Acute Myelogenous Leukemia

Definition
Acute myelogenous leukemia (AML) is a clonal, malignant disease of hematopoietic tissue
that is characterized by (1) accumulation of abnormal (leukemic) blast cells, principally in the
marrow, and (2) impaired production of normal blood cells. Thus, the leukemic cell
infiltration in marrow is accompanied, nearly invariably, by anemia and thrombocytopenia.
The absolute neutrophil count may be low or normal, depending on the total white cell count.
Etiology
Only three well-documented environmental factors are established causal agents: high-dose
external low-linear energy transfer radiation exposure, chronic benzene exposure, and
chemotherapeutic agents. Most patients have not been exposed to an antecedent causative
factor. Exposure to high linear energy transfer radiation from -emitting radioisotopes
such as thorium dioxide increases the risk of AML. Case control studies have sometimes
found a relationship between AML and organic solvents, petroleum products, radon
exposure, pesticides, and herbicides, but these data have not reached the level of the strong
association that exists for benzene, high-dose external irradiation, and certain
chemotherapeutic agents.
26
The predominance of studies, but not all, has suggested an
association between cigarette smoking and AML. Maternal alcohol use has been associated
with AML in infancy.
Molecular Pathogenesis
AML results from a series of somatic mutations in either a hematopoietic multipotential cell
or, occasionally, a more differentiated, lineage-restricted progenitor cell. Some cases of
monocytic leukemia, promyelocytic leukemia, and AML in younger individuals more likely
arise in a progenitor cell with lineage restrictions (progenitor cell leukemia). Other
morphologic phenotypes and older patients likely have disease that originates in a primitive
multipotential cell. In the latter case, all blood cell lineages can be derived from the leukemic
stem cell because it retains the ability for some degree of differentiation and maturation
Somatic mutation results from a chromosomal translocation in the majority of patients. The
translocation results in rearrangement of a critical region of a protooncogene. Fusion of
portions of two genes usually does not prevent the processes of transcription and translation;
thus, the fusion gene encodes a fusion protein that, because of its abnormal structure, disrupts
a normal cell pathway and predisposes to a malignant transformation of the cell. The mutant
protein product often is a transcription factor or element in the transcription pathway that
disrupts the regulatory sequences controlling growth rate or survival of blood cell progenitors
and differentiation and maturation.
83,84,85
Examples of genes often mutated are core binding
factor, retinoic acid receptor (RAR), HOX family, MLL, and others. Core binding factor has
two subunits: CBF- and AML1. Approximately 10 percent of AML cases have
translocations involving one or the other of these latter two genes, although the percentage
varies depending on the patient's age at onset. In patients younger than 50 years, the
frequency is approximately 20 percent. In patients older than 50 years, the frequency is
approximately 6 percent. Core binding factor activates genes involved in myeloid and
lymphoid differentiation and maturation. These primary mutations are not sufficient to cause
AML. Additional activating mutations, for example, in hematopoietic tyrosine kinases FLT3
and Kit or in N-ras and K-ras, are required to induce a proliferative advantage in the affected
primitive cell. Other protooncogene mutations occur in leukemic cells involving FES, FOS,
GATA-1, JUN B, MPL, MYC, p53, PU.1, RB, WT1, WNT, and other genes. Their interaction
with loss-of-function mutations in hematopoietic transcription factors probably causes the
acute leukemia phenotype characterized by disordered proliferation, programmed cell death,
differentiation, and maturation.
85
A minimum of two classes of genes has been proposed:
class I gene mutations, e.g., AML1, which lead to a proliferation and survival advantage to the
cells in the clone, and class II gene mutations, e.g., core binding factor, which interacts with
the class I mutation, conferring severely disturbed differentiation and maturation patterns on
the mutated cell and fostering the evolution of a classic AML phenotype.
85
Because the
mutant stem or early progenitor cell can proliferate and retains the capability to differentiate,
a wide variety of phenotypes can emerge from a leukemic transformation.
FLT3 encodes a tyrosine kinase receptor in normal myeloid and lymphoid progenitors.
Internal tandem duplications of FLT3 on chromosome 13 occurs in approximately one fourth
to one third of adult AML cases but occur more frequently in cases of AML with normal
cytogenetic patterns, monocytic phenotype, and PML-RAR- or DEK-CAN translocations.
The FLT3-ITD mutation confers a poor prognosis if the ratio of mutant to wild-type
expression is high. Hypermethylation of the death-associated protein kinase has been
observed in approximately 25 percent of AML cases and is twice as prevalent in cases of
AML following cytotoxic therapy. Deletions of all or part of a chromosome (e.g.,
chromosome 5, 7, or 9) or additional chromosomes (such as trisomy 4, 8, or 13) are common
cytogenetic abnormalities (see Chap. 10), although the specific causative oncogenes or tumor
suppressor genes in these latter circumstances have not been defined. Deletions in
chromosomes 5 and 7 and complex cytogenetics abnormalities are increased in frequency in
older patients and cases of AML following cytotoxic therapy compared to de novo cases.
98

Because the genes residing on the undeleted homologous segment of chromosome 5 are not
mutated, an epigenetic lesion, such as hypermethylation of a gene allelic to one on the deleted
segment on chromosome 5, may result in the leukemogenic event.
In acute promyelocytic leukemia, PML-RAR- fusion protein represses retinoic acid-
inducible genes, which prevent appropriate maturation of promyelocytes. The induced
disruption, which involves corepressorhistone deacetylase complexes, results in the
leukemic phenotype.

Classification
Variants of AML can be identified by morphologic features of blood films using
polychromatic stains and histochemical reactions,
Immunologic Phenotypes of AML


Usually Positive
Myeloblastic CD11, CD13, CD15, CD33, CD117, HLA-DR
Myelomonocytic CD11, CD13, CD14, CD15, CD32, CD33, HLA-DR
Erythroblastic Glycophorin, spectrin, ABH antigens, carbonic anhydrase I, HLA-DR
Promyelocytic CD11, CD13, CD15, CD33
Monocytic CD11, CD13, CD14, CD33, HLA-DR
Megakaryoblastic CD34, CD41, CD42, CD61, von Willebrand factor


NOTE: Chapter 14 provides the definition of the antigen that represents a cluster of
differentiation (CD).
Morphologic Variants of AML


Variant Cytologic Features Special Clinical
Features
Special Laboratory
Features
Acute
myeloblastic
leukemia (M0,
M1, M2)
1. Myeloblasts are
usually large; nuclear
cytoplasmic ratio 1:1.
Cytoplasm usually
contains granules and
occasionally Auer
bodies. Nucleus shows
fine reticular pattern
and distinct nucleoli.
1. Most common in
adults, and most
frequent variety in
infants.
1. Chromosomes +8,
5, 7, common.
2. Blast cells are
sudanophilic. They are
positive for
myeloperoxidase and
chloroacetate esterase,
negative for nonspecific
esterase, and negative
or diffusely positive for
PAS (no clumps or
blocks).
2. Three morphologic-
cytochemical types
(M0, M1, M2)
2. M0 type blast cells
positive with antibody
to myeloperoxidase
and anti-CD34 and
CD13 or CD33
coexpression. AML1
mutations in
25%.
3. Electron microscopy
shows primary
3. M1 expresses CD13
and CD33. Positive for
cytoplasmic granules. myeloperoxidase by
cytochemistry.
4. (M2) AML with
maturation often
associated with t(8;21)
karyotype.
Acute
promyelocytic
leukemia (M3,
M3v)
1. Leukemic cells
resemble romyelocytes.
They have large
atypical primary
granules and a kidney-
shaped nucleus.
Branched or adherent
Auer rods are common.
1. Usually in adults. 1. Cell contains
t(15;17) or other
translocation involving
chromosome 17 (RAR-
gene).
2. Peroxidase stain
intensely positive.
2. Hypofibrinogenemia
and hemorrhage
common.
2. Cells are HLA-DR
negative.
3. A variant has
microgranules (M3v),
otherwise the same
course and prognosis.
3. Leukemic cells
mature in response to
all-trans-retinoic acid.

Acute
myelomonocytic
leukemia (M4,
M4Eo)
1. Both myeloblastic
and monoblastic
leukemic cells in blood
and marrow.
1. Similar to
myeloblastic leukemia
but with more frequent
extramedullary disease.
1. Eosinophilic variant
has inversion or
translocation of
chromosome16.
2. Peroxidase-, Sudan-,
chloroacetate esterase-,
and nonspecific
esterase-positive cells.
2. Mildly elevated
serum and urine
lysozyme.

3. M4Eo variant has
marrow eosinophilia.

Acute monocytic
leukemia (M5)
1. Leukemia cells are
large; nuclear
cytoplasmic ratio lower
than myeloblast.
Cytoplasm contains
fine granules. Auer rods
are rare. Nucleus is
convoluted and may
contain large nucleoli.
1. Seen in children or
young adults.
1. t(4;11) common in
infants.
2. Nonspecific esterase-
positive inhibited by
NaF; Sudan-,
peroxidase-, and
chloroacetate esterase-
negative. PAS occurs in
granules, blocks.
2. Gum, CNS, lymph
node, and
extramedullary
infiltrations are
common.
2. Rearrangement of
q11;q23 very frequent.
3. DIC occurs.
4. Plasma and urine
lysozyme elevated.

5. Hyperleukocytosis
common.

Acute
erythroleukemia
(M6)
1. Abnormal
erythroblasts are in
abundance initially in
marrow and often in
blood. Later the
morphologic findings
may be
indistinguishable from
those of AML.
1. Pancytopenia
common at diagnosis.
1. Cells reactive with
antihemogloblin
antibody. Erythroblasts
usually are strongly
PAS and CD71-
positive, express ABH
blood group antigens,
and react with
antihemoglobin
antibody.
2. Cells reactive with
antiRc-84 (antihuman
erythroleukemia cell-
line antigen).
Acute
megakaryocytic
leukemia (M7)
1. Small blasts with
pale agranular
cytoplasm and
cytoplasmic blebs. May
mimic lymphoblasts of
medium to larger size.
1. Usually presents
with pancytopenia.
1. Antigens of von
Willebrand factor, and
glycoprotein Ib
(CD42), IIb/IIIa
(CD41), IIIa (CD61)
on blast cells.
2. Markedly elevated
serum lactic
dehydrogenase levels.
2. Platelet peroxidase
positive.
3. Marrow aspirates are
usually "dry taps"
because of the
invariable presence of
myelofibrosis.

4. Common phenotype
in the AML of Down
syndrome.



NOTE: Parentheses indicate FAB designation. NaF, sodium flouride; DIC, disseminated
intravascular coagulation.

Clinical Features
Signs and Symptoms
General
Signs and symptoms that signal the onset of AML include pallor, fatigue, weakness,
palpitations, and dyspnea on exertion. The signs and symptoms reflect the development of
anemia; however, weakness, loss of sense of well-being, and fatigue on exertion can be out of
proportion to the severity of anemia. Easy bruising, petechiae, epistaxis, gingival bleeding,
conjunctival hemorrhages, and prolonged bleeding from skin injuries reflect
thrombocytopenia and are frequent early manifestations of the disease. Very infrequently,
gastrointestinal, genitourinary, bronchopulmonary, or central nervous system (CNS) bleeding
occurs at the onset of disease.
Pustules or other minor pyogenic infections of the skin and of minor cuts or wounds are most
common. Major infections, such as sinusitis, pneumonia, pyelonephritis, and meningitis, are
uncommon presenting features of the disease, partly because absolute neutrophil counts less
than 500/ l (0.5 x 10
9
/liter) are uncommon until chemotherapy starts. With intensification
of neutropenia and monocytopenia after chemotherapy, major bacterial, fungal, or viral
infections become frequent. Anorexia and weight loss are frequent findings. Fever is present
in many patients at the time of diagnosis. Palpable splenomegaly or hepatomegaly occurs in
approximately one third of patients. Lymphadenopathy is extremely uncommon, except in the
monocytic variant of AML.
Specific Organ System Involvement
Leukemic blast cells circulate and enter most tissues in small numbers.
129
Occasionally,
biopsy or autopsy uncovers marked aggregates or infiltrates of leukemic cells. Collections of
such cells may cause functional disturbances. Extramedullary involvement is most common
in monocytic or myelomonocytic leukemia.
Skin involvement may be of three types: nonspecific lesions, leukemia cutis, or granulocytic
(myeloid) sarcoma of skin and subcutis. Nonspecific lesions include macules, papules,
vesicles, pyoderma gangrenosum, vasculitis, neutrophilic dermatitis (Sweet syndrome),
139

cutis vertices gyrata,
140
and erythema multiforme or nodosum. Skin involvement preceding
marrow and blood involvement is rare.
Sensory organ involvement is very unusual, but retinal, choroidal, iridial, and optic nerve
infiltration can occur.
142
Otitis externa and interna, inner ear hemorrhage, and mastoid tumors
with seventh nerve involvement may be presenting signs.
The gastrointestinal tract may be involved at any point, but functional disturbances are
unusual.
146,147
The mouth, colon, and anal canal are sites of involvement that most commonly
lead to symptoms. Oral manifestations may prompt the patient to visit the dentist. Gingival or
periodontal infiltration and dental abscesses may lead to an extraction, followed by prolonged
bleeding of an infected tooth socket.
148
Ileotyphlitis (enterocolitis), a necrotizing
inflammatory lesion involving the terminal ileum, cecum, and ascending colon, can be a
presenting syndrome or occur during treatment.
149,150,151
Fever, abdominal pain, bloody
diarrhea, or ileus may be present and occasionally mimic appendicitis. Intestinal perforation,
an inflammatory mass, and associated infection with enteric gram-negative bacilli or
clostridial species often are associated with a fatal outcome. Isolated involvement of the
gastrointestinal tract is rare.
152,153
Proctitis, especially common in the monocytic variant of
AML, can be a presenting sign or a vexing problem during periods of severe
granulocytopenia and diarrhea.
146

The respiratory tract can be involved by infiltrates or tumors, leading to laryngeal
obstruction, parenchymal infiltrates, alveolar septal infiltration, or pleural seeding. Each of
these events can result in severe symptoms and radiologic findings.
154,155,156,157,158

Cardiac involvement is frequent but rarely causes symptoms. Symptomatic pericardial
infiltrates, transmural ventricular infiltrates with hemorrhage, and endocardial foci with
associated intracavitary thrombi can occasionally cause heart failure, arrhythmia, and death.
1

Infiltration of the conducting system or valve leaflets or myocardial infarction has occurred.
The urogenital system can be affected. The kidneys are infiltrated with leukemic cells in a
high proportion of cases, but functional abnormalities are rare. Hemorrhage in the pelvis or
collecting system is frequent. Cases of vulvar, bladder neck, prostatic, or testicular
involvement have been described.
Osteoarticular symptoms may occur. Bone pain, joint pain, and bone necrosis can occur, and
rarely arthritis with effusion is present. Crystal-induced arthritis of either calcium
pyrophosphate dihydrate (pseudogout) or monosodium urate (gout) may be responsible for
the synovitis in some cases.
Central or peripheral nervous system involvement by infiltration of leukemic cells is very
uncommon, although meningeal involvement is an important consideration in the treatment
of the monocytic type of AML.
168,169
An association of CNS involvement and diabetes
insipidus in AML with monosomy 7
170
and inversion of chromosome 16
171,172
has been
reported
Laboratory Features
Blood Cell Findings
Anemia is a constant feature. Red cell life span may be mildly shortened, but the principal
cause of anemia is inadequate production of red cells. The reticulocyte count usually is
between 0.5 and 2.0 percent. Occasionally patients have rapid destruction of autologous and
transfused red cells as a result of an unknown mechanism (milieu hemolysis). The presence
of red cell autoantibodies (positive Coombs test) is very uncommon and may be nonspecific
(anti-C
3
), perhaps related to circulating immune complexes. Red cell morphology is mildly
abnormal, with exaggerated variation in cell size and occasional poikilocytes. Nucleated red
cells or stippled erythrocytes may be present. Less often, extreme abnormalities of red cell
size, shape, and hemoglobin content occur, but these changes are seen more often in
oligoblastic myelogenous leukemia.
Thrombocytopenia is nearly always present at the time of diagnosis. The mechanism of
thrombocytopenia is a combination of inadequate production and decreased survival of
platelets. More than half of patients have a platelet count less than 50,000/ l (50 x
10
9
/liter) at the time of diagnosis.
184
Giant platelets and poorly granulated platelets with
functional abnormalities can occur.
185
Defects in platelet aggregation and 5-
hydroxytryptamine release are frequent.
185

The total leukocyte count is less than 5000/ l (5 x 10
9
/liter) in approximately half of
patients at the time of diagnosis. The absolute neutrophil count is less than 1000/ l (1 x
10
9
/liter) in more than half of cases at diagnosis. Patients with very elevated total leukocyte
counts have a low proportion of mature neutrophils but may have a normal absolute
neutrophil count. Hypersegmented, hyposegmented, and hypogranular mature neutrophils
may be present. Cytochemical abnormalities of blood neutrophils include low or absent
myeloperoxidase or low alkaline phosphatase activity.
186
Defects in phagocytosis or
microbial killing are common.
187

Myeloblasts almost always are present in the blood but may be infrequent in leukopenic
patients. Diligent search may uncover the myeloblasts, or examination of a white cell
concentrate (buffy coat) may permit their identification. Classic leukemic blast cells are
agranular, but mixtures of immature cells, including agranular and slightly granular cells
ranging up to overt progranulocytes, can occur. Auer rods are elliptical cytoplasmic
inclusions approximately 1.5 m long and 0.5 m wide that derive from azurophilic
granules (see Chap. 59). The inclusions are present in the blast cells of approximately 15
percent of cases. When present, the inclusions are found in only a small percentage of blast
cells when examined with polychrome stains.
107,188
An exception is acute promyelocytic
leukemia (APL), in which a high proportion of cells have Auer rods and some have multiple
(bundles) of rods. This finding can be dramatic if peroxidase stain is used to highlight the
Auer rods.
Therapy
Remission-Induction Therapy
Principles
The cytotoxic therapy of AML rests on two tenets: (1) two competing populations of cells are
present in marrowa normal polyclonal and a leukemic monoclonal population; and (2)
profound suppression of the leukemic cells to the point they are inapparent in the marrow
aspirate and biopsy is required to permit restoration of polyclonal hematopoiesis.
454,455

Although these two principles hold in most cases, two deviations from these guidelines are
(1) the predisposition of patients with APL to enter remission despite cellular posttherapy
marrows
456,457
and (2) the occasional presence of monoclonal hematopoiesis in some cases of
AML during remission.
The goal of induction therapy in AML is achievement of complete remission (<2% blasts in
the marrow), a neutrophil count greater than 1000/ L, and a platelet count greater than
100,000/ L. An International Working Group for Diagnosis, Standardization of Response
Criteria, Treatment Outcomes, and Reporting Standards has redefined outcomes in an effort
to standardize reporting of and comparison of data.
458
Other treatment guidelines have been
recently published. Most adults enter remission with standard induction therapy, but for
patients with high-risk disease, consideration can be given to an experimental approach. How
durable a complete remission will be attained in an individual patient often is difficult to
predict at diagnosis. Gene expression profiling can separate some patients into prognostic
groups that may indicate patients with a high risk of not responding to standard approaches.

Cytotoxic Regimens
Anthracycline Antibiotic or Anthraquinone and Cytarabine
Current standard induction treatment for AML involves drug regimens with two or more
agents, which include an anthracycline antibiotic or anthraquinone and cytarabine. Remission
rates in the studies cited range from approximately 55 to 90 percent in adult subjects,
depending on the composition of the population treated .The two most important variables are
the age of the patients and the proportion of patients with therapy-induced leukemia or an
antecedent clonal myeloid disease. In the studies listed in Table 87-5, the median age of the
patient populations was much younger (30s to 50s) than the population of AML patients at
large (6570 years); thus the results cannot be generalized. A combination of anthracycline
and cytarabine has been the standard induction therapy since 1973.
11
A now classic, standard
induction regimen is cytarabine 100 mg/m
2
daily by continuous infusion on days 1 through 7
and daunorubicin at 45 mg/m
2
on days 1 through 3, the so-called "7 and 3 regimen." Dose or
schedule modulation of the anthracycline or cytarabine, addition of other agents such as
etoposide, in various schedules of administration, represent attempts to improve upon results
obtained with standard therapy.

Postremission Maintenance Therapy
Cytotoxic Therapy
General Considerations
Postremission therapy is intended to prolong remission duration and overall survival, but no
consensus exists regarding the best approach. Postremission chemotherapy that does not
produce profound prolonged cytopenias, closely simulating intensive induction therapy, has
produced on average only slight prolongation of remission or life. Regimens that fall between
these intensities have been used, with equivocal results. Intensive consolidation therapy after
remission results in a somewhat longer remission duration and, more significantly, a subset of
patients who have a remission of more than 3 years. The issue of postremission therapy and
its impact is complicated by the large proportion of patients with AML who are older than 60
years and the limits of tolerance to intensive therapy in the later decades of life. In addition, a
very small pool of leukemic stem cells sustains the process, and elimination of these cells
may require approaches other than intensive chemotherapy, especially in adults.
Several randomized trials have studied whether AML patients in first remission should
receive consolidation chemotherapy alone, autologous transplantation, or allogeneic marrow
transplantation, with no consensus. Allogeneic transplantation was compared to autologous
transplantation using unpurged marrow and two courses of intensive chemotherapy in 623
patients who had a complete remission after induction chemotherapy.
514
Disease-free survival
was 53 percent at 4 years for those receiving allogeneic marrow, 48 percent for those
receiving autologous transplantation, and 30 percent for patients receiving intensive
chemotherapy. Overall survival after complete remission was similar in all three groups
because patients who relapsed after chemotherapy could be rescued with marrow
transplantation. No significant difference in the 4-year disease-free survival between
allogeneic marrow transplant (42 percent) and other types of intensive postremission therapy
(40 percent) has been found.
515
In one study, a reduced relapse rate in patients receiving
autografts but no benefit in disease-free or overall survival was found.
516
In a randomized
study, the three postremission treatment groups all had comparable survival.
517
In another
study, only patients younger than 15 to 35 years with poor-risk cytogenetics had improved
disease-free survival if they had a sibling donor and underwent allogeneic transplantation
(43.5% vs. 18.5% at 4 years).
518
Thus, in several studies, the early mortality after allogeneic
transplantation and the chemotherapy-induced remissions in patients who relapse following
autologous marrow transplantation or chemotherapy have led to comparable overall survival
rates. However, leukemia-free survival was greater after allogeneic transplantation.
519
When
quality of life was measured for patients in complete remission for 1 to 7 years, those treated
with chemotherapy had the highest quality of life and those undergoing allogeneic stem cell
transplant the lowest.
520

The decision to utilize autologous or allogeneic stem cell transplantation or high-dose
cytarabine alone for consolidation is individualized based on the patient's age and other
prognostic factors, such as high-risk cytogenetic findings and antecedent hematologic
disease.
460
Patients with good-risk cytogenetics should receive four cycles of high-dose
cytarabine. Patients with poor-risk cytogenetics should be considered for allogeneic or
autologous stem cell transplantation after one or two cycles of high-dose cytarabine.
Intensive Consolidation Therapy
For patients who do not receive high-dose chemotherapy with autologous or allogeneic
transplantation in first remission, consolidation chemotherapy regimens containing high-dose
cytarabine provide better results than intermediate-dose cytarabine,
521,522
but these regimens
are not universally accepted.
523
Patients who have ablative allogeneic stem cell
transplantation do not require high-dose cytarabine.
524
Patients with t(8;21) have particularly
favorable responses to repetitive cycles of high-dose cytarabine. In patients who received
three or more cycles, a relapse rate of only 19 percent was seen.
525

Other regimens, such as those containing gemtuzumab ozogamicin and fludarabine, have
been used in postremission therapy.
526
Long-term disease-free survival at 5 years generally is
approximately 30 percent when two to four cytarabine-containing regimens are
administered.
527,528
Most centers utilize four cycles of 3 g/m
2
twice daily on days 1, 3, and 5,
providing six doses per cycle. The optimal number of cycles for this therapy is not known.
529

High-dose cytarabine can be administered at a dose of 3 g/m
2
in a 1- to 3- hour intravenous
infusion every 12 hours for up to 6 days (12 doses), but this regimen now is rarely utilized
because of its toxicity. High-dose cytarabine frequently causes conjunctivitis and
photophobia, and glucocorticoid eye drops are usually used every 6 h until 24 h after the last
dose of the drug. Cerebellar function abnormalities also may occur, and these require
cessation of drug administration. A one hour duration infusion of high-dose or reduced dose
(e.g., 2 g/m
2
) cytarabine may decrease the likelihood of severe cerebellar toxicity. Older
patients and patients with renal insufficiency require dose attenuation (i.e., to 2 g/m
2
).
.
Treatment of Older Patients
Biologic Features
Approximately 60 percent of patients with AML are older than 60 years at the time of
diagnosis.
827
The disease in this patient age group is less responsive to therapy, and this age
group has a higher proportion of patients who have oligoblastic leukemia (MDS); an
antecedent clonal myeloid disease; prior chemotherapy for cancer of the breast, ovary, or
another site; and comorbid conditions, which decrease the tolerance to intensive
chemotherapy programs. The AML cells of elderly patients often have more CD34+
expression, suggesting origin from a more primitive multipotential stem cell. This finding is
thought to contribute to longer duration of postchemotherapy aplasia and to the increased risk
of induction deaths in this age group.
828
Patients older than 55 years also have a high
frequency of unfavorable cytogenetic findings (32%) and higher MDR1 expression (71%)
and functional drug efflux (58%).
Chemotherapy
The therapist and patient determine whether a standard regimen, a standard regimen with
dose reductions, or a special regimen is used. Decisions based on chronologic age should be
supplanted by measurements of cognitive, neurologic, and physical fitness used by
geriatricians to evaluate the wisdom of considering intensive treatment. In patients older than
60 years who are fit and otherwise are considered good candidates, standard two-drug therapy
can be used. Remission rates of approximately 35 percent can be achieved. Chemotherapy
has been combined with growth factor support to accelerate neutrophil recovery in older
patients. In a study in which patients older than 55 years were randomized to receive either
placebo or G-CSF after induction therapy, no reduction in the duration of hospitalization,
survival prolongation, or costs of supportive care was noted. In previously untreated elderly
patients with AML, mitoxantrone induction therapy produces a slightly higher remission rate
than does daunorubicin but has no significant effect on remission duration and survival. In a
prospective randomized trial of idarubicin compared to daunorubicin in combination
chemotherapy for AML in patients aged 55 to 65 years, idarubicin resulted in higher
remission rates. Oral idarubicin alone has been used with success.
Attenuated standard regimens can be used in older patients. An example of an attenuated
regimen is cytarabine 100 mg/m
2
subcutaneously every 12 hours for 10 doses on days 1
through 5 and daunorubicin 30 mg/m
2
intravenously on days 1 through 3 of treatment. One
induction regimen is not superior to another in older patients with AML. Outcomes achieved
with cytarabine and daunorubicin are comparable to results with mitoxantrone and
etoposide.
840
Other regimens for elderly patients include lower total doses of idarubicin,
etoposide, and cytarabine (DIVA regimen).
841
Addition of PSC833 to mitoxantrone and
etoposide was well tolerated, but a reduction in chemotherapy dose was required to avoid
undue toxicity.
842

Autologous Stem Cell Infusion
Autologous stem cell transplantation has been used in fit patients older than 60 years.
843
The
incidence of relapse is lower when marrow stem cells are used compared to blood stem cells.
Postremission Therapy in Older Patients
No consensus exists regarding the best regimen or the number of treatment cycles for
postremission therapy in older adults. Regardless of the consolidation regimen, the duration
of the leukemia-free survival is longer with high-dose cytarabine and autologous stem cell
transplantation, just as it is in younger patients,
843
but fewer older patients can tolerate this
therapy. High-dose cytarabine can be used in older adults with AML, but usually at a reduced
dose.
844
Older patients treated with attenuated high-dose cytarabine at 750 mg/m
2

intravenously for 12 doses and then consolidated with four to six doses had an approximately
50 percent remission rate with a median duration of remission of 326 days.
845
Fifty-one
percent of 110 patients older than 60 years had a 9-month median remission duration when
consolidated with high-dose cytarabine.
846
Older patients are at higher risk for relapse despite
successfully completing intensive consolidation therapy, regardless of whether other adverse
prognostic features are present. Cytarabine as maintenance therapy may prolong disease-free
survival but does not improve overall survival.
847

Patients older than 80 years do not tolerate treatments well. Remission rates are
approximately 30 percent, but the median survival of treated patients is approximately 1
month. Less than 10 percent of patients survive for 1 year.
848

In summary, treatment options in older patients include (1) no treatment, (2) supportive care,
(3) palliative low-dose chemotherapy, (4) attenuated induction chemotherapy, or (5) high-
dose chemotherapy regimens. Lower-dose regimens are toxic and can lead to severe
cytopenias. Use of colony stimulating factors permit more older patients to tolerate full-dose
induction therapy. The Medical Research Council of the United Kingdom observed remission
rates of 80 percent in children, 70 percent in adults younger than 50 years, 68 percent in
adults 50 to 59 years old, 53 percent in adults 60 to 69 years old, 39 percent in adults 70 to 75
years old, and 22 percent in adults older than 75 years.
849
In one study of patients older than
60 years, the 2-, 5-, and 10-year survivals were 22, 11, and 8 percent, respectively.
850,851
The
older patients who remain free of leukemia beyond 1 year have a reasonable quality of life.
852

The National Cancer Institute 5-year relative survival rates for patients with AML are 5
percent for adults aged 65 to 74 years and 2 percent for adults aged 75 years and older.
820

Treatment of Children
AML represents approximately 15 percent of the acute leukemias in children (younger than
20 years) or approximately 500 children per year. APL is treated as in adults, with ATRA and
an anthracycline antibiotic. In other phenotypes of AML, intensive treatmentincluding
initial therapy with cytarabine and daunomycin or doxorubicin and a third drug such as
mitoxantrone or 6-thioguanine, followed by intensive multidrug consolidation therapy
including agents such as danorubicin, cytarabine, 6-thioguanine, etoposide, and intrathecal
cytarabinehas resulted in remission in approximately 80 percent of children and 5-year
relapse-free remissions in approximately 50 percent of treated children. Most of the children
are considered cured.
Monocytic leukemia and hyperleukocytic [>100,000/ l [>100 x 10
9
/liter]) myelogenous
leukemia are unfavorable phenotypes. In children, FLT3 internal tandem duplication
mutations are approximately half as common (15%) as in adults (30%) but are a very poor
prognostic indicator. Therapy can be adjusted for children based on the presence of poor
prognostic variables, which include age younger than 2 years or older than 10 years;
abnormalities of chromosome 3, 5, or 7; complex karyotypes; FLT3 mutations; elevated
white cell count (>50,000/ l [50 x 10
9
/liter]); male gender; and, perhaps, most
importantly, because it reflects the effect of all factors, the presence of greater than 15
percent blast cells in the marrow examined 14 days after onset of treatment.
864,865,866,867
The
presence of residual blast cells detected by flow cytometry after induction therapy is a very
poor prognostic finding.
868
The duration of first remission predicts the subsequent remission
rate and long-term survival in children with relapse.
Autologous stem cell transplantation has not improved outcome compared to current
intensive chemotherapy treatment regimens. Allogeneic stem cell transplantation from a
histocompatible sibling should be considered in children in first remission with a donor and
poor prognostic indicators or in children who relapse. Children younger than 2 years
previously had a very poor prognosis. They tend to present with myelomonocytic or
monocytic leukemia with high blast counts and CNS involvement. The t(9;11) abnormality
has a more favorable prognosis. Intensive multidrug regimens have resulted in 3-year
survivals approaching 70 percent of all infants treated. Thus, most infants can be successfully
treated with intensive chemotherapy or allogeneic stem cell transplantation. Cord blood may
be a suitable graft option for children with AML who lack an acceptably matched unrelated
marrow donor.
Growth failure, neurocognitive abnormalities, endocrine deficiencies, and cardiac
abnormalities are found in children treated at a young age. A second malignancy in cured
children is approximately 10-fold greater than expected in a matched population by age.
Indefinite followup of children in remission or believed to be cured is important to assess
developmental and intellectual progress and to evaluate long-term adverse events.

SOURCE: Williams hematology ,7
th
edition, Marshall A. Lichtman. 2007. The McGraw-
Hill Companies