Download acute myeloid leukemia

hematology Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Hematology Board Review
Manual is a study guide for fellows and prac­
ticing physicians preparing for board exami­
nations in hematology. Each manual reviews
a topic essential to the current practice of
hematology.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
editorial director
Debra Dreger
Associate EDITOR
Rita E. Gould
assistant EDITOR
Farrawh Charles
executive vice president
Acute Myeloid Leukemia
Series Editor:
Eric D. Jacobsen, MD
Instructor of Medicine, Harvard Medical School, Boston, MA;
Attending Physician, Dana-Farber Cancer Institute, Boston, MA
Contributors:
Brian T. Hill, MD, PhD
Hematology/Oncology Fellow, Taussig Cancer Institute, Cleveland
Clinic, Cleveland, OH
Mikkael A. Sekeres, MD, MS
Associate Professor of Medicine; Staff Physician, Hematologic Oncology
and Blood Disorders; and Co-Director, Hematology-Oncology Fellowship
Program; Cleveland Clinic, Lerner College of Medicine, Case Western
Reserve University, Cleveland, OH
Barbara T. White
executive director
of operations
Jean M. Gaul
Table of Contents
PRODUCTION Director
Suzanne S. Banish
PRODUCTION assistant
Nadja V. Frist
ADVERTISING/PROJECT director
Patricia Payne Castle
sales & marketing manager
Deborah D. Chavis
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Internal Medicine.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Epidemiology and Pathogenesis. . . . . . . . . . . . . . . . . 2
Clinical Evaluation and Treatment of AML. . . . . . . . 3
Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Cover Illustration by Kathryn K. Johnson
Copyright 2009, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of
this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or
otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship
subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full
control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications.
Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information
contained within this publication should not be used as a substitute for clinical judgment.
www.turner-white.comHematology Volume 3, Part 4 Hematology Board Review Manual
Acute Myeloid Leukemia
Brian T. Hill, MD, PhD, and Mikkael A. Sekeres, MD, MS
INTRODUCTION
Acute myeloid leukemia (AML), also known as acute
nonlymphocytic leukemia, represents a group of clonal
hematopoietic stem cell disorders in which both failure
to differentiate into mature cells and excessive proliferation in the bone marrow stem cell compartment
result in the accumulation of myeloblasts.1 For over 3
decades, the French-American-British (FAB) classification system has been used to describe the different categories of AML. In 2001, the World Health Organization
(WHO) published a new classification system for AML
incorporating morphologic, genetic, immunophenotypic, biologic, and clinical features.2 This system was
established in an attempt to more accurately predict
the prognosis and biologic properties of the subcategories of AML. Intensive treatment entails remission
induction followed by post-remission chemotherapy.
For patients who have poor-risk disease or who relapse,
this treatment approach may be followed by hematopoietic stem cell transplantation. However, treatment
recommendations vary, and factors such as patient age,
cytogenetics, performance status, and prognosis must
be considered when choosing treatment options. This
review will discuss epidemiology, pathogenesis, evaluation, and treatment of patients with AML.
EPIDEMIOLOGY AND PATHOGENESIS
Contrary to the popular impression that AML is a
disease of children and young adults, the median age at
diagnosis of AML is approximately 67 years in the United States.3,4 Prognostic and therapeutic information is
determined by whether a patient is considered younger
(< 60 yr) or older (≥ 60 yr). AML is the most common
leukemia, with approximately 12,000 new diagnoses
each year in the United States, and its incidence has
increased from 1992 through 1998.5 It represents 1.2%
of all new cancer diagnoses and 1.3% of estimated
cancer deaths.6
Similar to other malignancies, the pathogenesis of
Hospital Physician Board Review Manual
AML involves a combination of environmental insults
and genetic predisposition leading to DNA damage
or epigenetic changes in affected cells. In AML, the
normal process of myeloid stem cell differentiation is
interrupted, with a maturation block occurring at a
granulocytic cell precursor stage. This transformation
can occur either as a de novo event or be associated with
previous therapy or an antecedent hematologic disorder. This transformation results in the clonal expansion
of an immature precursor blast of myeloid lineage. The
malignant myeloblasts are unable to differentiate into
mature cells and disrupt normal bone marrow function, leading to impaired hematopoiesis.7
• What are the known risk factors for AML?
Several risk factors for AML have been identified.
Germline mutations in the AML1 gene, chromosomal
instability in certain autosomal dominant conditions
(eg, Fanconi’s anemia, ataxia telangiectasia, neurofibromatosis, and Bloom syndrome) as well as congenital immunodeficiency disorders (including infantile X-linked
agammaglobulinemia and Down syndrome) have been
associated with an increased incidence of AML.8 Environmental exposures have also been implicated. Ionizing radiation9 and organic solvents such as benzene
and other petroleum products have been associated
with a higher risk of developing AML.10,11 Both RAS mutations and polymorphisms resulting in inactivation of
NAD(P)H:quinone oxidoreductase have been found
in patients with these exposures.12
Other risk factors for AML may involve treatment of
hematologic malignancies. Therapy-related AML typically develops following alkylating agent–induced damage at a median of 5 to 7 years following therapy for the
primary malignancy. It usually is associated with an antecedent myelodysplastic disorder and abnormalities of
chromosomes 5 and 7.13 DNA-topoisomerase II agents
have also been shown to produce gene rearrangements leading to AML, typically involving an 11q23
abnormality (the MLL gene), with a short latency of
12 to 18 months following treatment.14 Secondary AML
may also develop in patients with various hematologic
disorders, including aplastic anemia, myelodysplastic
www.turner-white.com
Acute Myeloid Leukemia
syndromes, myeloproliferative disorders, and severe
congenital neutropenia. Other inherited hematologic
conditions, such as Bloom syndrome and Fanconi’s
anemia, have also been implicated.15 Finally, the incidence of AML increases with age. In the United States,
the median age of patients with AML is 67 years. Ageadjusted population incidence is 17.6 per 100,000 for
people aged 65 years or older, as compared with 1.8 per
100,000 for patients younger than age 65 years.4 Similarly, chromosomal abnormalities occur with greater
frequency among this population of patients.16
CLINICAL EVALUATION AND TREATMENT OF AML
CASE PRESENTATION
A previously healthy 47-year-old man presents
to his primary care physician with generalized
fatigue over several weeks. The patient’s past medical
history is notable only for essential hypertension and an
episode of acute cholecystitis 10 years ago that required
laparoscopic cholecystectomy. He has not undergone
any other surgeries. There is no family history of malignancy. He is a retired pesticide sales representative but
had no significant exposure to organic chemicals. He
lives with his wife of 45 years. He has never smoked and
drinks alcohol only socially. Review of systems is negative for recurrent infections, weight loss, night sweats,
fevers, bleeding, and dyspnea on exertion.
Physical Examination and Laboratory Studies
Other than fatigue, the patient has no other localizing symptoms. He is afebrile. With the exception of
mild pallor, the physical examination is unremarkable.
Specifically, there is no lymphadenopathy, hepatosple­
n­omegaly, or rash. A complete blood count (CBC)
performed reveals a hematocrit of 26% (normal,
41%–50%), platelet count of 48,000 cells/µL (normal,
150–450 cells/µL), and a total white blood cell (WBC)
count of 55,000 cells/µL (normal < 10,000 cells/µL). A
peripheral blood smear reveals 95% blasts, 4% lymphocytes, and 1% neutrophils.
•What is a typical presentation for patients with
AML?
AML often presents with the clinical sequelae attributable to pancytopenia. The deficient production
of red blood cells can lead to patient complaints of
weakness, fatigue, dyspnea on exertion, and even chest
pain. Pallor is a common physical examination finding.
Infection can result from insufficient numbers of WBCs
or impaired WBC function. Collections of leukemic
cells (seen in leukemia cutis, granulocytic sarcomas,
or chloromas) also may occur rarely. These collections
represent extramedullary sites of disease and may involve cutaneous as well as visceral tissues. In a minority
of cases (5%–20%),17 hyperleukocytosis can lead to ocular or cerebral dysfunction. Low numbers of platelets
can lead to petechiae, gingival bleeding, ecchymosis,
epistaxis, or menorrhagia. Acute promyelocytic leukemia is a distinct variant of AML that often presents
with hemorrhagic complications, including diffuse
intravascular coagulation. Palpable lymphadenopathy
and hepatosplenomegaly are rare findings in AML. It is
typical for patients to complain of flu-like symptoms for
4 to 6 weeks prior to diagnosis.18–21
CASE CONTINUED
The patient is admitted to the hospital for diagnostic evaluation of his abnormal blood count.
Comprehensive metabolic panel, prothrombin time,
and activated partial thromboplastin time are normal.
Both the uric acid and lactate dehydrogenase levels
are elevated at 8.6 mg/dL (normal, 2.5–8.0 mg/dL)
and 378 U/L (normal, 60–100 U/L), respectively. Iron
levels and total iron binding capacity are within normal
limits, but ferritin is elevated at 472 mg/L (normal, 15–
200 mg/L). A repeat CBC performed approximately
18 hours after the patient’s initial CBC test reveals that
the WBC count has increased from 55,000 cells/µL to
69,000 cells/µL with 98% blasts. Staining of peripheral
blasts for myeloperoxidase is strongly positive. The patient is diagnosed with AML.
•When does the diagnosis of AML constitute a medical emergency?
In some patients, particularly younger adults and
those with higher presenting WBC counts, the diagnosis
of AML can constitute a medical emergency, making
prompt referral to a medical hematologist/oncologist
requisite.22 Hyperleukocytosis and/or leukostasis can
cause impairment of blood flow, most often resulting in
central nervous system, cardiac, or pulmonary symptoms.
Rapid lowering of the WBC count can be achieved with
the institution of cytotoxic chemotherapy, leukapheresis, or low-dose cranial radiation. Central nervous system
leukemia is not commonly seen in AML but may present
as headache, lethargy, or cranial nerve signs. For these
patients, intrathecal chemotherapy or, less commonly,
www.turner-white.comHematology Volume 3, Part 4 Acute Myeloid Leukemia
cranial radiation are treatment options. Additionally,
metabolic abnormalities (including those associated
with tumor lysis syndrome) can occur either spontaneously due to high tumor burden or due to cytotoxic chemotherapy. Many patients will present with neutropenia; fever in this population should prompt immediate
hospital admission and institution of appropriate antibiotic agents. Severe thrombocytopenia (platelet count
< 10,000 cells/µL) requires prompt platelet trans­fusions
to avoid spontaneous bleeding episodes.
is performed, along with flow cytometry to identify
myeloid-specific antigens on the myeloblast cell surface.
The leukemic clone that gives rise to AML can occur at
any point along differentiation of the myeloid cell,
creating pathologic heterogeneity among patients. Cytogenetics and fluorescent in situ hybridization (FISH)
testing may further differentiate the various AML subtypes. Table 1 shows a list of suggested tests that should
be performed in newly diagnosed AML patients.
CASE CONTINUED
A double lumen central venous catheter is
placed in the femoral vein, and the patient undergoes emergent leukapheresis. Hydroxyurea therapy
is initiated at 0.75 g every 6 hours (total daily dose, 3 g).
Aggressive intravenous fluid repletion is instituted with
a 5% dextrose solution supplemented with 3 ampules
of sodium bicarbonate and titrated to maintain a urine
output greater than 60 mL/hr. In addition, allopurinol
(300 mg/day) is initiated in order to minimize hyperuricemia. The patient undergoes a bone marrow biopsy and aspirate with cytogenetic analysis, flow cytometry
measurements, and specific genetic testing (described
below) on hospital day 1. Electrolyte, lactate dehydrogenase, and uric acid values are measured every
12 hours during the first several days of hospitalization.
On hospital day 3, the patient’s electrolytes normalize and his WBC count stabilizes at approximately
8000 cells/µL. Renal function is preserved, and the pa­
tient is clinically stable.
The FAB classification system divided AML into
8 subtypes, M0 through M7.24 In 2001, however, the
WHO reclassified AML into 4 categories (Table 2).23
This change in classification was made (1) to reflect
entities with similar biologic features; (2) to incorporate the prognostic and therapeutic importance of
cytogenetic distinctions and clinical history of antecedent hematologic disorders or previous treatment with
radiation and/or chemotherapy; and (3) to enhance
the clinical relevance of the system.25 In addition to
these biologic and clinical features, the system also
takes into account the morphologic and immunophenotypic features of the disease entities. The 4 categories
include AML with recurrent genetic abnormalities,
AML with multilineage dysplasia, AML-therapy related,
and AML not otherwise categorized, which roughly
correlates with the FAB classification. The WHO classification system also differs from the FAB system in that
the previous blast cell threshold of 30% for diagnosis of
AML was reduced to 20%, and patients with recurring
cytogenetic abnormalities are now classified as AML
regardless of blast percentage.23
•What laboratory and imaging studies should be obtained for patients with an initial diagnosis of AML?
A complete evaluation of a patient with newly diagnosed AML requires CBC and assessment of renal and
hepatic function and electrolyte levels. Surveillance
for spontaneous tumor lysis syndrome is essential. In
addition, disseminated intravascular coagulation must
be evaluated by d-dimer levels, fibrinogen levels, and
standard coagulation screening. Baseline cardiac studies including electrocardiogram, chest radiograph, and
echocardiogram should be obtained, as therapeutic approaches may involve cardiotoxic anthracycline drugs.
For most patients, the diagnosis of AML requires a
bone marrow biopsy and aspirate. Within the aspirate
specimen, the identification of at least 20% leukemic
blasts confirms the diagnosis of acute leukemia.23 To
determine commitment along the myeloid lineage,
immunohistochemical staining for myeloperoxidase
Hospital Physician Board Review Manual
•How is AML classified?
CASE CONTINUED
The patient’s bone marrow examination reveals
a relatively hypercellular marrow (60%) with a
high preponderance of immature myeloblasts. There
is impairment of normal hematopoiesis. Cytogenetic
and FISH analyses identify the presence of translocation of portions of chromosome 8 to chromosome 21
(t[8;21]—involving the AML1-ETO genes). Polymerase
chain reaction does not reveal the presence of an internal tandem duplication or tyrosine kinase domain
mutation in the FMS-like tyrosine kinase 3 (FLT3)
gene; however, a common mutation in nucleophosmin
(NPM1) gene is detected.
•What is the role of cytogenetics and other genetic
testing in the treatment of AML?
www.turner-white.com
Acute Myeloid Leukemia
Table 1. Recommended Laboratory Testing and Imaging for Patients Undergoing Initial Evaluation for Acute Myeloid Leukemia
Test
Indication
Complete blood count
Assess degree of leukocytosis and monitor for anemia, thrombo­
cytopenia
Comprehensive metabolic panel including phosphorous and uric acid
Evaluate for tumor burden and spontaneous tumor lysis syndrome
Prothrombin time
Assess for coagulopathy
Activated partial thromboplastin time
Assess for coagulopathy
Screen for diffuse intravascular coagulation including fibrinogen and
d-dimer levels
Assess for diffuse intravascular coagulation
Chest radiograph
Evaluate for pulmonary congestion secondary to leukostasis
Cardiac evaluation with electrocardiogram and either echocardiogram
or multiple uptake gated acquisition scan
Baseline evaluation prior to administration of potentially cardiotoxic
chemotherapy agents (ie, anthracycline drugs)
Tunneled multilumen central venous catheter (eg, Hickman)
Central administration of chemotherapy and reduces frequent
phlebotomy
Bone
•
•
•
•
Essential for the diagnosis of acute myeloid leukemia and subse­
quent risk stratification and prognosis
marrow biopsy/aspirate including:
Flow cytometry
Cytogenetics
Special studies for FLT3 and NPM1 gene mutations
FISH for CBF abnormalities
HLA typing of patient and available siblings
Indicated prior to administration of induction chemotherapy if allo­
genic bone marrow transplant is to be considered in the future
CBF = core binding factor; FISH = fluorescent in situ hybridization; FLT3 = FMS-like tyrosine kinase 3; HLA = human-leukocyte antigen; NPM1 =
nucleophosmin.
There are a number of well-described genetic variations that commonly occur in AML that confer important prognostic information. Cytogenetic prognostic risk
schemas have been developed by the Medical Research
Council, the Cancer and Leukemia Group B (CALGB),
and the Southwest Oncology and Eastern Cooperative
Oncology Groups (SWOG/ECOG).26 For instance, AML
patients with abnormalities that include t(8;21), inv(16),
and t(16;16) (associated with the transcription factor
AML1-CBF β) are placed in a favorable risk group.27,28 In
contrast, 6% to 8% of AML patients harbor structural
alterations of 11q23, leading to MLL rearrangement,
which portends a worse outcome.29 A well-documented
chromosomal abnormality in AML is the t(15;17), which
results in acute promyelocytic leukemia. In this case,
translocation of these chromosomes results in the fusion
of the retinoic acid receptor gene alpha on chromosome
15 with the PML gene on chromosome 17, giving rise to
a fusion product that prevents differentiation to mature
granulocytes.30 Therapy specific for acute promyelocytic
leukemia will be discussed later (see page 7).
Patients can be separated into 3 categories based
on response to induction treatment, relapse risk, and
overall survival: favorable, intermediate, and adverse
cytogenetic groups.31 Typically, patients with favorable
cytogenetic features have core binding factor (CBF) abnormalities, while those with adverse features include
complex (≥ 3 abnormalities) cytogenetics or chromosome 7 abnormalities. Some of the more common cytogenetic abnormalities are shown in Table 3 according
to their risk category.
More recently, gene-expression profiling has also
been shown to improve the molecular classification
and outcome prediction in patients with AML.32 In
particular, testing for FLT3 and NPM1 has become
increasingly common. The NPM1 gene encodes a
nucleolar protein termed nucleophosmin. Wild-type
nucleophosmin normally shuttles between the nucleus
and cytoplasm, whereas a mutant version commonly
found in AML localizes to the cytoplasm.33 NPM1 is
the most commonly mutated gene in AML, occurring in approximately 50% to 60% of cases.34 Patients
who have AML containing mutant NPM1 have a more
favorable outcome than those who do not.35 Recently,
the German-Austrian Acute Myeloid Leukemia Study
Group published data on the impact of molecular lesions on outcome in 872 adults with cytogenetically
normal AML. The investigators found that patients
with a mutant CEBPA or NPM1 (without the FLT3 internal tandem duplication) were significantly more likely
www.turner-white.comHematology Volume 3, Part 4 Acute Myeloid Leukemia
Table 2. World Health Organization Classification of Acute
Myeloid Leukemia
Table 3. Acute Myeloid Leukemia Cytogenetic Risk Groups
Risk Group
Abnormality
Favorable
t(8;21), t(15;17), inv(16)
Intermediate
Normal karyotype, +8, +21, +22, del(7q), del(9q)
Abnormal 11q23, all other structural/numerical
abnormalities
Acute promyelocytic leukemia with t(15;17)(q22;q12), (PML/
RARα) and variants
Adverse
–5, –7, del(5q), abnormal 3q, complex (≥ 3 abnor­
malities)
Acute myeloid leukemia with 11q23 (MLL) abnormalities
Adapted with permission from Grimwade D, Walker H, Oliver F, et al.
The importance of diagnostic cytogenetics on outcome in AML: analy­
sis of 1,612 patients entered into the MRC AML 10 trial. The Medical
Research Council Adult and Children’s Leukaemia Working Parties.
Blood 1998;92:2325. © The American Society of Hematology.
Acute myeloid leukemia with recurrent genetic abnormalities
Acute myeloid leukemia with t(8;21)(q22;q22), (AML1/ETO)
Acute myeloid leukemia with abnormal bone marrow eosinophils
and inv(16)(p13q22) or t(16;16)(p13;q22), (CBFβ/MYH11)
Acute myeloid leukemia with multilineage dysplasia
Following MDS or MDS/MPD
Without antecedent MDS or MDS/MPD, but with dysplasia in
≤ 50% of cells in ≥ 2 myeloid lineages
Acute myeloid leukemia and MDS, therapy related
Alkylating agent/radiation–related type
Topoisomerase II inhibitor–related type (some may be lymphoid)
Others
Acute myeloid leukemia, not otherwise categorized, classify as:
Acute myeloid leukemia, minimally differentiated
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute monoblastic/acute monocytic leukemia
Acute erythroid leukemia (erythroid/myeloid and pure erythro­
leukemia)
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Adapted with permission from Vardiman JW, Harris NL, Brunning RD.
The World Health Organization (WHO) classification of the myeloid
neoplasms. Blood 2002;100:2293. © The American Society of Hema­
tology.
MDS = myelodysplastic syndromes; MPD = myeloproliferative disease.
to attain a complete remission (with odds ratios of 1.33
and 1.48, respectively) and have improved disease-free
and overall survival (P < 0.001 for both) as compared
with other genotypes.36
The FLT3 gene encodes a receptor tyrosine kinase
that is involved in cell proliferation and differentiation
signaling. In approximately 30% of AML patients, the
malignant clone harbors an FLT3 mutation. In general,
these patients have a poorer clinical outcome than patients in whom AML expresses normal copies of FLT3.37
Thus, it is crucial to test for cytogenetics and FISH for
the t(15;17) or CBF abnormalities as well as mutations
Hospital Physician Board Review Manual
in FLT3 and NPM1 at the time of diagnosis, as the results of these studies may help dictate therapy.
CASE CONTINUED
After confirming the diagnosis of AML with
recurrent genetic abnormalities by bone marrow biopsy and aspirate, induction chemotherapy is
initiated with a 7-day continuous infusion of cytarabine in addition to daunorubicin on days 1 through 3.
There are no acute complications during chemotherapy administration. As anticipated, the patient develops
progressive pancytopenia with a nadir in his neutrophil count (absolute neutrophil count, 40 cells/mL)
occurring approximately 2 weeks after the first day of
treatment. He is treated with supportive care consisting
of periodic packed red blood cells and platelet transfusions. The patient experiences a fever associated with
profound neutropenia 15 days after the initiation of
treatment. He is treated with a broad-spectrum anti­
pseudomonal β-lactam, and blood cultures do not grow
any organisms. After 28 days, the patient’s neutropenia
resolves and he is discharged. Two weeks later, the
patient reports to his hematologist for a repeat bone
marrow examination. The peripheral blood smear
reveals improving hematocrit (43%), a platelet count
of 175,000 cells/µL, and a normal absolute neutrophil
count. Bone marrow examination demonstrates normal hematopoiesis with blasts numbering less than 5%,
indicating a complete remission.
•What is the role of induction chemotherapy in AML?
Therapy for AML includes remission induction followed by post-remission chemotherapy. The goal of
induction chemotherapy is to reduce the number of
leukemic cells as well as return proper function of the
www.turner-white.com
Acute Myeloid Leukemia
bone marrow. Treatment recommendations for AML
are often divided into those for patients younger than
age 60 years (“younger” adults) and those aged 60 years
and older (“older” adults). The most common induction regimen for both age-groups is cytarabine administered on days 1 through 7 plus an anthracycline or
anthracenedione (daunorubicin, idarubicin, or mitoxantrone) administered on days 1 through 3.38–43
•What is the role of post-remission chemotherapy in
AML?
Post-remission chemotherapy aims to eradicate any
residual disease in an attempt to obtain a cure. Postremission chemotherapy includes high-dose cytarabine
(HiDAC) for patients younger than age 60 years, given
every 12 hours on days 1, 3, and 5 of a 28-day cycle
for up to 3 or 4 cycles, while cytarabine administered
by continuous infusion over 5 days with or without
an anthracycline or anthracenedione given by bolus
for 2 days is preferred for patients age 60 years and
older for 1 to 2 cycles. HiDAC has proven to be quite
efficacious in younger patients, particularly those with
CBF abnormalities.29 In patients younger than age
60 years, HiDAC yields a 44% 4-year disease-free survival with relatively few relapses but carries with it a 5%
treatment-related mortality rate.44 In contrast, HiDAC
failed to improve the outcome of patients aged 60 years
and older and was associated with higher toxicities including severe neurologic complications.45
•What other therapies are being studied?
Gemtuzumab ozogamicin, an anti-CD33 immunotoxin conjugate, has been approved by the US Food
and Drug Administration for use in refractory AML.
It was shown to have a 30% response rate (complete
response as well as pathologic complete response) in
AML patients in first relapse with previous first remission duration of 6 months or longer.46 To determine if
upfront chemotherapy plus gemtuzumab ozogamicin
has a role in previously untreated patients, a phase 3
Medical Research Council trial compared cytarabinebased therapy with gemtuzumab to standard cytarabinebased induction therapy in 1115 younger AML patients.
Patients randomized to the gemtuzumab arm had a
similar complete remission rate and rates of induction death and resistant disease but higher disease-free
survival at 3 years of follow-up when compared with
patients randomized to standard therapy (51% versus
40%; P = 0.008).47
Clofarabine is a purine nucleoside analogue with
several purported mechanisms of action that has shown
promise in older AML patients. Inhibition of ribonucleotide reductase, incorporation into DNA, and
induction of apoptosis are all thought to underlie
clofarabine’s action. Data from 1 trial that used singleagent clofarabine in newly diagnosed older adults
demonstrated a complete remission rate of 59%.48 It
is being studied alone and in combination with cytarabine in the upfront and refractory setting.49
CASE CONTINUED
Because of the patient’s age, good underlying
functional status, and his CBF cytogenetic abnormality, his best chance for long-term survival is to
receive 4 cycles of HiDAC. He completes all 4 cycles but
develops febrile neutropenia during the second and
fourth cycles, requiring readmission for therapy with
intravenous antibiotic drugs. Following his fourth cycle,
he undergoes a repeat bone marrow biopsy and aspirate, which demonstrates that he remains in complete
response, and cytogenetic analysis and FISH studies for
the t(8;21) are negative.
•What is the role of bone marrow transplantation in
AML patients?
Allogenic bone marrow transplantation is an additional option for post-remission therapy. For some
patients under age 60 years with poor-risk cytogenetic abnormalities and for whom a human leukocyte
antigen–matched sibling or matched-unrelated donor is
available, allogenic stem cell transplantation may follow
induction chemotherapy. This procedure is not without risk and has an associated 20% to 25% treatmentrelated mortality rate and a 1-year mortality rate that
may approach 40%.50 It also represents the only potentially curative therapy for patients with relapsed or
refractory disease. Because of the patient’s relatively
young age, favorable cytogenetic status, and achievement of complete response, he does not undergo
hematopoietic stem cell transplant as it is unlikely
to provide survival benefit. Older patients and those
with suboptimal performance statuses may undergo
reduced intensity (nonmyeloablative) bone marrow
transplantation.
•How is treatment of acute promyelocytic leukemia
different from AML?
A discussion of AML would not be complete without
reviewing the unique characteristics of acute promyelocytic leukemia. Much like other leukemias, acute
www.turner-white.comHematology Volume 3, Part 4 Acute Myeloid Leukemia
promyelocytic leukemia is treated using remission induction therapy but with the addition of differentiation
therapy with all-trans retinoic acid (ATRA), a vitamin A
derivative.51–53 ATRA promotes differentiation of leukemic promyelocytes into mature cells and has been
shown to improve both disease-free and overall survival
as compared with chemotherapy alone.54 ATRA, along
with an anthracycline, is currently the standard of care
for patients with acute promyelocytic leukemia. Arsenic
trioxide, another differentiation agent, has been shown
in a large intergroup trial to improve survival when
administered in the post-remission setting and may
become a standard part of therapy for acute promyelocytic leukemia.55
OUTCOMES
Success in the treatment of patients with AML has
only modestly improved for patients under age 60 years
over the past few decades. In 1966, the median survival
of patients with AML was 40 days.56 Today, AML patients
younger than age 60 years have complete response rates
of 70% to 80% after induction chemotherapy.40 Overall
survival, however, remains at approximately 50% for
those whom attain a complete response, which translates
into 30% overall survival when all patients under age
60 years are considered.57 In 1998, the Medical Research
Council AML 10 trial found that patients could be
separated into 3 prognostic groups: favorable, intermediate, and adverse, defined by pretreatment cytogenetics.
Overall survival at 5 years was found to be 65%, 41%,
and 14%, respectively.31 If a patient undergoes an allogenetic hematopoietic stem cell transplant while in first
remission, the complete response rate has been shown
to range from 45% to 65%, although patient selection
influences these numbers.58 In relapsed AML, however,
complete response after allogenic hematopoietic stem
cell transplant was shown to be 35% or less.59
The prognosis for older patients with AML remains
poor. In the Medical Research Council AML 8 trial, the
remission rate was 70% for patients under age 50 years,
52% for those aged 60 to 69 years, but only 26% for
those over age 70 years.60 One theory for such disparity
in results is that neutropenia after chemotherapy lasts
longer and is less well-tolerated among older adults as
compared with younger patients.16 Another possible
answer is the finding that hematopoietic cells of older
patients are derived from a leukemic clone at diagnosis,
in contrast to normal stem cells found in their younger
counterparts.61 The use of colony-stimulating factors
following the completion of induction chemotherapy
Hospital Physician Board Review Manual
has been shown to reduce the period of neutropenia
and the duration of hospitalization by approximately
2 days; unfortunately, this has not translated into
improved overall survival or a decrease in infectious
complications; hence, the use of these agents is not
indicated in this patient population.16,62
CONCLUSION
Although the diagnosis of leukemia is frequently
suggested by routine laboratory evaluation, prompt
recognition of AML is required to prevent early complications. Rapid cytoreduction and attention to the
patient’s clinical status is essential while establishing
the diagnosis. Bone marrow biopsy specimens should
routinely be analyzed for cytogenetic abnormalities in
addition to specific gene mutations, as these studies
have significant bearing on prognosis and course of
treatment. Chemotherapy with standard regimens for
AML is intense and requires prolonged hospitalization but is reasonably effective at achieving a complete
response, particularly in younger patients. For older
patients, standard chemotherapy is often less effective. The role of hematopoietic stem cell transplant in
AML continues to be defined but represents the best
chance for long-term survival for many patients. As new
drugs are developed, future treatment of AML may be
tailored to the specific genetic defect(s) found in individual patients.
REFERENCES
1. Stone RM, O’Donnell MR, Sekeres MA. Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2004:
98–117.
2. Vardiman JW, Harris NL, Brunning RD. The World Health
Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292–302.
3. Heath C. Epidemiology and hereditary aspects of acute
leukemia. In: Wiernik P, Canellos G, Dutcher J, Kyle R, editors. Neoplastic diseases of the blood. New York: ChurchillLivingstone; 1996:177.
4. Ries L, Eisner M, Kosary C, et al. SEER Cancer Statistics
Review, 1975–2001, National Cancer Institute. Available at
http://seer.cancer.gov/csr/1975_2001. Accessed 25 Aug
2008.
5. Howe HL, Wingo PA, Thun MJ, et al. Annual report to
the nation on the status of cancer (1973 through 1998),
www.turner-white.com
Acute Myeloid Leukemia
featuring cancers with recent increasing trends. J Natl Cancer Inst 2001;93:824–42.
6. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 51;2001:15–36.
7. Giles FJ, Koeffler HP. Secondary myelodysplastic syndromes
and leukemias. Curr Opin Hematol 1994;1:256–60.
65–7.
22. Sekeres MA, Elson P, Wang, X, et al. Time from diagnosis
to treatment initiation predicts survival in acute myeloid
leukemia (AML) [abstract]. American Society of Hematology Annual Meeting Abstracts. Blood 2007;110:598.
8. Sandler DP, Ross JA. Epidemiology of acute leukemia in
children and adults. Semin Oncol 1997;24:3–16.
23. Vardiman JW, Harris NL, Brunning RD. The World Health
Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292–302.
9. Levine EG, Bloomfield CD. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure. Semin Oncol 1992;19:47–84.
24. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the
classification of the acute leukaemias. French-AmericanBritish Cooperative Group. Br J Haematol 1976;33:451–8.
10. Brandt L, Nilsson PG, Mitelman F. Occupational exposure
to petroleum products in men with acute nonlymphocytic
leukemia. Br Med J 1978;1:553.
25. Brunning RD, Matutes E, Harris NL, Flandrin G. Acute myeloid leukemia. In: Jaffe ES, Harrie NL, Stein H, Vardiman
JW. World Health Organization classification of tumours.
Pathology and genetics of tumours of haematopoietic and
lymphoid tissues. Lyon (France): IARC Press; 2001.
11. Austin H, Delzell E, Cole P. Benzene and leukemia. A
review of the literature and a risk assessment. Am J Epidemiol 1988;127:419–39.
12. Smith MT, Wang Y, Kane E, et al. Low NAD(P)H:quinone
oxidoreductase 1 activity is associated with increased risk of
acute leukemia in adults. Blood 2001;97:1422–6.
13. Le Beau MM, Albain KS, Larson RA, et al. Clinical and
cytogenetic correlations in 63 patients with therapy-related
myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of
chromosomes no. 5 and 7. J Clin Oncol 1986;4:325–45.
14. Albain KS, Le Beau MM, Ullirsch R, Schumacher H.
Im­plication of prior treatment with drug combinations
including inhibitors of topoisomerase II in therapyrelated monocytic leukemia with a 9;11 translocation.
Genes Chromosomes Cancer 1990;2:53–8.
15. Lowenberg B, Downing JR, Burnett A. Acute myeloid
leukemia [published erratum appears in N Engl J Med
1999;341:1484]. N Engl J Med 1999;341:1051–62.
16. Stone RM, Berg DT, George SL, et al. Granulocytemacrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J
Med 1995;332:1671–7.
17. Lichtman MA, Heal J, Rowe JM. Hyperleukocytic leukaemia: rheological and clinical features and management.
Baillieres Clin Haematol 1987;1:725–46.
18. Colman RW, Rubin RN. Disseminated intravascular coagulation due to malignancy. Semin Oncol 1990;17:172–86.
19. Stone RM, Mayer RJ. The unique aspects of acute promyelocytic leukemia. J Clin Oncol 1990;8:1913–21.
20. Gralnick HR, Sultan C. Acute promyelocytic leukaemia:
haemorrhagic manifestation and morphologic criteria. Br
J Haematol 1975;29:373–6.
21. Sica S, Salutari P, d’Onofrio G, et al. Bulky lymphadenopathy in acute myeloid leukemia. Ann Hematol 1998;77:
26. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic
analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest
Oncology Group/Eastern Cooperative Oncology Group
study. Blood 2000:96;4075–83.
27. Erickson P, Gao J, Chang KS, et al. Identification of
breakpoints in t(8;21) acute myelogenous leukemia and
isolation of a fusion transcript, AML1/ETO, with similarity
to Drosophilia segmentation gene, runt. Blood 1992;80:
1825–31.
28. Liu P, Tarle SA, Hajra A, et al. Fusion between transcription
factor CBF beta/PEBP2 beta and a myosin heavy chain in
acute myeloid leukemia. Science 1993;261:1041–4.
29. Byrd JC, Mrozek K, Dodge RK, et al; Cancer and Leukemia
Group B (CALGB 8461). Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative
incidence of relapse, and overall survival in adult patients
with de novo acute myeloid leukemia: results from Cancer
and Leukemia Group B (CALGB 8461). Blood 2002;
100:4325–36.
30. de The H, Chomienne C, Lanotte M, et al. The t(15;17)
translocation of acute promyelocytic leukaemia fuses the
retinoic acid receptor alpha gene to a novel transcribed
locus. Nature 1990;347:558–61.
31. Grimwade D, Walker H, Oliver F, et al. The importance
of diagnostic cytogenetics on outcome in AML: analysis
of 1,612 patients entered into the MRC AML 10 trial. The
Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998;92:2322–33.
32. Bullinger L, Dohner K, Bair E, et al. Use of gene-expression
profiling to identify prognostic subclasses in adult acute
myeloid leukemia. N Engl J Med 2004;350:1605–16.
33. Falini B, Nicoletti I, Martelli MF, Mecucci C. Acute myeloid
leukemia carrying cytoplasmic/mutated nucleophosmin
(NPMc+ AML): biologic and clinical features. Blood 2007;
www.turner-white.comHematology Volume 3, Part 4 Acute Myeloid Leukemia
109:874–85.
34. Falini B, Mecucci C, Tiacci E, et al; GIMEMA Acute
Leukemia Working Party. Cytoplasmic nucleophosmin
in acute myelogenous leukemia with a normal karyotype
[published erratum appears in N Engl J Med 2005;352:
740]. N Engl J Med 2005;352:254–66.
35. Verhaak RG, Goudswaard CS, van Putten W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities
and previously established gene expression signatures and
their favorable prognostic significance. Blood 2005;106:
3747–54.
36. Schlenk RF, Dohner K, Krauter J, et al; German-Austrian
Acute Myeloid Leukemia Study Group. Mutations and
treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358:1909–18.
37. Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine
kinase domain mutations for acute myeloid leukemia: a
meta-analysis. Leukemia 2005;19:1345–9.
38. Bishop JF, Lowenthal RM, Joshua D, et al. Etoposide in
acute nonlymphocytic leukemia. Australian Leukemia
Study Group. Blood 1990;75:27–32.
39. Bishop JF, Matthews JP, Young GA, et al. A randomized
study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996;87:1710–7.
40. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia.
Cancer and Leukemia Group B. N Engl J Med 1994;331:
896–903.
41. Rees JK, Gray RG, Wheatley K. Dose intensification in
acute myeloid leukaemia: greater effectiveness at lower
cost. Principal report of the Medical Research Council’s
AML9 study. MRC Leukaemia in Adults Working Party. Br
J Haematol 1996;94:89–98.
42. Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized
investigation of high-dose versus standard-dose cytosine
arabinoside with daunorubicin in patients with previously
untreated acute myeloid leukemia: a Southwest Oncology
Group study. Blood 1996;88:2841–51.
43. Burnett A. Tailoring the treatment of acute myeloid leukemia. Curr Opin Oncol 1999;11:14–9.
44. Byrd JC, Ruppert AS, Mrozek K, et al. Repetitive cycles of
high-dose cytarabine benefit patients with acute myeloid
leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results from CALGB 8461. J Clin Oncol 2004;22:1087–94.
45. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia.
Cancer and Leukemia Group B. N Engl J Med 1994;331:
896–903.
Study Group. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia
in first relapse. J Clin Oncol 2001;19:3244–54.
47. Burnett AK, Kell WJ, Goldstone AH, et al. The addition of
gemtuzumab ozogamicin to induction chemotherapy for
AML improves disease free survival without extra toxicity:
preliminary analysis of 1115 patients in the MRC AML15
trial [abstract]. American Society of Hematology Annual
Meeting Abstracts. Blood 2006;108:13.
48. Bunett AK, Baccarani M, Johnson P, et al. Clofarabine in
previously untreated elderly (> 65 yrs) AML patients with
an unfavourable cytogenetic profile who are considered
unfit for standard intensive chemotherapy. ASCO Meeting
Abstracts. J Clin Oncol 2006;24(Suppl):6513.
49. Faderl A, Ravandi F, Huang X, et al. A randomized study
of clofarabine versus clofarabine plus low-dose cytarabine
as frontline therapy for patients age >= 60 years with acute
myeloid leukemia and high-risk myelodysplastic syndrome
Blood 18 Jun 2008 [Epub ahead of print].
50. Gorin NC. Autologous stem cell transplantation in acute
myelocytic leukemia. Blood 1998;92:1073–90.
51. 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:
1192–200.
52. Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 1990;76:1704–9.
53. 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;82:3241–9.
54. Tallman MS, Andersen JW, Schiffer CA, et al. All-transretinoic acid in acute promyelocytic leukemia [published
erratum appears in N Engl J Med 1997;337:1639]. N Engl
J Med 1997;337:1021–8.
55. Powell BL, Moser B, Stock W, et al. Effect of consolidation
with arsenic trioxide (As2O3) on event-free survival (EFS)
and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710. J Clin Oncol 2007;25:2.
56. Treatment of acute leukaemia in adults: comparison of steroid and mercaptopurine therapy, alone and in conjunction. Second report to the Medical Research Council of
the Working Party on the evaluation of different methods
of therapy in leukaemia. Br Med J 1966;1:1383–9.
46. Sievers EL, Larson RA, Stadtmauer EA, et al; Mylotarg
57. Appelbaum FR, Rowe JM, Radich J, Dick JE. Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2001:62–86.
10 Hospital Physician Board Review Manual
www.turner-white.com
Acute Myeloid Leukemia
58. Grigg AP, Szer J, Beresford J, et al. Factors affecting the
outcome of allogeneic bone marrow transplantation for
adult patients with refractory or relapsed acute leukaemia.
Br J Haematol 1999;107:409–18.
59. Edenfield WJ, Gore SD. Stage-specific application of allogeneic and autologous bone marrow transplantation in
the management of acute myeloid leukemia. Semin Oncol
1999;26:21–34.
60. Rees JK, Gray RG, Swirsky D, Hayhoe FG. Principal results
of the Medical Research Council’s 8th acute myeloid leu-
kaemia trial. Lancet 1986;2:1236–41.
61. Fialkow PJ, Singer JW, Raskind WH, et al. Clonal development, stem-cell differentiation, and clinical remissions in
acute nonlymphocytic leukemia. N Engl J Med 1987;317:
468–73.
62. Dombret H, Chastang C, Fenaux P, et al. A controlled study
of recombinant human granulocyte colony-stimulating
factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J
Med 1995;332:1678–83.
test yourself with self-assessment questions
Questions for self-assessment in selected specialties are available on Hospital Physician’s Web site.
Go to www.turner-white.com, click on Hospital Physician, then click on “Self-Assessment Questions.”
Copyright 2009 by Turner White Communications Inc., Wayne, PA. All rights reserved.
www.turner-white.comHematology Volume 3, Part 4 11