• 6‐mercaptopurine 50 mg/m2 po daily (day 1–91) followed by 15 days
of rest for 7 cycles
•• MTX 15 mg/m2 im/po once weekly for 91 days followed by 15 days of
rest for 7 cycles
•• ATRA 45 mg/m2 po in two single doses daily for 15 days (prior to day
1 or after day 91) every 3 month for a total of 6 cycles; during ATRA
therapy treatment break of 6‐MP and MTX

Table 6.6 Therapy of high-risk APL with ATRA+ chemotherapy according to AIDA. APL, acute
promyelocytic leukemia; ATRA, all trans retinoic acid; CR, complete response; MTX, methotrexate;
iv, intravenous; po, orally; Data from [18].
60 • HAN D B O O K O F AC U TE L E U K E M IA

website (http://www.leukemia-net.org/content/leukemias/aml/apl).
Patients with molecular resistance or relapse (hematologic or molecular)
should be treated in a clinical trial or according to these guidelines and
documented in disease-specific patient registries.
Depending on previous therapy that the patient has received ATO or
AIDA/chemotherapy-based protocols are recommended. After frontline
therapy with ATRA/chemotherapy, an intensified ATO/ATRA-based salvage
is the treatment of choice. In the case of first-line ATO/ATRA an ATRA/
chemotherapy-based salvage might be used, although this recommendation
is based on expert opinions and so far not supported by randomized studies.

Molecular resistand, hematological/molecular relapse

AIDA-based salvage
ATO-based salvage
in case of previous
according to the European
ATO-based therapy:
consensus recommendations:*
AIDA-based induction --Donor search-- 1 cycle ATO +/- ATRA and up to
followed by ARA-C based
4 cycles ATO +/- ATRA consolidation
consolidation
(see chapter non-high-risk APL)
(see chapter high-risk APL)

RT-PCR RT-PCR
negative positive

stem cell allogenic

mobilization HSCT

yes no

autologous Maintenance therapy:

HSCT ATRA +/- LD-CTx
ATRA+/- ATO

Figure 6.2 Treatment algorithm for patients with relapsed acute promyelocytic leukemia.
AIDA, all trans retinoic acid plus idarubicin; APL, acute promyelocytic leukemia; ARA-C, cytarabine;
ATO, arsenic trioxide; HSCT, hematopoietic stem cell transplantation; RT-PCR, reverse transcription
polymerase chain reaction. Data from [18].
 THER APEUTIC MANAGEMENT OF ACUTE PROMYELOC Y TIC LEUKEMIA • 61

When a bone marrow molecular remission is achieved, patients proba-

bly benefit from autologous transplantation. Persistence of PML-RAR MRD
indicates a poorer prognosis and an allogeneic stem cell t­ ransplantation
should be considered.

Supportive management of acute promyelocytic leukemia

according to the European LeukemiaNet recommendations
Experts from the European LeukemiaNet and the German Intergroup
have developed ­recommendations for supportive management of APL
as follows [17,18].

Leukocytosis
Hydroxyurea (HU) has been used successfully in patients who develop sus-
tained leukocytosis (>10 G/L). It should be dosed to keep the WBC <10G/L
and subsequently tapered. For WBC 10–50 G/L 500 mg four times daily
and WBC >50 G/L 1000 mg four times daily can be recommended [18].
Recommendations for therapy of leukocytosis according to the
European LeukemiaNet [17] indicate that:
• chemotherapy should be started without delay, even if the
molecular results are still pending;
• leukapheresis should be avoided due to risk of precipitating fatal
hemorrhage; and
• prophylactic steroids can be given, which may reduce the risk of
APL differentiation syndrome.

Coagulopathy
The coagulation abnormalities in APL can manifest as a severe hypofi-
brinogenemia, a prolonged prothrombin time, and thrombocytopenia
but also thromboembolic complications.
Recommendations for therapy of coagulopathy according to the
European LeukemiaNet [17] indicate that:
• treatment with ATRA should be started immediately once a
diagnosis of APL is suspected;
• transfuse liberally with fresh frozen plasma, fibrinogen, and/or
cryoprecipitate and platelet transfusions to maintain the fibrinogen
62 • HAN D B O O K O F AC U TE L E U K E M IA

concentration and platelet count above 100–150 mg/dL and

30–50 G/L, respectively; and
• the benefit of heparin, tranexamic acid, or other anticoagulant or
antifibrinolytic therapy remains questionable and should not be
used routinely outside the context of clinical trials.

Differentiation syndrome
During treatment with ATRA or ATO a differentiation syndrome can
develop rapidly and can be lethal if untreated. The presence of one of
the following signs should raise suspicion:
• weight gain, peripheral edema;
• dyspnea;
• unexplained fever;
• unexplained hypotension;
• acute renal failure or congestive heart failure;
• interstitial pulmonary infiltrates; and
• pleural or pericardial effusions with or without leukocytosis.
Prophylaxis with prednisone is recommended.
Recommendations for therapy of differentiation syndrome state that [17]:
• steroids (10 mg dexamethasone intravenously bd) should be
started immediately at the earliest clinical suspicion of incipient
APL differentiation syndrome;
• once the syndrome has resolved, steroids can be discontinued and
ATO/ATRA recommenced; and
• temporary discontinuation of differentiation therapy (ATRA or ATO)
is indicated only in case of severe APL differentiation syndrome.

Toxicities of arsenic trioxide treatment

Although ATO treatment has a low overall toxicity profile hepatotoxicity
and QTc prolongation typically occur, which require dose adjustment or
temporary discontinuation. Detailed recommendations were developed
by the German Intergroup [18].
 THER APEUTIC MANAGEMENT OF ACUTE PROMYELOC Y TIC LEUKEMIA • 63

References
1 Sanz MA, Lo Coco F, Martin G, 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.
2 Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed
acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91
Group. Blood. 1993;82:3241-3249.
3 Tallman MS, Andersen JW, Schiffer CA, et al. All-trans-retinoic acid in acute promyelocytic
leukemia. N Engl J Med. 1997;337:1021-1028.
4 Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid
(ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance
therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood.
1999;94:1192-1200.
5 Lo-Coco F, Awisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia
with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years:
results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010;116:3171-3179.
6 Mandelli F, Diverio D, Awisanti G, et al. Molecular remission in PML/RAR alpha-positive acute
promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy.
Gruppo Italiano-Malattie Ematologiche Maligne dell’Adulto and Associazione Italiana di
Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood. 1997;90:1014-1021.
7 Sanz MA, Martín G, Rayón C, et al. A modified AIDA protocol with anthracycline-based
consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/
RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood. 1999;94:3015-3021.
8 Lengfelder E, Reichert A, Schoch C, et al. Double induction strategy including high dose
cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed
acute promyelocytic leukemia. German AML Cooperative Group. Leukemia. 2000;14:1362-1370.
9 Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood. 2009;114:5126-5135.
10 Adès L, Chevret S, Raffoux E, et al. Is cytarabine useful in the treatment of acute promyelocytic
leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia
Group. J Clin Oncol. 2006;24:5703-5710.
11 Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count
and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated
with all-trans retinoic acid: result of the Randomized MRC Trial. Blood. 1999;93:4131-4143.
12 Sanz MA, Martín G, González M, et al. Risk-adapted treatment of acute promyelocytic leukemia
with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the
PETHEMA group. Blood. 2004;103:1237-1243.
13 Sanz MA, Montesinos P, Rayón C, et al. Risk-adapted treatment of acute promyelocytic
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16 Burnett AK, Russell NH, Hills RK, et al. Arsenic trioxide and all-trans retinoic acid treatment for
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phase 3 trial. Lancet Oncol. 2015;16:1295-1305
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 Chapter 7

Therapeutic management of acute

lymphoblastic leukemia
Karsten Spiekermann

General approach for management of acute

lymphoblastic leukemia
Treatment of patients with acute lymphoblastic leukemia (ALL) requires a
multidisciplinary team and expertise in handling patients, application of
therapy, and subsequent complications of therapy such as infections and
toxicity. ALL therapy protocols represent the most complex protocols in
oncology and treatment in experienced centers is strongly recommended.
There is no accepted standard protocol for the treatment of adult
ALL. Therefore, all patients should be treated within a clinical trial.
If the patient does not qualify for a clinical trial or refuses enrolment,
prospective treatment recommendations from study groups should be
followed and the treatment should be documented in disease registries.
Detailed diagnosis and treatment recommendations were developed by
the European Working Group for Adult ALL (EWALL) [1].

Prognostic factors and risk-adapted therapy

Prognostic factors include parameters of disease biology (for example,
genetics and immunologic subtype), patient specific factors (such as
age and comorbidity), and response to treatment (for example, time to

Ó Springer International Publishing Switzerland 2016 65

W. Hiddemann (ed.), Handbook of Acute Leukemia,
DOI 10.1007/978-3-319-26772-2_7
66 • HAN D B O O K O F AC U TE L E U K E M IA

complete remission [CR] and minimal residual disease [MRD] status).

The following risk groups can be identified:
• low (or standard) risk group (SR), with a probability of long-term
remission >0.50
• intermediate risk group (IR), with a probability <0.50–0.40;
• high risk group (HR), with a probability <0.40–0.25; and
• very high risk group (VHR), with a probability <0.25.
Prognostic factors differ slightly between study groups and therefore
different risk models have been developed by the German multicenter
ALL (GMALL) group, the Sidney Kimmel Comprehensive Cancer Center
(SKCC), the MD Anderson Cancer Center (MDACC), and the Cancer and
Leukemia Group B (CALGB). The prognostic factors are summarized in
a risk model that estimates the individual risk of relapse and mortality
to guide a risk-adapted therapy.
The following risk factors are accepted in most study groups:
• patient: age
• ALL characteristics: white blood cell (WBC) count, genetics,
and immunophenotype
• response to induction: time to CR; and
• response to post-induction: early MRD reduction (months 1–6).
Modern treatment protocols stratify patients according to disease-specific
risk factors (genetics and subtype), treatment response (CR and MRD),
and age. Adolescents and young adults (AYA) represent a group of patients
between 15–39 years of age that benefit from pediatric-based treatment
protocols. Elderly patients (>55 years of age) are usually treated with
lower intensity protocols

Clinical trials supporting current treatment

algorithms in first-line therapy
Induction regimens for Ph-negative ALL
National Comprehensive Cancer Network (NCCN) Guideline
­recommendations for adult patients ≥40 years of age:
• CALGB 881 Larson regimen: daunorubicine, vincristine,
prednisone, peg-asparaginase, and cyclophosphamide; for patients
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E LY M P H O B L A S T I C L EU K E M I A • 67

aged ≥60 years of age, reduced doses for cyclophosphamide,

daunorubicine, and prednisone [2];
• Linker 4-drug regimen: daunorubicine, vincristine, prednisone,
and peg-asparaginase [3];
• Hyper-CVAD +/– rituximab: hyper-fractionated cyclophosphamide,
vincristine, doxorubicine, and dexamethasone, alternating with
high-dose methotrexate and cytarabine; with or without rituximab
for CD20-positive disease [4,5]; and
• MRC UKALLXII/ECO2993 regimen: daunorubicine, vincristine,
prednisone, and peg-asparaginase (induction Phase I); and
cyclophosphamide, cytarabine, and 6-mercaptopurine (induction
Phase II) [6].

Recommended pediatric-inspired protocols for AYA patients 15–39

years of age:
• GRAALL-2003 regimen: daunorubicine, vincristine, prednisone,
peg-asparaginase, and cyclophosphamide (patients <60 years of
age) [7];
• COG AALL-0434 regimen with nelarabine (for T-ALL):
daunorubicine, vincristine, prednisone, and peg-asparaginase;
nelarabine added to consolidation regimen (NCT00408005;
ongoing study);
• CCG-1961 regimen: daunorubicine, vincristine, prednisone,
peg-asparaginase (patients ≤21 years of age) [8,9];
• PETHEMA ALL-96 regimen: daunorubicine, vincristine,
prednisone, peg-asparaginase and cyclophosphamide (patients
aged ≤30 years) [10];
• CALGB 10403 regimen: daunorubicine, vincristine,
prednisone, and peg-asparaginase (NCT00558519; in patients
<40 years of age);
• DFCI ALL regimen based on DFCI Protocol 00-01: daunorubicine,
vincristine, prednisone, high-dose methotrexate, and
peg-asparaginase (NCT00165178; in patients <50 years of age); and
68 • HAN D B O O K O F AC U TE L E U K E M IA

• USC ALL regimen based on CCG-1882 regimen: daunorubicine,

vincristine, prednisone, and methotrexate with augmented
peg-asparaginase (patients aged 18-57 years) [11].
The recommended NCCN-maintenance regimen is:
• Weekly methotrexate + daily 6-mercaptopurine + monthly
vincristine/prednisone pulses (for 2–3 years)

Induction regimens for BCR-ABL-positive acute

lymphoblastic leukemia
For adult patients ≥40 years of age the recommendations are:
• Tyrosine kinase inhibitors (TKIs) + hyper-CVAD: imatinib or
dasatinib; and hyper-fractionated cyclophosphamide, vincristine,
doxorubicine, and dexamethasone, alternating with high-dose
methotrexate, and cytarabine [12,13]
• TKIs + multiagent chemotherapy: imatinib and daunorubicine,
prednisone and cyclophosphamide [14,15]
• TKIs (imatinib or dasatinib) + corticosteroids [16,17]
The protocols for AYA patients 15–39 years of age are:
• COG AALL-0031 regimen: vincristine, prednisone (or
dexamethasone), and peg-asparaginase, with or without
daunorubicine; or prednisone (or dexamethasone) and peg-
aspargase with or without daunorubicine; imatinib added during
consolidations blocks [18]
• TKIs + hyper-CVAD: imatinib or dasatinib and hyper-
fractionated cyclophosphamide, vincristine, doxorubicine, and
dexamethasone, alternating with high-dose methotrexate and
cytarabine [12,13]
• TKIs + multiagent chemotherapy: imatinib; and daunorubicine,
vincristine, prednisone, and cyclophosphamide [14,15]
The recommended maintenance regimen for this population is:
• Addition of TKIs (imatinib or dasatinib) to maintenance regimen
• Monthly vincristine/prednisone pulses (for 2–3 years). May include
weekly methotrexate + daily 6-mercaptopurine (6-MP) as tolerated
Results of these trials are shown in Table 7.1 yielding an average cure
rate of 35–40% in unselected large adult series from multi-centric trials.
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E LY M P H O B L A S T I C L EU K E M I A • 69

Study No of Median age SCT strategy Survival

(publication year) patients (years)
CALGB 9111 (1998) [19] 198 35 (16–83) BCR-ABL+ 40%, 3 years
LALA 87 (2000) [20] 572 33 (15–60) All patients* 27%, 10 years
NILG 08/96 (2001) [21] 121 35 (15–74) Risk-oriented** 48%, 5 years
GMALL 05/93 (2001) [22] 1163 35 (15–65) Risk-oriented 35%, 5 years
JALSG 93 (2002) [23] 263 31 (15–59) All patients 30%, 6 years
UCLA (2002) [3] 84 27 (16–59) Risk-oriented 47%, 5 years
Sweden (2002) [24] 153 42 (16–82) Risk-oriented 28 %, 5 years
GIMEMA 02/88 (2002) [25] 767 28 (12–60) – 27%, 9 years
MD Anderson (2004) [4] 288 40 (15–92) BCR-ABL+ 38%, 5 years
EORTC ALL3 (2004) [26] 340 33 (14–79) All patients 36% 6 years
LALA94 (2004) [27] 922 33 (15–55) Risk-oriented 36%, 5 years
GOELAL 02 (2004) [28] 198 33 (15–59) Risk-oriented 41%, 6 years
MRC-ECOG (2005) [29] 1521 15–59 All patients 38%, 5 years
GIMEMA 04/96 [30] 450 16–60 – 33%, 5 years
PETHEMA ALL-93 [31] 222 27 (15–50) Risk-oriented 34%, 5 years
JOCG 9004 (2007) [32] 143 41 (<64) All patients 32%, 5 years
GRAALL (2009) 225 31 (15–60) – 60%, 4years
only BCR-ABL-negative [7]
NILG (2009) [33] 280 38 (16–66) – 34%, 5 years
CALGB 19802 (2013) [34] 161 40 (16–82) high-risk 39%, 5 years
cytogenetics
8038 27–60%

Table 7.1 Results of modern treatment protocols for adult acute lymphoblastic
leukemia. *allogeneic SCT applicable to all patients with potential compatible donor (genetic
randomization); **risk stratification criteria vary among studies. SCT, stem cell transplant.
Adapted from © Masaryk University Press, 2011. All rights reserved. Gökbuget et al [35].

Overview of treatment options

The following sections will provide an overview of treatment options
according to the European Working Group of Adult Acute Lymphoblastic
Leukemia recommendations [35].

Chemotherapy and central nervous system therapy

Multi-agent chemotherapy is the backbone of all treatment regimens
(with the exception of BCR-ABL+ induction therapy in some trials). In
addition, CNS prophylaxis is an essential part of treatment and must
be started from the beginning of induction. All patients should receive
70 • HAN D B O O K O F AC U TE L E U K E M IA

intrathecal therapy at the diagnostic lumbar puncture. It is a controver-

sial issue whether the diagnostic lumbar puncture should be postponed
in patients with high peripheral blast count to prevent spread of leuke-
mic cells to the CNS. Currently available methods for CNS prophylaxis
are intrathecal chemotherapy, systemic therapy with drugs that cross
the blood-brain barrier, and radiotherapy. The drugs that are in use for
intrathecal administration in ALL are methotrexate (15 mg), cytarabine
(40 mg), prednisone (40 mg), or dexamethasone (4 mg). These drugs
are given either as monotherapy (methotrexate) or as triple combina-
tion. In addition, liposomal cytarabine with a prolonged half-life may
be used for treatment of CNS relapse. Prophylactic radiotherapy (12–24
Gy) is part of the induction treatment and is administered parallel to
chemotherapy in some trials.

Targeted therapies: tyrosine kinase inhibitors and CD20

antibodies
Tyrosine kinase inhibitors in BCR-ABL+ acute lymphoblastic leukemia
BCR-ABL is an initiating event and stable oncogenic driver mutation in
ALL. First- (imatinib) and second-generation tyrosine kinase inhibitors
(TKIs; nilotinib, dasatinib, bosutinib, and ponatinib) are available and
their optimal use in BCR-ABL+ ALL is under intensive investigation.
Although no randomized trials have been performed in ALL, retrospec-
tive analyses have clearly shown their therapeutic activity [36]. Based
on these findings all patients with BCR-ABL+ ALL should be treated with
a TKI. In contrast to CML, resistance frequently develops and requires
combination therapy and close monitoring. The following general recom-
mendations can be made: (1) the use of second-generation TKI should
be restricted to clinical trials or patients in whom mutational analysis
suggests their utility; and (2) BCR-ABL monitoring by real-time quantita-
tive polymerase chain reaction (RQ-PCR) is strongly recommended and
must be combined with screening for BCR-ABL TK domain mutations in
case of suspected resistance.
Recommendations for induction therapy in BCR-ABL+ ALL are that:
• young adults (<55 years of age or those eligible for allogeneic
hematopoietic stem cell transplantation [HSCT]) should be treated
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E LY M P H O B L A S T I C L EU K E M I A • 71

with imatinib (recommended dose 600 mg) + chemotherapy (4-5

drugs based induction); and
• elderly patients (>55–60 years of age who are not eligible for
HSCT) should be offered imatinib-based induction therapy with
the option of adding steroids and/or chemotherapy.
• The use of second-generation TKIs is under investigation in
clinical trials.
Recommendations for post-induction and maintenance therapy in BCR-
ABL+ ALL suggest that:
• allogeneic SCT is strongly recommended for all eligible patients
(sibling or matched unrelated donor [MUD]). Autologous SCT is
an option after induction and consolidation in minimal residual
disease (MRD)-negative patients and should be followed by
maintenance therapy with TKI and/or chemotherapies; and
• for maintenance the combination of TKI and oral chemotherapy is a
widely proposed option.
Imatinib does not cross the blood-brain barrier whereas dasatinib does
and there is evidence that dasatinib can be effective in treating CNS
disease in patients who have relapsed during treatment with imatinib.

Rituximab
CD20 antibodies have significantly improved the prognosis of patients
with indolent and aggressive lymphomas and CD20 is expressed in
30–50% of adult B-cell precursor (BCP)-ALL. Very recently, the activity
of rituximab has been shown to improve event-free survival (EFS) in the
randomized prospective pediatric-inspired Graall-R 2005 Study trial in
CD20+ BCR-ABL- adult BCP-ALL [37].

Allogeneic stem cell transplantation

The optimal integration of allogeneic SCT into frontline therapy of adult
ALL is currently being actively evaluated in clinical studies. The follow-
ing risk-adapted indications for allogeneic SCT have been developed by
the European Working Group for Adult ALL (EWALL) and are generally
accepted for treatment outside clinical trials:
• high-risk conventional risk factors and/or MRD-based risk factors;
72 • HAN D B O O K O F AC U TE L E U K E M IA

• standard risk molecular non-responders;

• relapse including molecular relapse; and
• All patients in second CR (if necessary in good PR or
beginning relapse).

Immunotherapy
In addition to conventional monoclonal antibodies such as those that
work against CD20 (rituximab) or CD22 (inotuzumab), bispecific T-cell
engager (BiTE) antibodies have been developed to engage cytotoxic
T-cells for lysis of selected target cells. The CD19 BiTE antibody blina-
tumomab is composed of CD19- and CD3-binding portions and links T
cells to CD19+ ALL cells.
In a pivotal trial, blinatumumab has been shown to eradicate MRD
in 80% of ALL patients. This approach has the potential to cure patients,
even in the absence of consolidation by stem cell transplantation [38].
Blinatumumab has also shown impressive activity in some patients
with relapsed/refractory disease and is currently being intensively
­investigated [39].

Treatment by phase
The following sections will provide an overview of treatment by phase
according to the European Working Group of Adult Acute Lymphoblastic
Leukemia recommendations [35].

Remission induction
After diagnosis and parallel to risk stratification the following treatment
phases can be distinguished:
• preparative regimen: this is mandatory to prevent metabolic
dysfunctions particularly in hyperleukocytotic states, tumor lysis
syndrome, and treatment/ prophylaxis of infectious complications;
• pre-induction (optional): corticosteroids +/– other drugs such as
cyclophosphamide for disease debulking;
• induction regimen I: patients should receive a four or five
drug combination (vincristine-corticosteroids anthracycline-
asparaginase +/– cyclophosphamide, or vincristine-
 T H E R A P EU T I C M A N AG E M E N T O F AC U T E LY M P H O B L A S T I C L EU K E M I A • 73

corticosteroids-anthracycline, cyclophosphamide) for 3–4 weeks;

response evaluation (peripheral blood [PB]/bone marrow [BM])
should be carried out approximately on day 28;
• early CNS prophylaxis: during induction I with intrathecal
drug application;
• induction regimen II (optional): similar to pediatric regimens,
this extends the induction period up to week 7 in all patients,
and usually consists of cyclophosphamide and fractionated
conventional doses of cytarabine and mercaptopurine;
• other: G-CSF to shorten and ameliorate neutropenia from cytotoxic
drugs; addition of CD20 antibodies in CD20+ ALL; and
• BCR-ABL+ ALL and Burkitt/B-cell ALL: treatment with highly
specific elements is required.

Consolidation
• Chemotherapy: essential backbone that must follow clinical study
or current national or international treatment programs;
• CNS prophylaxis: treatment has to include intrathecal therapies
and systemic therapies that penetrate the blood-CNS barrier;
• risk-oriented therapy: chemotherapy or allogeneic transplantation
based on pre- and postdiagnostic (for example, MRD risk factors);
response monitoring must be performed to detect early or
impending relapse (MRD); and
• complications: prophylaxis, early diagnosis, and vigorous treatment
of infectious complications to reduce therapy-related mortality.

Maintenance
Maintenance therapy represents a standard treatment of adult ALL with
the exception of patients with mature B-ALL. A total treatment dura-
tion of 2 years with a corresponding length of maintenance is used in
the majority of study groups. MRD should be regularly analyzed with
validated methods to identify and treat molecular relapse. Maintenance
after allogeneic SCT is not recommended (the only exception to this is
for BCR-ABL-positive ALL).
74 • HAN D B O O K O F AC U TE L E U K E M IA

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 Chapter 8

Future outlook for acute leukemias

Marion Subklewe

Emerging therapies in acute leukemias

In the past 40 years our knowledge about the genetic characteristics of
leukemic cells has increased tremendously. This has led to the develop-
ment of new therapeutic modalities acting on different pathways and
utilizing various mechanisms. Examples include the BCR-ABL inhibitors,
which have substantial activity in Ph+ B-precursor acute lymphoblastic
leukemia (ALL) and multi-targeted protein kinase inhibitors such as midos-
taurin, which have improved survival in patients with mutated fms-like
tyrosine kinase 3 (FLT3) when applied in combination with conventional
chemotherapy. New modalities have also been developed for allogeneic
hematopoietic stem cell transplantation (HSCT), which still remains the
most successful therapy for prevention of relapse in non-favorable risk
patients [1]. Moreover, novel strategies have evolved utilizing the immune
system to eliminate leukemic cells. These approaches include antibody-
based immunotherapy and adoptively ­transferred cells (adoptive cellular
therapy [ACT]) among others.

Molecular-targeted therapies
Major advances in understanding leukemia biology and its genetic land-
scape have formed the basis for the development of molecular-targeted
therapies, ideally tailored to each patient’s disease [2]. A therapeutic
breakthrough has been the success of the tyrosine kinase inhibitors

Ó Springer International Publishing Switzerland 2016 77

W. Hiddemann (ed.), Handbook of Acute Leukemia,
DOI 10.1007/978-3-319-26772-2_8
78 • HAN D B O O K O F AC U TE L E U K E M IA

(TKIs) for the treatment of chronic myeloid leukemia (CML), gastro-

intestinal stromal tumors (GIST), and to some extent Ph+ ALL. New
investigational drugs against potential driver mutations such as FLT3
or isocitrate dehydrogenase (IDH) have generated promising results in
clinical trials in acute myeloid leukemia (AML). However, leukemias
often harbor multiple mutations and are potentially composed of sub-
clones with various mutations, rendering combinatorial approaches, drug
dosing, and administrative schedules an open issue.

Molecular-targeted therapies in acute lymphoblastic

leukemia
The advent of TKIs has completely changed the therapeutic landscape of
Ph+ ALL (Table 8.1). A TKI combined with chemotherapy is now used as
the standard treatment for newly diagnosed Ph+ ALL patients. However,
development of resistance to first but also to second-generation TKIs (for
example, dasatinib, nilotinib, and bosutinib) due to T315I mutations are
common causes of disease recurrence. Third generation TKIs such as
ponatinib might overcome this problem but there are also other molecular
targets for combinatorial or alternative strategies [3]. Preclinical data
have demonstrated promising efficacy of pan-phosphoinositide 3 kinase
(PI3K) and mechanistic target of rapamycin (mTOR) inhibitors against
B- and T-ALL cell lines and phase I studies are under way for relapsed
and refractory (r/r) ALL. In T-ALL, NOTCH1, a transmembrane protein
that is important during normal thymocyte development, has been found
to be mutated and translocated in up to 60% of cases. Multiple small
molecules inhibiting the intracellular γ-secretase of NOTCH have been
developed but unfortunately the first trials have failed to demonstrate
clinical benefit [4].

Molecular-targeted therapies in acute myeloid leukemia

Next-generation sequencing has also facilitated the design of molecular-
targeted therapies in AML (Table 8.1). Small molecules targeting mutated
or overexpressed proteins involved in a variety of pathways have been
developed. These molecules act by inhibiting signaling pathways (eg,
kinase inhibitors) or cellular functions (eg, regulators of apoptosis)
 FU T U R E O U T LO O K F O R AC U T E L EU K E M I A S • 79

[5]. FLT3 is the most common mutation in AML and occurs in approxi-
mately one-third of all de novo AML cases. However, first-generation
FLT3 inhibitors (sorafenib and sunitinib) have failed to show sustain-
able responses as single agents in phase I/II trials in r/r AML. Current
developments focus on more selective inhibitors of FLT3 but more
importantly on combinatorial approaches [6]. The relevance of genomic
studies is demonstrated by the successful development of IDH type 2
(IDH2) inhibitors after the revelation of recurrent hot-spot mutations in
IDH1 and IDH2 in normal karyotype AML. The first clinical data from
r/r, IDH2-mutated AML patients resulted in an overall response rate of
41%. Other agents against molecular targets have entered clinical trials
potentially offering treatment options for patients with molecularly
defined AML subtypes (DOT1L inhibitor, bcl-2 inhibitor, bromodomain
[BET] inhibitor). Currently, it appears unlikely that small molecules will
replace conventional chemotherapy in AML but they will rather be inte-
grated into combinatorial approaches with cytotoxic, hypomethylating,
or ­immunotherapeutic approaches.

Allogeneic hematopoietic stem cell

transplantation
Allogeneic HSCT is the most promising approach for preventing recur-
rence of acute leukemia. However, although transplant-related mortal-
ity (TRM) has significantly decreased in the past decades, controversy
remains about which patients will benefit from HSCT in first remission;
in particular, as risk categories are refined and standard risk factors are
annihilated by minimal residual disease (MRD) assessment [7,8]. The
patient cohort eligible for allogeneic HSCT is markedly growing as trans-
plant recipient age and stem cell availability is increasing. T-cell-replete
haploidentical transplantation has recently emerged as a new alternative
transplant modality. Prospectively, advances in immunotherapy will
empower us with more specific tools to eradicate leukemia-initiating
cells responsible for relapse.
80 • HAN D B O O K O F AC U TE L E U K E M IA

Target Indication Inhibitor Phase Patient Response NCT

number rate identifier
ALL: examples of published and registered clinical trials
BCR-ABL Ph+, <60 Imatinib III 268 OS 43% at NCT00327678
5 years
BCR-ABL Ph+ Dasatinib II 53 OS of 69%/ NCT00391989
DFS of 51% at
20 months
BCR-ABL Ph+ Nilotinib II 91 OS of 72% at NCT00844298
24 months
BCR-ABL Ph+ Ponatinib II 60 NA NCT01424982
PI3K, r/r BEZ235 I 23 NA NCT01756118
mTOR
NOTCH T-ALL / LY3039478 I-II 92 NA NCT02518113
T-LBL
AML: examples of published and registered clinical trials
FLT3 FLT3 Crenolanib I-II 88 NA NCT02400281
mutated
FLT3 FLT3 Quizartinib III 326 NA NCT02039726
mutated
FLT3 FLT3 Midostaurin III 717 23% increase NCT00651261
mutated, in OS
<60
FLT3 FLT3 Midostaurin II 18 NA NCT01830361
mutated,
c-KIT
mutated
c-KIT c-KIT Dasatinib III 277 NA NCT02013648
mutated
IDH2 IDH2 AG-221 I-II 375 NA NCT01915498
mutated
Bcl-2 IDH2 Venetoclax II NA NA NCT01994837
mutated,
other
BET MLL OTX015 I-II 180 NA NCT01713582
proteins rearranged,
NPM1c,
other, NHL,
MM
hDOT1L MLL EPZ-5676 I 60 NA NCT01684150
rearranged

Table 8.1 Molecular targeted therapy in acute leukemia. ALL, acute lymphoblastic leukemia;
AML, acute myeloid leukemia; FLT3, fms-like tyrosine kinase 3; IDH2, isocitrate dehydrogenase;
LBL, lymphoblastic lymphoma/leukemia; NA, not applicable. Data from clinicaltrials.gov
(last update: 03/2016).
 FU T U R E O U T LO O K F O R AC U T E L EU K E M I A S • 81

Allogeneic hematopoietic stem cell transplantation in acute

lymphoblastic leukemia
Several meta-analyses of randomized trials have concluded that allogeneic
HSCT with myeloablative conditioning is beneficial for high-risk adult
patients with ALL in first complete remission. In contrast, the benefit
of HSCT in standard risk ALL is controversial. More recent results have
demonstrated the relevance of MRD status prior to allogeneic HSCT.
Thus, MRD negativity is able to confirm standard risk in ALL patients
with a low risk of relapse. Accordingly, most ALL study groups do not
recommend to proceed to allogeneic HSCT in this setting. For the MRD-
negative, high-risk group of ALL patients the recommendations are
more controversial. In contrast, HSCT is the treatment of choice in Ph+
ALL patients. The combination of TKI-based induction-consolidation
chemotherapy and myeloablative allogeneic HSCT has resulted in very
promising 3-year overall survival rates in younger patients [9]. Across all
studies and all ALL subtypes, the MRD status prior to allogeneic HSCT
is highly predictive of relapse. Since persistence of MRD after HSCT is
also significantly associated with poor outcome, these patients should
be considered for early interventional trials including antibody- or
­cell-based immunotherapy.

Allogeneic hematopoietic stem cell transplantation in acute

myeloid leukemia
Allogeneic HSCT is the preferred type of post-remission therapy in the
adverse genetic risk group of AML. In contrast, the relevance of allogeneic
HSCT in intermediate-risk AML is still being debated [10]. Recent data
demonstrate the high association of MRD positivity and relapse rate at
the time of myeloablative allogeneic HSCT [7]. In the future, a differen-
tial genetic risk profile in addition to MRD status will most likely guide
the choice of post-remission therapy. In principle, increased options for
conditioning regimens and donor source have opened up the possibility
of allogeneic HSCT for the vast majority of medically fit patients. Double
umbilical cord blood donor transplantation is another option for adult
AML patients. Most recently, T-cell repleted haploidentical HSCT has
shown comparable results to matched unrelated donor (MUD) HSCT
82 • HAN D B O O K O F AC U TE L E U K E M IA

with high rates of engraftment and acceptable rates of severe acute graft
versus host disease.
In summary, the current data suggest similar results for stem cell
transplantation using alternative donor strategies. Although feasibility of
allogeneic HSCT is increasing, questions on donor hierarchy and preferred
conditioning regimens remain. Moreover, novel post-transplant strate-
gies are needed to modulate graft-versus leukemia effects and prevent
relapse. Agents against molecular and immunotherapeutic targets have
evolved and should to be applied in the post-transplant setting [11].

Antibody-based immunotherapy for acute leukemia

Until recently, only anti-CD20-directed antibody therapy has been
applied as a beneficial additive to conventional chemotherapy in ALL.
Rituximab is a chimeric monoclonal antibody directed against CD20,
which has been incorporated into treatment protocols in ALL and B-cell
lymphoma. Several study groups, including the German Multicenter
Study Group for ALL (GMALL) have reported an improvement in 5-year
overall survival rates with the addition of rituximab to standard induc-
tion and consolidation chemotherapy in patients <55 years of age
[12]. Second generation anti-CD20 antibodies such as ofatumumab
and obinutuzumab bind to an alternative epitope of CD20 and have
been glycoengineered for an increased induction of cell death through
antibody-mediated cytotoxicity. Novel monoclonal antibody formats
target CD19 or CD22 in the case of ALL and CD33 or CD123 in the case
of AML, and are either available as conventional antibodies or conju-
gated to cytotoxic agents. Novel T-cell recruiting antibodies adopt a
completely different approach by serving as adaptor molecules between
T cells and leukemic cells (Figure 8.1).

Antibody drug conjugates in acute lymphoblastic leukemia

Inotuzumab ozogamicin is a humanized monoclonal IgG4 antibody
directed against the B-cell surface molecule CD22. It is conjugated to
the bacterial-derived toxin calicheamicin, which is also used as a toxic
agent in gemtuzumab ozogamicin for AML. Upon binding, CD22 is rapidly
internalized thereby delivering the toxin into the cell, which induces
 FU T U R E O U T LO O K F O R AC U T E L EU K E M I A S • 83

Monoclonal antibody Antibody drug conjugate

Monospecific
antibodies

Monoclonal IgG Antibody drug conjugate

150 kDa ≈150 kDa

Bispecific antibody fragments

Nanobody BiTE DART TandAb

>25 kDa 50 kDa 50 kDa 100 kDa

Bispecific fusion proteins Conjugated IgG

Bispecific antibody constructs

Tandem
Dock and Lock ImmTAC scFv-toxin IgG(H)-sc Fv
160 kDa 75 kDa 120 kDa 200 kDa

Bispecific IgG derivates

Rat Mouse

Cross Mab Triomab DAF (two-in-one)

150 kDa 150 kDa 150 kDa

Figure 8.1 Monospecific (top) and bispecific (bottom) antibody formats currently in clinical
trials for benign and malignant conditions. Red: primary domain; blue: secondary domain;
dark shades: heavy chains; light shades: light chains; green circles: toxin/drug/radioisotope. BiTE,
bispecific T-cell engager; DART, dual affinity retargeting molecule. Adapted from [13].
84 • HAN D B O O K O F AC U TE L E U K E M IA

cell death through DNA double-strand breaks. Similar to CD20, CD22 is

widely expressed on B-ALL cells (> 90% pre-B-ALL and 100% in mature
B-ALL) and normal B cells with lack of expression on hematopoietic stem
cells. However, its rapid internalization makes it an unsuitable target
for conventional antibody formats. In r/r ALL, inotuzumab ozogamicin
has shown an overall response rate (ORR) of 57% as single dose therapy
and 59–66% ORR given in an attenuated weekly dose schedule [14].
Despite the promising results of inotuzumab ozogamicin in r/r ALL
with two-thirds of patients achieving complete remission (CR) including
MRD negativity, the responses were not durable. Future clinical trials
will have to explore the role of inotuzumab ozogamicin in combinato-
rial approaches with chemotherapy in the frontline setting as well as its
role in MRD eradication prior to HSCT. There are several other antibody
drug conjugate (ADC) constructs in clinical development that differ in
target antigen or drug conjugate (Table 8.2).

Antibody drug conjugates in acute myeloid leukemia

By far the most prominent anti-CD33 antibody in clinical application is
gemtuzumab ozogamicin, a calicheamicin-toxin conjugated construct
inducing DNA double-strand breaks upon internalization. In 2010, gem-
tuzumab ozogamicin was voluntarily withdrawn from the market due to
failure to verify clinical benefit and concerns about increased side effects.
Adverse events were attributed to linker instability resulting in toxin-
related off-target toxicities [15]. In recent years, a considerable effort
has been made to optimize immune-conjugated anti-CD33 antibodies.
One such construct (SGN-CD33A) has improved the technology to reduce
linker instability and to allow precise and uniform drug loading [16].
SGN-CD33A is currently being tested in a Phase I clinical study as a single
agent or in combination with a hypomethylating agent (NCT01902329).
Other toxin-conjugated anti-CD33 antibodies have been investigated in
preclinical and clinical studies [17], with only moderate success so far.

T-cell engaging antibodies in acute lymphoblastic leukemia

Bispecific T-cell engagers (BiTE) are a novel class of bispecific antibod-
ies in cancer immunotherapy. They are composed of two single-chain
 FU T U R E O U T LO O K F O R AC U T E L EU K E M I A S • 85

Fv (scFv) fragments, one targeting a tumor-associated antigen, the other

binding a T-cell associated surface receptor. Through binding of CD3ε
in the T-cell receptor complex, BiTEs are able to recruit T cells irrespec-
tive of their antigen specificity. Blinatumomab is the first-in-class BiTE
antibody construct targeting CD19 in B-cell malignancies [18]. The
target antigen CD19 is expressed in 90% of pre-B-ALL and mature B-ALL
patients. In normal hematopoiesis CD19 is expressed at all stages of B-cell
differentiation, with the highest expression on mature B cells but little
expression on terminal differentiated plasma cells [19].

Target Name Phase Format Mechanism of

action
ALL: published and registered clinical trials
CD3 x CD19 Blinatumomab Approved in US BiTE T-cell-mediated
and in EU cytotoxicity
CD22 Inotuzumab III ADC Toxin-mediated
ozogamicin cytotoxicity
CD22 Moxetumomab II ADC Toxin-mediated
pasudotox cytotoxicity
CD19 ADCT-402 I ADC Toxin-mediated
cytotoxicity
CD19 Denintuzumab I ADC Toxin-mediated
mafodotin cytotoxicity
CD19 x CD22 DT2219ARL I 2 scFv + Toxin-mediated
Diphtherie-toxin cytotoxicity
AML: published and registered clinical trials
CD33 Gemtuzumab IV ADC Toxin-mediated
ozogamicin cytotoxicity
CD33 Vadastuximab I/II ADC Toxin-mediated
talirine cytotoxicity
CD25 ADCT-301 I ADC Toxin-mediated
cytotoxicity
CD37 AGS67E I ADC Toxin-mediated
cytotoxicity
CD33 IMGN779 I ADC Toxin-mediated
cytotoxicity
CD3 x CD33 AMG330 I BiTE T-cell-mediated
cytotoxicity
CD3 x CD123 MGD006 0 DART T-cell-mediated
cytotoxicity
Table 8.2 Antibody-based approaches in acute leukemia. ADC, antibody drug conjugate; ALL,
acute lymphoblastic leukemia; AML, acute myeloid leukemia; BiTE, bispecific T-cell engager; DART,
dual affinity retargeting molecule. Data from [13,24] and clinicaltrials.gov (last update: 03/2016).
86 • HAN D B O O K O F AC U TE L E U K E M IA

In a Phase II clinical study of ALL patients in hematologic and mor-

phologic CR but with persistent MRD, blinatumomab induced an MRD
conversion in 80% of patients after 1 cycle. Twelve of the 20 patients
remained in CR after an observation period of 33 months. In December
2014, blinatumomab was approved by the United States Food and Drug
Administration (US FDA) for the treatment of r/r ALL after 43% of patients
achieved a CR/incomplete blood count recovery (CRi) in a confirmatory
clinical Phase II study [20]. Blinatumomab-related toxicities are pre-
dominantly related to a cytokine release syndrome (CRS) due to T-cell
activation and hypogammaglobulinemia due to B-cell depletion [18].

T-cell engaging antibodies in acute myeloid leukemia

Based on the promising results for blinatumomab in ALL, a similar
construct targeting CD33 has been developed for AML (AMG 330).
In preclinical studies, AMG 330 recruited and expanded autologous
residual T cells within the patient sample and efficiently mediated lysis
of primary AML cells [21]. Recently, an international, multi-center first-
in-human study was initiated evaluating the safety and dose limiting
toxicity (DLT) of AMG 330 in r/r AML. Dual affinity retargeting (DART)
molecules are composed of heavy and light chain variable domains of
two antigen-binding specificities on two independent polypeptide chains
[22]. Recently, a DART molecule targeting CD123, the interleukin recep-
tor alpha, was developed for AML (MGD006) [23]. MGD006 is currently
tested in a Phase I clinical study in r/r AML patients (NCT02152956).
T-cell engaging antibody constructs overcome some of the pitfalls of
immuno-chemotherapy approaches (for example, toxin-related off-target
toxicity) and represent a promising alternative strategy as immunotherapy
in acute leukemia.

Chimeric-antigen receptor T cells

Chimeric-antigen receptor T cells for acute lymphoblastic
leukemia
Chimeric antigen receptor T cells (CARTs) are genetically engineered T
cells composed of an extracellular single chain variable fragment (scFv)
fragment targeting a tumor-associated antigen and an intracellular
 FU T U R E O U T LO O K F O R AC U T E L EU K E M I A S • 87

signaling domain (Figure 8.2, Table 8.3). Due to missing efficacy the first
generation CAR construct was further equipped with an intracellular
co-stimulatory domain (second generation CARs). Third generation CAR
T cells comprise a second co-stimulatory domain. A fourth generation
of CAR T cells is emerging that is equipped with additional transgenes
for cytokine secretion or additional co-stimulatory ligands (Figure 8.2).
The most prominent and advanced CAR T-cell constructs target CD19. In
multiple Phase I studies investigating CD19 CAR T cells in r/r ALL, CR
rates of 70–90% could be achieved. In analogy to the T-cell recruiting
antibody constructs, CRS was the most common adverse event related to
high tumor burden. In contrast to CD19, the choice of the target antigen
in other entities, including AML, will be more difficult due to a more
ubiquitous expression pattern in normal hematopoiesis. Alternatively,
technological advances are needed, for example to put an inducible suicide
gene into the genetically modified CAR T cells [25,26].

1st generation 2nd generation 3rd generation

scFv scFv scFv scFv

CD3ζ CD28 4-1BB CD28

CD3ζ CD3ζ 4-1BB

CD3ζ

4th generation

scFv scFv

CD28 CD28
or 4-1BB or 4-1BB

CD3ζ CD3ζ
Cytokine Costimulatory
transgene ligand transgene

Figure 8.2 Chimeric antigen receptors used for CAR T-cell therapy. Adapted from © American
Society of Hematology, 2012. All rights reserved. Brentjens, Curran [27].
 Target antigen Costimulatory Indication Phase Patient Response rate NCT identifier Reference
domain number
ALL: published clinical trials
CD19 4-1BB B-cell leukemia/lymphoma I/IIA 30 90% (CR) NCT01626495, [28]
NCT01029366
B-cell leukemia/ lymphoma I 3 66% (CR) NCT01029366 [29]
CD19 CD28 B-cell malignancies II 10 30% NCT01087294 [30]
B-cell leukemia/lymphoma I 21 60% (CR) NCT01593696 [31]
B-cell malignancies II 15 80% NCT00924326 [32]
CD19 CD28 r/r B-ALL I 16 88% (CR) NCT01044069 [33]
88 • HAN D B O O K O F AC U TE L E U K E M IA

CD19 CD28 r/r B-ALL I 4 50% (CR) NCT01860937 [34]

CD19 CD28 B-cell malignancies I 8 33% NCT00840853 [35]
AML: published and registered clinical trials
LeY CD28 r/r AML I 4 75% CTX 08-0002 [36]
CD33 4-1BB r/r AML I 1 NA NCT01864902 [37]
NKG2D MDS, AML, MM I NA NA NCT02203825 *
CD123 CD28 r/r AML I NA NA NCT02159495 *
CD123 4-1BB r/r AML 0 NA NA NCT02623582 *

Table 8.3 Chimeric antigen receptor T-cell-based approaches in acute leukemia. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CR, complete
remission; NA, not applicable; r/r, relapsed and remitting. *Data from clinicaltrials.gov (last update: 03/2016).
 FU T U R E O U T LO O K F O R AC U T E L EU K E M I A S • 89

Chimeric antigen receptor T cells for acute myeloid leukemia

The choice of suitable target antigens in AML is challenging, as typical
leukemia-associated antigens (LAAs) are also expressed in the normal
myeloid cell compartment. Kenderian et al showed considerable hematopoi-
etic toxicities in a xenograft mouse model after treatment with CD33 CAR
T cells. Efforts to increase the safety profile have been made including the
usage of transient expressing vectors [38]. Until today, four Phase I clinical
trials have been initiated that study the application of CAR T cells for the
treatment of AML including a CD123 CART (NCT02159495). Recently, a
safety study evaluating CAR T cells targeting NKG2D ligands has been
opened (NCT02203825). Finally, a small study testing a LeY specific CAR
T-cell construct has been completed, reporting feasibility and safety of the
therapy as well as persistence of CAR T cells for up to 10 months [36].
The success of CAR T cells in B-cell malignancies has shown the
potency of this tool for the treatment of acute leukemia. Data in the
context of AML are still sparse. Considering the strong on-target off-
leukemia effect inherently associated with CAR T cells directed against
targets that are not exclusively expressed on AML cells, their applica-
tion will most probably be restricted to the induction of a remission in
relapsed or chemorefractory patients, particularly in the context of HSCT.

Checkpoint inhibitors in acute leukemia

Immune checkpoint molecules expressed on cancer cells dampen adaptive
or therapy-induced immune responses through interaction with their ligands
on immune effector cells [39]. The use of blocking antibodies against the
most prominent inhibitory molecules programmed cell death 1 (PD-1) and
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown
to reverse peripheral tolerance in various clinical trials in advanced solid
tumors. These results led to US FDA and European Medicines Agency
(EMA) approval of ipilimumab (anti-CLTA-4 antibody) for advanced
malignant melanoma [40] and pembrolizumab/nivolumab (anti-PD-1
antibody) for advanced melanoma and lung cancer [41]. However, little is
known about the relevance of immune checkpoint molecules in the treat-
ment of acute leukemia [42]. Studies addressing the expression pattern
of immune checkpoints in AML revealed low or even no expression of the
90 • HAN D B O O K O F AC U TE L E U K E M IA

immune checkpoint molecule PD-L1 [43]. However, PD-L1 was shown to

be upregulated upon stimulation with proinflammatory cytokines [43].
The induction of immune checkpoint molecules through targeted immuno-
therapies needs to be further explored. It is conceivable that novel immuno-
therapeutic approaches induce immune escape mechanisms that might be
suitable for checkpoint inhibitors or combinatorial approaches. Currently,
several trials are evaluating the safety and efficacy of checkpoint inhibi-
tors for treatment of AL and myelodysplastic syndromes (NCT02532231,
NCT02508870, and NCT01953692).

Conclusions and future outlook

A large number of novel agents are in clinical development for the
treatment of acute leukemia. Advances in acute leukemia biology and
genetics have opened the door for molecular-targeted agents that act
on various pathways and mechanisms. Targeted immunotherapeutic
approaches have revolutionized cancer immunotherapy in the past
years. Blinatumomab was the first T-cell recruiting antibody approved
for the treatment of cancer. Inotuzumab ozogamicin is now being filed
for approval. International, multicenter clinical trials using CD19 CAR T
cells have been initiated and are currently being evaluated. The success
stories of kinase inhibitors, haploidentical HSCT, blinatumomab and
inotuzumab ozogamicin, and the promising, albeit preliminary data of
CD19 CAR T cells have generated a lot of optimism for the treatment
of acute leukemia. Both advanced characterization of leukemic cells
and multiple therapeutic tools need to be matched to identify the most
­suitable therapeutic approach for each individual patient.

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