Acute Myeloid Leukemia
Richard M. Stone, Margaret R. O’Donnell, and Mikkael A. Sekeres
Advances in our understanding of the patho-
physiology of acute myeloid leukemia (AML)
have not yet led to major improvements in
disease-free and overall survival of adults with
this disease. Only about one-third of those
between ages 18–60 who are diagnosed with AML
can be cured; disease-free survival is rare and
current therapy devastating in older adults. In
this chapter, challenges in the management of
the adult with AML are discussed, including
ongoing questions concerning the optimal
choice of induction and postremission therapy
such as the rationale for and role of allogeneic
and autologous stem cell transplantation in a
variety of settings, the special considerations
pertaining to the older patient, and the develop-
ment of new, so-called targeted therapies.
In Section I, Dr. Richard Stone reviews state-
of the-art therapy in AML in the era of change
from a morphological to a genetically based
classification system. Questions being addressed
in ongoing randomized cooperative group trials
include anthracycline dose during induction, the
efficacy of drug-resistance modulators, and the
utility of pro-apoptotic agents such as the anti-
bcl-2 antisense oligonucloetide. Developmental
therapeutics in AML include drug resistance
modulation, anti-angiogenic strategies, immuno-
therapy, and signal transduction-active agents,
particularly the farnesyl transferase inhibitors as
well as those molecules that inhibit the FLT3
I. AML: CURRENT LANDSCAPE
AND FUTURE DIRECTIONS
Richard M. Stone, MD*
Acute myeloid leukemia (AML) represents a group of
clonal hematopoietic stem cell disorders in which both
failure to differentiate and overproliferation in the stem
cell compartment result in accumulation of non-func-
tional cells termed myeloblasts. While the specific cause
for this biological abnormality in any individual pa-
tient is usually unknown, the burgeoning understand-
98
tyrosine kinase, activated via mutation in 30% of
patients.
In Section II Dr. Margaret O’Donnell dis-
cusses the role of stem cell transplantation in
AML. Several advances including expanded
donor pools, the movement toward peripheral
blood stem cell collection, newer immunosup-
pressive drugs and antifungals, and particularly
the advent of nonmyeloablative transplant have
made the allogeneic option more viable. The
subset-specific role for high-dose chemotherapy
with autologous stem cell support and/or for
allogeneic transplant in AML patients in first
remission is outlined. Although preconceived
notions about the role of transplant abound, the
clinical data supporting a risk-adapted approach
are covered. Finally, guidance concerning the
use of nonmyeloablative or reduced-intensity
allogeneic transplantation is provided.
In Section III Dr. Mikkael Sekeres reviews the
approach to the older patient with AML. Unique
biological and therapeutic considerations make
AML in this age group a vastly different disease
than that in younger adults. The outcome data,
including the role of specific anthracylines,
hematopoietic growth factors, and drug-resis-
tance modulators, are summarized. Communicat-
ing with older adults with AML and their families
regarding selection of the optimal treatment
strategy, often a stark choice between induction
chemotherapy and palliative care, is covered.
ing of the genetic underpinnings of leukemia is begin-
ning to lead to a wide array of so-called targeted thera-
pies, many of which are in clinical development.
Despite current optimism, most patients with AML
will die of their disease. The basic therapeutic approach
to patients with AML has changed little over the last 20
years. Nonetheless, before beginning to introduce novel
therapies in the clinic, a thorough understanding of the
* Dana-Farber Cancer Institute, 44 Binney Street, Room D-840,
Boston MA 02115-6084
American Society of Hematology
current approach to treatment is required. The evolu-
tion of the classification system in AML from mor-
phology to cytogenetic/genetic-based reflects the rec-
ognition of the importance of subtype-specific biology.1
The two major prognostic factors in newly diagnosed
AML, patient age and chromosome status, form the
basis of important treatment decisions. Recently, sev-
eral molecularly based prognostic factors, such as the
adverse impact of an FLT3 tyrosine kinase gene length
(or ITD) mutation (repeat of 3–30 amino acids in the
juxtamembrane region,2 leading to constitutive activa-
tion) and duplication of the MLL gene on the long arm
of chromosome 113 have been described; however, the
impact of such findings on treatment decisions remains
unclear. Patients with treatment-related AML require
special consideration because, in the absence of bal-
anced translocations known to carry a favorable prog-
nostic impact, such patients fare poorly with standard
approaches. The management of AML in older adults,
who have a highly inferior prognosis and an increased
rate of treatment morbidity and mortality, is highlighted
in Section III.
The approach to adults aged 18–60 years with AML
classically involves separate treatment phases. The first
consists of induction chemotherapy in which the goal
of myelosuppressive chemotherapy is to “empty” the
bone marrow of all hematopoietic elements (both be-
nign and malignant) and to allow repopulation of the
marrow with normal cells, thereby yielding remission
(< 5% marrow blasts). The primacy of the standard
regimen of 3 days of an anthracycline and 7 days of
cytarabine has not been definitely altered despite clini-
cal trials that have substituted alternative anthracyclines
such as idarubicin, added or substituted high-dose
cytarabine, or added etoposide. Recent trials by the
Cancer and Leukemia Group B (CALGB) have em-
ployed high doses of daunorubicin and etoposide.4 While
tolerable, whether such higher doses offer disease-free
or overall survival benefits remains to be proven by
ongoing clinical trials (Table 1). Given the high (75%–
80%) complete remission rate typically achieved in
younger adults with standard chemotherapy, an ex-
tremely large trial or a highly effective agent would be
required to show superiority over conventional chemo-
therapy. Most of the trials that have reported an im-
provement with a new chemotherapeutic agent or with

Table 1. Selected clinical trials in acute myeloid leukemia (AML).

US Intergroup APL: ATRA/daunorubicin/ara-C induction, followed by As203 + daunorubicin/ATRA x 2 vs daunorubicin/

ATRA x 2 consolidation, followed by ATRA/6MP/methotrexate vs ATRA x 1 yr for maintenance.
AML (age > 70 years and not a candidate for chemotherapy): Oral tipifarnib (R115777) at 2 doses and 2
schedules
CALGB AML (age > 60): dauno/ara-C vs dauno/ara-C/oblimersen
AML (age < 60): dauno/ara-C/etoposide, followed by post-chemotherapy/PBSCT, followed by IL-2 vs observation
ECOG AML (age > 60): dauno/ara-C ± MDR modulator (LY335979)
AML (age < 60): daunorubicin (45 mg/m2 x 3 d)/ara-C vs daunorubicin (90 mg/m2 x 3 d)/ara-C, followed by
± gemtuzumab ozogamicin (GO) prior to autoPBSCT (if no sib donor)
SWOG AML (age > 55): continuous infusion daunorubicin/ara-C ± cyclosporine A followed by assignment to mini-allo BMT
(if HLA-matched sibling donor)
AML (age < 55): daunorubicin/ara-C vs daunorubicin/ara-C + GO
EORTC AML (age > 60): ida/ara-C vs ida/ara-C/GO
AML (age < 60): ida/ara-C vs ida/high dose ara-C, followed by intensive consolidation/allogeneic BMT,
followed by IL-2
HOVON AML (age > 60): dauno (45 mg/m2)/ara-C vs dauno (90 mg/ m2)/ara-C f/b intermediate dose ara-C,
followed by GO x 4 vs observation
AML (age < 60): ida/ara-C ± G-CSF vs ida/high-dose ara-C ± G-CSF, followed by mitoxantrone/etoposide
(good risk) or Mito/etop vs autoBMT or alloBMT (if sibling donor)
MRC APL: ATRA/dauno/high-dose ara-C/6-thioguanine (MRC) vs ATRA/ida (Spanish), followed by MRC or Spanish
chemo ± GO
AML (age > 60): intensive chemo (dauno/ara-c at various doses) vs non-intensive chemo (hydroxyurea/
low dose ara-C ± ATRA)
AML (age < 60): dauno/high dose ara-C/6-thioguanine vs fludarabine/ara-C/G-CSF/ida +/- GO, followed by
allo BMT (if sibling; and will be nonmyeloablative if > 50, ‘full’ if under 35 years old)

Abbreviations: APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; ara-C, cytosine arabinoside; 6MP, 6-mercapto-
purine; AML, acute myeloid leukemia; PBSCT, peripheral blood stem cell transplantation; IL, interleukin; MDR, multidrug resistance;
BMT, bone marrow transplantation; G-CSF, granulocyte colony-stimulating factor

Hematology 2004 99
a higher dose of a standard drug during induction have
documented a disease-free survival benefit, implying
that such remissions yield a lower disease burden. How-
ever, the inability to translate such benefits into overall
survival improvements suggests a limited ability to af-
fect a major difference in the depth of remission.
It is definitely clear that once remission is achieved,
additional therapy is required to reduce the undetect-
able burden of leukemic cells to a level low enough
that long-term disease-free survival (i.e., cure) might
be possible. The most effective anti-leukemic approach
is allogeneic stem cell transplantation. However, this
technique carries a high degree of initial mortality and
a significant degree of long-term morbidity in the form
of chronic graft-versus-host disease (GVHD), tending
to offset the low likelihood of disease relapse. Chemo-
therapy-based approaches with or without autologous
stem cell rescue can be performed relatively safely, but
there remains a high chance for disease recurrence. Some
of the patients who relapse after chemotherapy or even
high-dose chemotherapy with autologous stem cell res-
cue can be salvaged with an allogeneic transplant per-
formed in early relapse or second remission. The role
of autologous and allogeneic (both standard and reduced
intensity) strategies in the post-remission management of
AML patients with various risks of disease relapse based
on karyotype at diagnosis is discussed in Section II.
Specific therapies have proven benefit for small
subsets of patients defined by recurring cytogenetic ab-
normalities. Post-remission chemotherapy with high-
dose cytarabine is generally accepted as the best ap-
proach for the 15% of patients with favorable progno-
sis chromosome abnormalities [e.g., t(8:21); or
inv(16)].5 While the optimal number of such cycles re-
mains to be defined, at least three are probably required.6
Whether the high-dose cytarabine or repetitive cycles
of intensive chemotherapy is the critical factor remains
debatable; however, a cure rate of 60%–70% with che-
motherapy suggests that the more risky strategy of al-
logeneic transplant should be reserved for early relapse
or second complete remission in this subset of patients.
Patients who present with acute promyelocytic leuke-
mia (APL; another 8%–12% of patients) should be
treated with all-trans retinoic acid (ATRA) and an
anthracycline in induction.7,8 Although many still em-
ploy cytarabine in the induction and postremission man-
agement of APL patients, its use is probably not neces-
sary.7 ATRA/anthracycline-based postremission therapy
should be augmented with a year of maintenance therapy,
not generally thought effective in other AML subtypes,
with ATRA, probably in combination with oral anti-
metabolites.9 APL is the one subtype of APL in which
molecular monitoring after achievement of complete
100
response (CR) has proven useful. Few patients who
achieve polymerase chain reaction (PCR)-negative sta-
tus after postremission chemotherapy relapse; whereas
those with persistently detectable PML-RARα fusion
transcripts have a 25% risk of relapse,10 yet whether
such relapses can be prevented with additional therapy
remains unclear. While the cure rate in APL with “stan-
dard” therapy is favorable (60%–70%), the problems
of secondary myelodysplasia11 and late central nervous
system (CNS) relapses8 have recently been described.
In summary, the young adult who presents with
AML should have studies performed on leukemic cells
leading to morphologic and cytogenetic classification.
Those with non-APL AML should receive induction
therapy with 3 days of an anthracyline and 7 days of
infusional cytarabine followed by risk-adapted post-
remission therapy [intensive chemotherapy for those
with inv 16 or t(8;21)], allogeneic transplant for those
with high-risk cytogenetics, and either intensive che-
motherapy, high-dose chemotherapy with autologous
stem cell rescue or sibling-matched allogeneic trans-
plant for the remainder. That a “standard approach” to
the treatment of AML in the 18–60 year old patient can
be described is still compatible with the notion that all
should be referred for a clinical trial. Many questions
need to be answered, even for those with so-called ‘fa-
vorable’ prognoses, that usually involve the addition of
a new agent onto a backbone of “standard” therapy.
The ideal candidates for investigational therapy, many
of whom are described subsequently, with a single agent
are those likely to fare poorly with induction chemo-
therapy, including older adults and those with disease
relapse less than a year from diagnosis. While many
different chemotherapy regimens exist for AML in re-
lapse, the choice of regimen is less important than the
duration of first remission. Those who relapse more
than one year after diagnosis have good chance to achieve
a second remission after administration of the original
induction regimen, or at least one of similar intensity.
However a second remission is achieved, the only post-
remission therapy with significant utility is allogeneic
transplant if possible, or high-dose chemotherapy with
autologous stem cell rescue.
Developmental Therapeutics in AML
The increased understanding of the pathophysiology of
AML has led to the development of a host of new so-
called targeted therapies. The success of imatinib in the
treatment of chronic myeloid leukemia (CML) and other
diseases pathophysiologically based on the constitutive
activation of a tyrosine kinase that is inhibited by the
drug has spurred the search for similarly effective agents
in AML. Table 2 lists some of the newer therapies ac-
American Society of Hematology
Table 2. Categories of novel therapies for acute myeloid
leukemia (AML).
Drug-resistance modifiers
Proteosome inhibitors
Pro-apoptotic approaches
Signal transduction inhibitors
“RAS”-targeted (e.g., farnesyl transferase inhibitors)
Tyrosine kinase targeted (e.g., FLT3, c-kit)
Downstream signal inhibitors
Immunotherapeutic approaches
Antigens known
anti-CD33
anti-GM-CSF receptor
Antigens unknown
stimulate immune system (IL-2, GM-CSF)
present tumor antigens effectively
dendritic cell fusion
transfer hematopoietic growth factor genes
Abbreviations: IL, interleukin; GM-CSF, granulocyte-macroph-
age colony-stimulating factor
cording to their proposed mechanism of action. Whether
any of these will prove to alter the natural history of
AML when used either alone or in combination with
each other or with standard chemotherapy remains to
be determined. That there are so many therapies in de-
velopment is certainly positive; the challenge posed by
this surfeit in a relatively rare disease for which fairly
effective therapy already exists remains daunting. Im-
munological therapies in AML based on enhancement
of the host immunity or elegant strategies of making
AML cells “visible” to the immune system are men-
tioned in Section II.
Two agents have recently been approved for use in
AML: arsenic trioxide12 and gemtuzumab ozogamicin.13
Their place in the therapeutic armamentarium is now
being better defined. Both could be considered models
for other new therapies, because they were shown to be
effective (in highly varying degrees) in relapsed pa-
tients. Post-approval studies are being done to define
their role in newly diagnosed patients to increase their
overall impact. Arsenic trioxide leads to a four-log re-
duction in the acute promyelocytic leukemia disease
burden in heavily pre-treated relapsed patients12 and is
now being evaluated to consolidate first remissions
(Table 1). Gemtuzumab ozogamicin is an anti-CD33
immunotoxin conjugate that was approved based on a
30% response rate (half of whom were patients who
never fully recovered their platelet count) in patients
Hematology 2004
with untreated first relapse who had, in most cases, a
first remission of 6 months or longer.13 Disappointment
with this drug due to its low single-agent efficacy in
treatment of patients with refractory AML as well as its
association with hepatic veno-occlusive disease when
administered proximal to or following a bone marrow
transplant14 has dampened enthusiasm. Nonetheless,
based on the apparent safety of combining this agent
with chemotherapy in newly diagnosed patients,15 im-
portant studies are now underway to determine if
gemtuzumab ozogamicin combined with induction or
consolidation chemotherapy, or as a single agent in the
post-remission setting in older adults might lead to a
better outcome (Table 1).
Agents Not Expected to Be Effective as Single Drugs
Drug-resistant modulators
The notion that blasts from AML patients, and particu-
larly from older individuals, are likely to express genes
capable of mediating drug resistance, most notably the
GP170 drug efflux pump, has prompted clinical trials
with so-called reversing agents that inhibit this func-
tion. Since many of these agents also inhibit the me-
tabolism of chemotherapeutic drugs like anthracyclines,
pharmacokinetic considerations are important. Most of
the trials that have compared chemotherapy with or
without a drug-resistant modulator (DRM) have shown
no benefit or have been terminated early due to excess
toxicity.16 However, a randomized clinical trial involv-
ing cyclosporine A as a reversing agent has been posi-
tive,17 prompting the Southwest Oncology Group to treat
older adults with chemotherapy (using a novel regimen
including continuous infusion daunorubicin) with and
without cyclosporine A. Secondly, trials with newer
DRMs that do not have pharmacological effects on che-
motherapy are also underway (Table 1).
A problem with these drugs as well as with many
novel approaches is that the mechanism of resistance is
likely to be pleiotropic. The inability to initiate cell
death in response to chemotherapy is another potential
mechanism of resistance. Overexpression of the bcl-2
anti-apoptotic gene has been associated with poor prog-
nosis in AML patients. Preclinical data documenting
synergism between chemotherapy and the antisense 18-
mer oligonucleotide oblimersen (G3139) have prompted
Phase I clinical trials documenting the safety of induc-
tion chemotherapy with this agent.18 The CALGB has
begun a randomized a trial in older adults that com-
pares chemotherapy alone to chemotherapy adminis-
tered with oblimersen (Table 1). Synergistic antileuke-
mic activity between chemotherapy agents and the
proteosome inhibitor bortezomib19 has spurred the clini-
101
cal development of this agent in conjunction with che-
motherapy in AML.
The use of hematopoietic growth factors (HGFs)
in AML has received much attention. Once concerns
diminished that growth factors would enhance disease
resistance via their known ability to stimulate leukemia
cells to enter S-phase, a host of clinical trials examined
the ability of HGFs to shorten the period of neutrope-
nia and reduce infectious mortality. While the duration
of neutropenia was reduced by several days when G-
CSF or granulocyte-macrophage colony-stimulating
factor (GM-CSF) was used in the postchemotherapy
period, the inability of these agents to alter the nadir,
allay mucositis, or decrease the death rate diminished
their utility. Perhaps more interesting is the use of these
agents before or during chemotherapy in an effort to
increase the S-phase fraction of cells, thereby using them
as chemosensitizing agents. Although most of the trials
using HGFs in this fashion have been disappointing, a
recent randomized study in which G-CSF was used be-
fore and during chemotherapy, yielding a disease free
survival benefit,20 has prompted renewed interest in this
strategy. At the present time the use of G- or GM-CSF
can be considered optional using supportive care guide-
lines for neutropenic fever while their use as chemo-
therapy-enhancing agents needs to be explored further
before routine use is warranted.
Agents That Promote Differentiation
Almost a quarter century has elapsed since clinical tri-
als suggested that low-dose cytarabine’s effect in AML
and myelodysplasia resulted from hematopoietic cell
differentiation. In the ensuing years, the enthusiasm for
low-dose cytarabine as an effective therapy that induces
maturation of AML cells has waned. However, an in-
creased understanding of how the transcription of dif-
ferentiation-associated genes is regulated has prompted
the exploration of new and potentially effective thera-
pies. Among the many biochemical events that must
occur as a cell changes from a stem cell to a mature
functional blood cell are removal of methyl groups from
DNA bases and addition of acetyl groups to the histone
DNA protein coat. Such effects change the conforma-
tion of the DNA and allow transcription of certain genes.
The DNA hypomethylating agent azacitidine21 was re-
cently approved by the US Food and Drug Administra-
tion (FDA) for use in all subtypes of myelodysplastic
syndrome. Many clinical trials are now underway with
so-called histone deacetylase inhibitors, although out-
come data are sparse. Given the general hypothesis that
AML results from a combination of over proliferation
of the stem cell compartment as well as failure to dif-
ferentiate, it is rational to consider the future use of
102
these differentiating agents in combination with agents
that inhibit mitogenic signals.
Signal Transduction Inhibition
The mechanism by which cells receive and transmit
mitogenic signals is complex and involves the coordi-
nated action of many different proteins, commonly rep-
resented by so-called signal transduction cascades. In-
sofar as such cascades might be overactive in leukemia
cells compared to normal hematopoietic cells, a thera-
peutic opportunity is provided. Moreover, an activat-
ing mutation in one of the proteins responsible for trans-
mitting proliferative signals in AML defines a poten-
tial target. Mutations in one of the RAS family pro-
teins, 21-KD guanine-nucleotide binding proteins, have
been described in 10%–50% of AML patients. Such
activating mutations are thought to allow autonomous
growth. RAS proteins require several post-translational
modification steps including addition of a farnesyl lipid
moiety that allows translocation to the plasma mem-
brane and activation. Farnesyl transferase inhibitors
(FTIs) have been shown to inhibit the growth of mu-
tant RAS-transformed cell lines. The FTI in furthest
development in AML, tipifarnib (R115777), was asso-
ciated with responses in advanced-stage patients in a
Phase I trial.22 Despite disappointing results in an inter-
national Phase II trial in refractory/relapsed patients
(although RAS mutations were not required), the drug
has been administered to over 100 chemotherapy-naïve
AML patients. A preliminary report documented a 20%
complete remission rate in this group of poor progno-
sis, largely older patients who received this oral agent
as their initial therapy.23 These exciting results, if con-
firmed, might provide a new and less toxic therapy com-
pared to chemotherapy for older adults with AML. FTIs
are also being evaluated in younger patients in earlier
disease states and in combination with chemotherapy.
An active area of current research in AML is the devel-
opment of agents known as FLT3 inhibitors. FLT3 is a
transmembrane tyrosine kinase. Approximately 30% of
AML patients can be shown to have an activating mu-
tation that generally carries a poor prognosis.2 The ac-
tivating mutation may be a duplication of between 3
and 60 amino acids in the juxtamembrane region or,
less commonly, a point mutation in the activation loop.2
Activating mutations of the FLT3 tyrosine kinase trans-
form leukemic cell lines into growth factor indepen-
dence and cause a fatal myeloproliferative syndrome in
a murine bone marrow transplant model. Small mol-
ecules capable of inhibiting FLT3 enzyme activity can
selectively kill such transformed cell lines and improve
survival in the murine model.2 Thus, the preclinical
data supporting the development of these drugs as thera-
American Society of Hematology
Table 3. FLT3 inhibitors in clinical development (modified from Wadleigh et al29).

Tyrosine Receptor
Kinase Inhibitor Clinical Trials/
Inhibitor Class Activity† FLT3 IC50 ‡ Comments Toxicity
PKC-412 Benzoylstaurosporine PKC Phase II: AML with/without FLT3-ITD Nausea,
PDGFR In FLT 3 mut pts (n = 20), 35% emesis, fatigue
KDR significant reduction in blast
KIT count25
FLT3 528 nM
ABL
CEP-701 Indolocarbazole FLT3 2–3 nM Phase II: AML with FLT3-ITD Nausea,
TRKA Several pts had reduced blast emesis, fatigue
KDR counts, autophosphorylation
PKC inhibited26
PDGFR
EGFR
MLN-518 Piperazinyl quinazoline KIT Phase I: AML/MDS with/without Generalized
PDGFR FLT3-ITD weakness,
FLT3 170–220 nM Phase II: AML with FLT3-ITD fatigue, nausea
FMS A few pts with FLT3 ITD treated and vomiting
at higher doses had biological
response 27
SU5416 Indolinone FLT3 250 nM Phase II: Refractory Fatigue,
KDR AML/MDS/MPD/MM nausea, sepsis
KIT Phase II: Refractory AML (c-KIT and bone pain
positive). No responses in
FLT3 ITD pts.24
† Receptor inhibitor activity in descending order of potency
‡ FLT3 autophosphorylation in vitro 1
Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; MPD, myeloproliferative disease; MM, multiple
myeloma

peutic agents in AML is at least as strong as that used to
support clinical trials with imatinib in patients with
CML. There are two major differences between imat-
inib’s development and that of the FLT3 inhibitors: 1)
CML in chronic phase is probably based solely on the
activation of bcr-abl, whereas AML is almost certainly
a “multi-hit” disease; 2) Multiple agents and drug com-
panies are developing FLT3 inhibitors. However, just
as was the case for imatinib, these drugs have a spec-
trum of activity beyond FLT3 inhibition alone. For
example, PKC-412 (N-benzoylstaurosporine) inhibits
FLT3 as well as protein kinase C and the vascular en-
dothelial growth factor receptor. Such a wide spec-
trum of activity could have positive or negative conse-
quences. SU5416, which inhibits FLT3 reasonably po-
tently, was developed as a c-kit inhibitor. The drug dem-
onstrated modest activity in AML, but no activity was
observed in the 7 patients who retrospectively were
found to have an activating mutation of FLT3 in their
myeloblasts.24 Minor responses have been observed in
patients without known FLT3 mutations who have re-
ceived PKC-412. Available clinical data from early tri-
als with the three drugs specifically developed as FLT3
inhibitors, PKC-412,25 CEP-701,26 and MLN-518,27 are
summarized in Table 3. Biological responses, demon-
strated by a major reduction in peripheral blast count,
have occurred with each of these drugs. However, they
have minimal ability to reduce the bone marrow blast
count, and therefore, complete remissions have occurred
in 1/42 reported patients. Moreover, the duration of
response has been brief. Although much more work
with these oral agents needs to be done, initial impres-
sions suggest that (1) the multiplicity of genetic lesions
in the typical AML cell may be problematic for expect-
ing these agents to work alone; (2) pharmacokinetic
issues require prolonged therapeutic drug levels and the
ability to get to the target leukemia progenitor cell; and
(3) the contribution of alternative enzymes and path-
ways are important.28
Nonetheless, further development of these drugs at
different doses and schedules and in combination with
other signal transduction inhibitors and/or chemotherapy
is warranted. Other tyrosine kinase inhibitors, includ-
ing those that inhibit the vascular endothelial growth
factor receptor, are also in clinical trials in AML.29

Hematology 2004 103

 II. THE ROLE OF AUTOLOGOUS AND ALLOGENEIC
(“FULL” AND “MINI”) STEM CELL
TRANSPLANTATION IN AML
Margaret R. O’Donnell, MD*
Hematopoietic cell transplantation (HCT) is an effec-
tive therapy for AML. Obstacles to broad applicability
of HCT therapy for the majority of patients with AML
have included inability to control leukemia with pri-
mary induction therapy, lack of suitable hematopoietic
cell donors, toxicities of HCT conditioning regimens
and long-term complications of the transplant proce-
dure. While all antileukemia therapies are complicated
by the problems of chemotherapy-related toxicities and
disease relapse, allogeneic HCT also exposes patients
to the risks of potential failure of engraftment; organ
toxicities caused by GVHD and prolonged immuno-
suppression with its attendant risks of post-HCT infec-
tious complications.
In the last decade, several developments have made
allogeneic HCT a more “user-friendly” treatment mo-
dality. Expansion of the pool of donors in national and
international registries as well as the establishment of
cord blood banks has vastly increased the likelihood of
success in identifying a suitable HLA match for pa-
tients who lack matched family donors, although cord
blood HCT is still utilized primarily for pediatric re-
cipients. The refinement of tissue typing using molecu-
lar probes permits better matching of unrelated donor-
recipient pairs, thereby decreasing the risks of both graft
rejection and GVHD.
There has also been a recent change in the type of
hematopoietic progenitor cell (HPC) product used for
graft reconstitution. Autologous transplant procedures
had transitioned from marrow to cytokine-primed (G-
CSF and/or GM-CSF) peripheral blood stem cells
(PBSC) for ease of collection and rapid engraftment by
the early 1990s. However, expectation of higher rates
of GVHD due to the 10-fold increase in T cells in PBSC
products delayed their use in allogeneic settings until
the latter-half of the 1990s. In 2003, National Marrow
Donor Program (NMDP) statistics showed 60% of un-
related donor products collected for transplants for AML
were PBSC. Collection via apheresis is physically easier
for many donors. The 4- to 5-fold higher number of
CD34+ cells in a PBSC product facilitates more rapid
engraftment in comparison with a marrow product (me-
dian of 17 days versus 24 days for granulocytes and
* City of Hope National Medical Center, 1500 East Duarte
Road, Duarte CA 91010
104
median of 28 days versus 47 days for platelets, respec-
tively), which decreases the risk for bacterial infections
in the early post-transplant period.1 Despite initial con-
cerns that a 10-fold increase in the number of CD3+
cells in the PBSC graft would lead to higher incidence
of severe GVHD, this has not been demonstrated in
clinical trials. Several studies have shown no signifi-
cant difference in the incidence of acute GVHD; how-
ever, higher rates of late onset chronic GVHD (beyond
6 months) have been reported.2 In both a large random-
ized trial and a retrospective review of International
Bone Marrow Transplant Registry (IBMTR) data, PBSC
grafts were associated with improved relapse-free sur-
vival in patients with leukemia beyond first remission
(CR1).1,3,4 In addition to producing a HPC product that
results in more rapid engraftment, G-CSF exposure also
shifts donor T cells to Type 2 cytokine secretion
(interleukin [IL]-4 and IL-10) and downregulates Type
1 (IL-2 and interferon γ ) cytokine production, phe-
nomena which may be associated with less severe acute
GVHD.
Improvements in post-transplant supportive care
and the development of newer immunosuppressive
agents have also had an impact on transplant-related
toxicities. More refined PCR-based screening for cy-
tomegalovirus reactivation allows pre-emptive therapy
tailored to viral load. Newer less toxic antifungal agents
such as voriconazole and caspofungin have decreased
early mycotic infections and make it feasible to pro-
vide long-term fungal prophylaxis in patients at high
risk due to chronic GVHD. Newer immunosuppressive
agents, such as sirolimus and mycophenolate mofetil
(MMF) are being incorporated into GVHD prophylac-
tic regimens to decrease the incidence of acute and chronic
GVHD in high-risk populations including unrelated do-
nor recipients and older (> 50 years) patients.5,6
However, the change that may have the greatest
impact on AML treatment is the advent of reduced in-
tensity or nonmyeloablative HCT. Reduced-intensity
HCT relies upon the graft-versus-leukemia effect of
the allograft rather than the direct tumoricidal activity
of the conditioning regimen. Because of the paucity of
any direct antileukemic effect of the conditioning regi-
mens, the truly nonmyeloablative (NMABT) regimens
can only be used in patients with low volumes of dis-
ease, whereas the reduced-intensity conditioning regi-
mens, which usually contain fludarabine and some alky-
lating agent, do have direct antileukemia activity and
can be used with more extensive disease. The shortened
duration of cytopenias and the minimal mucosal toxic-
ity of the newer reduced-intensity conditioning regi-
mens provide a reasonably safe transplant option for
patients two decades older than the population that was
American Society of Hematology
treated with traditional fully ablative high-dose chemo-
radiotherapy regimens.
Choosing the Type and Timing of HCT
(To Transplant or Not to Transplant)
The possible need for HCT as a component of future
therapy should be acknowledged at diagnosis in AML.
For all patients under age 56 who do not have signifi-
cant co-morbid conditions, HLA typing should be part
of the patient’s initial evaluation, and family typing
should be initiated when the cytogenetic information is
available. Only a minority of patients will have a fa-
vorable karotype that would obviate consideration of
allogeneic HCT either as part of consolidation or for
salvage of resistant disease. For patients with poor-risk
cytogenetics, antecedent myelodysplasia or therapy-
related AML, an unrelated donor search should be
promptly instituted in patients lacking a family donor.
Early donor identification allows optimal timing for
HCT as consolidation or salvage therapy. In older pa-
tients (56–70 years), however, it is reasonable to delay
HLA typing of family members until remission is
achieved and the patient has recovered a good perfor-
mance status since there is substantial attrition in the
rank of candidates for the investigational use of reduced-
intensity or nonmyeloablative HCT as consolidation due
to failure to achieve a remission or decline of func-
tional status as a consequence of induction therapy.
The decision to proceed to either autologous or allo-
geneic HCT is strongly influenced by the following
factors: expectations of outcome with the prevailing
non-HCT conventional therapy, the effectiveness of sal-
vage options for disease relapse, the toxicities of trans-
plant including long-term complication of infertility
and second malignancy, and the individual patient’s co-
morbid conditions. The patient’s cytogenetic risk group
and time to achieve remission are currently the major
disease-specific factors to be considered in opting for
HCT as consolidation therapy, whereas donor availability
and the impact of recipient performance status on the
ability to tolerate the rigors of even a reduced-intensity
HCT are important factors to consider at relapse. While
there are several studies with long-term outcome data
comparing myeloablative conditioning regimens fol-
lowed by either autologous or allogeneic HCT, the fol-
low-up data on reduced intensity HCT is much shorter
and the patient populations are not comparable.
Comparisons of Autologous Transplantation,
Allogeneic and Reduced-Intensity HCT
Autologous transplantation has been used primarily as
a component of consolidation following initial remis-
sion; less commonly, it can be used as a component of
Hematology 2004
salvage therapy for patients in second remission. To
minimize both the total body leukemic burden and the
contamination of the PBSC product, current practice is
to administer one to two cycles of a high-dose
cytarabine-based consolidation to achieve “in vivo purg-
ing” prior to collection of G-CSF–mobilized PBSC.
To assure that an adequate hematopoietic progenitor
cell product of at least 5 × 106 CD34+ cells/kg recipient
body weight can be collected, it is recommended that
no more than 2 cycles of consolidation occur before
PBSC collection. While the nonhematologic toxicities
of the conditioning regimens used for autologous HCT
are significantly greater than those seen with high-dose
cytarabine consolidation, the hematologic recovery is
quite rapid (8–11 days) following infusion of autolo-
gous G-CSF–mobilized PBSC. The combined treat-
ment-related mortality (TRM) for one cycle of high-
dose cytarabine-based consolidation followed by 1200
cGy fractionated total body irradiation (FTBI), etopo-
side and cyclophosphamide (Cy) and autologous HCT
at our institution ranged between 3% and 6% in three
sequential trials inclusive of patients up to age 60. At-
trition between consolidation and autologous transplant
ranged from 18% to 24% due to relapse, inadequate
HPC collection or treatment-related toxicities such as
invasive fungal infection and cytarabine-induced neuro-
toxicity, making this a reasonable consolidation option
for most patients up to age 60.7
Over the last 15 years, the upper age limit consid-
ered to be acceptable for a fully ablative allogeneic HCT
has advanced from 40 to “robust” 60 year olds (perhaps
in response to the maturing age of the transplanters them-
selves as much as to improvements in supportive care
and GVHD prophylaxis).8 If an HLA-matched donor
has been identified while the patient was receiving in-
duction therapy, there is no advantage to administering
postremission chemotherapy prior to allogeneic HCT.9
GVHD and transplant-related toxicity remain the ma-
jor obstacles to successful outcome with allogeneic HCT.
The introduction of two new immunomodulatory drugs
for GVHD prophylaxis may have an important impact
on both these problems. Investigators from the Dana-
Farber recently reported a Phase II trial in which
sirolimus was substituted for methotrexate (MTX) in a
tacrolimus-based GVHD prophylaxis regimen for PBSC
HCT utilizing a fully myeloablative conditioning regi-
men.5 Engraftment was prompt and only 3/30 (10%)
patients developed acute GVHD (all Grade II) com-
pared to the expected incidence of 35%–40% acute
GVHD in sibling-donor HCT with tacrolimus/MTX.
TRM was only 6% at 1 year compared to 25%–30% in
most traditional allogeneic studies. Chronic GVHD de-
veloped in 40% of the study patients. Toxicities in-
105
cluded significant hyperlipidemia, thrombotic micro-
angiopathy and a 10% incidence of veno-occlusive dis-
ease primarily in patients with recent exposure to
gemtuzumab ozogamicin. Other studies of the substitu-
tion of mycophenolate mofetil (MMF) for MTX in
GVHD prophylaxis regimens have demonstrated de-
creased regimen-related toxicities of severe mucositis and
interstitial pneumonias, as well as more rapid engraft-
ment compared to a MTX-containing regimen (14–16
days versus 19–22 days for neutrophil engraftment).10,11
Improvements in molecular matching for unrelated
donor-recipient pairs have significantly improved out-
comes for this group, although there continues to be an
approximately 10% higher incidence of TRM when sib-
ling allogeneic HCT is compared to allogeneic HCT
from molecularly matched unrelated donors for patients
in CR1. Because of the perception of higher TRM, the
profile of patients who undergo unrelated donor HCT
in CR1 is skewed toward those with poorer risk cytoge-
netics, prolonged time to achieve a remission, or a his-
tory of antecedent myelodysplasia or therapy-related
AML. The majority of unrelated donor transplants are
still being performed for AML patients beyond CR1.
The foremost advantage of the nonmyeloablative
or reduced-intensity HCT is the reduction of TRM. Mu-
cositis in the immediate post-HCT period is much re-
duced due to the low antiproliferative activity of the
conditioning regimen and the substitution of MMF for
MTX in the GVHD prophylaxis regimen. The reduc-
tion in mucosal disruption led to a decreased incidence
of acute (12%) and chronic (19%) GVHD for reduced-
intensity fludarabine/melphalan versus 36% acute and
40% chronic GVHD for patients receiving ablative sib-
ling HCT in an MD Anderson Cancer Center study.11
Infectious complications are also reduced, with a 9%
incidence of bacteremia at day 100 for nonmyeloablative
conditioning versus 27% for standard HCT and a dif-
ference in day 100 survivals of 93% versus 81%, re-
spectively, in a case-matched control series from Se-
attle.12 However, other investigators have reported higher
rates of CMV reactivation before day 100 and persis-
tent risk of bacteremia and fungal infections late post-
HCT with nonmyeloablative regimens because of the
prolonged immunosuppressive effects of fludarabine

Table 4. Treatment outcomes and toxicity for autologous and allogeneic hematopoietic cell transplantation (HCT) for
consolidation or salvage therapy.

Reduced-Intensity
Autologous HCT Allo HCT (Sib) AlloHCT/MUD AlloHCT + MUD
CONSOLIDATION (CR1)
Cytogenetic risk
t(15;17) No role No role No role No role
t(8;21)inv(16) DFS 60%–80%* DFS 65%
TRM 4%–8% TRM 18% = No Role No role No role
Intermediate DFS 42%–55% DFS 48%–62% Insufficient data for
TRM 4%–6% TRM 16%–20% nonmyeloablative
Poor DFS 18%–25% DFS 35%–45% 5-yr DFS 30%–40% Reduced intensity DFS 50%
TRM 4%–8% TRM 18%–20% TRM 30% for older AML CR1 at 2 yr
SALVAGE
CR2 DFS 30% overall DFS 40% Pediatric 40% 2-yr DFS 40%–50%reduced
DFS 60%–80% Adult 5-yr DFS 30% intensity
for t(15;17) TRM 30%
Relapse Not an option unless DFS 20%–30% Pediatric DFS 20% 2-yr DFS 10%–30%
“back-up” product from Adult 5-yr DFS depending on the volume
CR1 available 10%–15% of residual disease
Induction Failure No Role DFS 30%–40% (3 yrs) DFS 20%–30%** 1-yr DFS 15%–30% (sibling)
(20% for untreated
secondary AML)

* Because of high salvage rate and long-term sequelae, many would reserve autologous HCT for relapse for patients with
favorable cytogenetics.
** Most of these patients represent patients with high grade myelodysplastic syndrome (MDS) in which an unrelated donor search
was initiated prior to leukemic evolution.
*** DFS interval will be 5 years unless otherwise noted
Abbreviations: AML, acute myeloid leukemia; DFS, disease-free survival; TRM, treatment-related mortality; HCT, hematopoietic cell
transplantation; MUD, matched unrelated donor; allo, allogeneic; CR, complete response

106 American Society of Hematology

even in the absence of GVHD.
Table 4 provides a schematic of current thinking
on the role of the various types of HCT in the therapy
of AML. A caveat for interpretation of all consolida-
tion trials in which HCT is a component is the exist-
ence of selection bias. There have been several large
national or co-operative group trials conducted between
1986 and 1995 that tried to answer the question of the
role of transplantation in consolidation in younger pa-
tients with AML.13-15 Patients with sibling donors were
assigned to the allogeneic marrow transplantation and
the remainder were randomized, between a variety of
consolidation (2–4 cycles) chemotherapy versus autolo-
gous marrow transplant after 1–4 cycles of consolida-
tion. The conclusions ranged from no survival advan-
tage to either form of HCT compared with consolida-
tion chemotherapy in the initial analysis of the US Na-
tional Trial involving the Eastern Cooperative Oncol-
ogy Group (ECOG), Southwest Oncology Group
(SWOG) and CALGB to a significant difference in dis-
ease-free survival for both allogeneic (55%) and au-
tologous HCT (48%) compared to chemotherapy (30%)
in the European Organisation for Research and Treat-
ment of Cancer (EORTC) trial (albeit with no overall
survival advantage as a high percentage [58%] of che-
motherapy relapses were salvaged with transplant).
When the US National Trial was reanalyzed using
cytogentic risk groupings there were clear differences
in favor of HCT (allo and auto) for favorable risk and
for allogeneic in patients with poor risk cytogenetics.15
In all these trials as well as the MRC10 trial, there was
considerable patient attrition from achieving remission
to initiating any form of consolidation.16 Fully one third
of younger (< 55 yr) patients received no documented
form of consolidation; 50%–80% of patients actually
received the designated HCT treatment. While it is ap-
propriate to compare treatment strategies on an intent-
to-treat basis from the time CR is achieved, the inter-
position of multiple nontransplant therapies before HCT
may cause high attrition rates that provide a negative
bias, while analyses that start only at time of transplant
may give an overly optimistic prediction of outcome.
Consolidation
Good-risk cytogenetics
Given the high curability of acute promyelocytic leu-
kemia (APL) with conventional chemotherapy, there is
no role for autologous or allogeneic HCT for patients
in CR1 who achieve a molecular remission by the
completion of consolidation. Several series have dem-
onstrated that autologous HCT can produce durable sec-
ond remissions in 75%–100% of the patients in whom
Hematology 2004
a molecularly negative product can be collected.17 How-
ever, for patients with persistence of the PML/RAR gene
product, allogeneic transplantation should be consid-
ered since the relapse rate following infusion of a mo-
lecularly positive product exceeds 85%.
Relapse free-survivals of 60%–83% have been re-
ported for patients with t(8;21) or inv(16) using intent-
to-treat analysis from the start of high-dose cytarabine
consolidation through autologous HCT with relapse rates
of 15%–20% post-HCT and TRM of 4%–8% over-
all.18,19 While these disease-free survival (DFS) rates
are higher than the DFS seen with multiple cycles of
high-dose cytarabine-based consolidation and the time
to completion of treatment may be shorter, long-term
toxicities associated with autologous HCT need to be
factored into the decision to pursue autologous HCT in
individual patients. Many with expertise in AML would
reserve autologous HCT for relapse in patients with
good risk cytogenetics. In patients who opt for conven-
tional chemotherapy, one should consider cryopreserving
autologous PBSC as a “back-up” for salvage therapy in
the event of relapse in patients who lack a histocompat-
ible sibling. Autologous HCT can provide long-term
salvage for 40% of patients who achieve a second re-
mission overall; factors that correlate with better out-
come include cytogenetics and duration of first remis-
sion.20 Sibling allogeneic HCT in CR1 in the group with
favorable cytogenetics had only 62% DFS with a 17%
TRM in the EORTC/GIMEMA (Gruppo Italiano
Malattie Ematologiche dell’ Adulto) trial based on in-
tent-to-treat from time of remission that compared au-
tologous to allogeneic transplant during the time pe-
riod of 1993–1999 (Figure 1A). The high TRM asso-
ciated with allogeneic HCT indicates that allogeneic
HCT has no advantage over conventional chemotherapy
or autologous HCT until the toxicity profile improves.19
Intermediate cytogenetics
The European Bone Marrow Transplant (EBMT) group
reported an overall 2-year leukemia-free survival of
49% for 1040 patients who received autologous
unpurged marrow transplant during the period of 1986–
1994.21 The TRM was 11%, with a median time to
granulocyte and platelet recovery of 29 days and 42
days, respectively. Factors that influenced outcomes
were time to achieve remission (1 vs 2 inductions) for
leukemia-free survival and older age (> 35 years) for
TRM. Karyotypic analysis was not included in that study.
In the EORTC/GIMEMA study, patients with normal
karyotype who underwent autologous HCT had a 48%
DFS with a 5% TRM compared to 45% DFS and 20%
TRM in patients transplanted from a sibling donor.14 In
a consortium study that included 128 patients up to age
107
Figure 1. Disease-free survival (DFS) from complete response (CR) for four prognostic cytogenetic risk groups—
EORTC/GIMEMA trial comparing sibling allogeneic versus autologous HCT for consolidation.
The cytogenetic risk groups are good risk (1A), normal (1B) and bad/very bad risk (1C). 1D captures the data for patients in whom
cytogenetics were unknown. Reprinted with permission from Blood. 2003;102,1237.

65 receiving autologous HCT in CR1, Linker et al re- Poor-risk cytogenetics

ported a 51% DFS for patients with intermediate risk
cytogenetics, with a combined TRM of 3% for both
consolidation and transplant.18 Since TRM in alloge-
neic recipients increases significantly with age, autolo-
gous transplant may offer equivalent DFS with less mor-
bidity for older patients (≥ 50 years) than standard
myeloablative allogeneic transplant. Younger (≤ 40
years) patients with a sibling donor can expect a better
relapse-free survival of 62% with a 15% relapse rate
and TRM of 15%–20%. Since TRM is 10%–18% higher
for unrelated-donor HCT using myeloablative condi-
tioning, a donor search is rarely initiated during CR1
for intermediate-risk patients in the absence of other
risk factors such as antecedent MDS.
A donor search for a related or unrelated donor should
be initiated as soon as the patient is identified as having
poor-risk cytogenetics as this group may not achieve
remission and may require allogeneic HCT for early
salvage. Patients with poor-risk cytogenetics are pro-
portionally underrepresented in autologous transplant
series, accounting for less than 10% of patients because
remissions are more difficult to achieve and the recov-
ering marrow may have underlying myelodysplasia,
which impairs the ability to collect adequate numbers
of stem cells with normal proliferative capacity. In most
series, the results of autologous HCT for patients in
this group are poor, with DFS of 20% or less.21 In con-
trast, sibling allogeneic transplant for this group results

108 American Society of Hematology

in a 40%–45% DFS for patients ≤45 years of age19
(Figure 1C). Most unrelated donor transplants in CR1
are performed in patients with poor-risk cytogenetics.
Data from the NMDP demonstrated an overall 40% 5-
year relapse-free survival for all AML patients in CR1
transplanted between 1987 and 2001, which is compa-
rable to the 44% reported by the EORTC for sibling
HCT of patients with poor-risk karyotypes.
Reported outcomes for reduced intensity transplants
in patients with AML in CR1 are based on small
samples. The group from the University of Michigan
treated 21 patients over age 55 (median 61 years) with
MDS or AML who had HLA-matched sibling donors
with the reduced intensity regimen of fludarabine (Flu)
and busulfan (Bu) with tacrolimus and MMF for GVHD
prophylaxis.22 Seven of 12 patients who were in CR at
time of transplant remain in remission with a median
follow-up of 1 year (range 210–733 days). There were
3 relapses and 2 treatment-related deaths. All the pa-
tients with active disease died (5 relapse and 4 TRM)
with a median survival of 108 days. Overall, the inci-
dence of acute GVHD was 38% with a maximum se-
verity of grade 2. TRM at day 100 for the whole group
was 19% and was only 8% in the patients who did not
have active disease at transplant.
The German Cooperative Transplant Study Group
reported on 113 AML patients treated with Bu/Flu (93
patients) or Flu/TBI (20 patients) with a radiation dose
of either 400 or 800 cGy. The reduced intensity regi-
mens were chosen for these patients because of age > 50,
co-morbid condition or prior HCT; the median age was
51 and more than half the patients received unrelated
donor allografts.23 The minority of patients (22%) were
in CR1, and half the patients were in relapse at HCT.
Five patients with relapse did not clear their disease
and 1 did not engraft. Acute GVHD (Grade 2–4) oc-
curred in 42% of patients and chronic GVHD occurred
in 35% of patients at risk after day 100 with the major-
ity of these cases being of limited extent. The 2-year
DFS was 50% for those in CR1, 40% for those in CR2
or 3, and 15% for those with relapsed disease. Causes
of death were evenly divided between relapse and treat-
ment-related toxicity (29 patients each). In addition to
remission status, performance status (≤70%) and do-
nor type (sibling versus unrelated donor) were predic-
tive factors for event-free survival.
Salvage
The majority of allogeneic transplants are performed
as salvage for patients who have relapsed after conven-
tional chemotherapy or autologous HCT. The decision
regarding reinduction prior to salvage transplant is in-
fluenced by (1) the availability of an identified donor
Hematology 2004
and (2) the likeliness of achieving a remission, which
in turn is based on cytogenetic risk group, duration of
CR 1 and comorbid conditions. Data from EBMT,
IBMTR and the NMDP show DFS of 44% with sibling
allografts and 30% with matched unrelated donor al-
lografts at 5 years for patients transplanted in second
remission and DFS of 35%–40% in sibling transplants
and 10% in unrelated donor transplants for patients with
induction failures or HCT in relapse.24 It should be noted
that the majority of these patients received marrow rather
than PBSC. In the Seattle study comparing sibling mar-
row versus PBSC in patients with more advanced dis-
ease, there was a significant difference in DFS (57% vs
33%) using PBSC compared to marrow.1 Additional
data from the IBMTR also showed an advantage for
PBSC compared to marrow for patients transplanted in
second remission.3 The reduced intensity regimens have
had a tremendous impact on TRM in the setting of sec-
ond transplants or secondary MDS/AML following prior
autologous HCT, increasing the DFS from 16% with
standard Bu plus Cy conditioning to 40% with Flu/Bu
or Flu/Melphalan conditioning.25 The recent formation
of the Blood and Marrow Transplant Clinical Trials
Network (CTN) to facilitate the conduct of large scale
comparative transplant trials should enable the trans-
plant community to expeditiously define the role of
newer reduced-intensity conditioning regimens and
GVHD prophylaxis regimens in exploiting the antileu-
kemic effect of donor alloreactivity, minimizing trans-
plant-related toxicities and broadening the applicabil-
ity of HCT as a curative treatment strategy for patients
with AML.
III. AML IN OLDER ADULTS: ARE WE LISTENING?
Mikkael A. Sekeres, MD, MS*
AML is a disease of older adults. In the US, the median
age is 68 years and the age-adjusted population inci-
dence is 17.6 per 100,000 for people 65 years of age or
older, compared with an incidence of 1.8 per 100,000
for people under the age of 65 years.1 Therefore, of the
estimated 11,900 new AML diagnoses in the US in
2004, over half will affect patients 60 years of age or
older, a population considered “elderly” in the leuke-
mia literature.2-5 This number will only increase as the
population of US citizens 65 years or older, estimated
to be approximately 35 million in the year 2000, is
* The Cleveland Clinic Foundation, Hematology and Medical
Oncology, Desk R35, 9500 Euclid Avenue, Cleveland OH
44195
109
expected to double by the year 2030.
Older adults with AML, when compared to
younger patients with the same disease, have a poor
prognosis and represent a discrete population in terms
of disease biology, treatment-related complications, and
overall outcome. As a result, older patients require dis-
tinctive management approaches to determine whether
standard treatment, investigational treatment, or low-
dose therapy or palliative care is most appropriate. Par-
ticularly in this population, the tradeoff between po-
tential for cure or survival prolongation and quality of
life must be weighed carefully.
Disease Biology
older patients,8,9 though it is not clear that this finding
holds for patients older than 65 years.
Bone marrow biology
In older adults, AML is more likely to arise from a
proximal bone marrow stem cell disorder, such as
myelodysplastic syndrome (MDS), and with leukemia-
specific abnormalities in more than one hematopoietic
cell lineage. This may explain the different disease be-
havior in this group, as well as prolonged neutropenia
following chemotherapy.3 Older adults with AML also
are more likely to have reduced proliferative capacities
in normal hematopoietic stem cells, which may affect
blood count recovery following intensive chemotherapy.

Cytogenetics Drug-resistance genes

Older adults with AML have a lower incidence of fa- The expression of genes that mediate drug resistance
vorable chromosomal abnormalities [including the core occurs with increased frequency in this age cohort.
binding factor abnormalities, such as t(8;21) or abnor- MDR1, the so-called P-glycoprotein (gp170) chemo-
malities of chromosome 16, or the t(15;17) associated therapy efflux pump, was found in 71% of leukemic
with APL] and a higher incidence of unfavorable ab- blasts in subjects in a SWOG study of AML patients
normalities (including complex cytogenetics or abnor- over the age of 55 years, compared to a prevalence of
malities of chromosomes 5, 7, or 8) compared to 35% in younger AML patients.10 MDR1/P-glycopro-
younger adults with AML (Table 5).6-8 The rare older tein expression is associated with lower complete re-
patient fortunate enough to have good-risk cytogenetic mission (CR) rates and more chemo-resistant disease.
abnormalities may have a survival advantage over other
Prior stem cell insult
Older adults with AML are more likely to have a sec-
Table 5. Characteristics of older and younger adults with ondary leukemia arising from an antecedent MDS or
acute myeloid leukemia (AML).
from prior treatment with chemotherapy or radiation
Older AML Younger AML
therapy for another cancer. Patients with this type of
Characteristic PatientsA PatientsA AML are predisposed to having abnormalities in chro-
Population incidenceB 17.6 1.8 mosome 5 and/or 7.7 Secondary AML (AML that arose
Favorable cytogeneticsC after MDS, myeloproliferative disorders, and therapies
t(8;21) 2% 9% of malignancy) comprises 24%–56% of AML diagno-
inv 16 or t(16;16) 1–3% 10% sis in older patients,10,11 compared to a prevalence of
t(15;17) 4% 6–12%
approximately 8% in younger AML patients in the
Unfavorable cytogeneticsC
-7 8–9% 3%
Medical Research Council (MRC) AML 10 trial.7 AML
+8 6–10% 4% arising from prior bone marrow stem cell disorders or
Complex 18% 7% antecedent hematologic disorders, particularly when the
MDR1 expression 71% 35% process is greater than 10 months in duration prior to
Secondary AML 24–56% 8% the development of AML, is less responsive to chemo-
Treatment-related mortalityD 25–30% 5–10% therapy, resulting in shorter event-free survival, a lower
Complete remissionD 38–62% 65–73% CR rate, and conferring a worse prognosis.12
Long-term survivalC 5–15% 30%
Response to Therapy
A In general, Older AML Patients are defined as ≥ 60 years of Older adults are not as tolerant of or responsive to re-
age; Younger AML Patients as < 60 years of age. mission induction and consolidation chemotherapy com-
B New diagnoses, per 100,000 US citizens per year. Older/ pared to their younger counterparts. High mortality rates
younger division occurs at 65 years. likely result from inherent disease biology, an increased
C Percentages rounded to nearest whole number prevalence of comorbid disease, and a differential me-
D Rates following remission-induction therapy with an tabolism of induction regimen drugs, particularly
anthracycline- or anthracenedione-based regimen.
cytarabine, resulting in supratherapeutic drug levels.4

110 American Society of Hematology

Concern over potential treatment-related toxicities may
result in undertreatment of disease. Paradoxically, ad-
ministration of full-dose daunorubicin, for example,
may result in a reduction in early deaths by effecting a
more rapid CR.
The outcome of older adults with AML is also
worse. Adults under the age of 60 years treated with an
induction regimen consisting of an anthracycline com-
bined with cytarabine have a 65%–73% chance of at-
taining a complete remission (CR), while those over 60
years of age have a 38%–62% chance of a CR.2-4,13-15
Patients who fall into the “very elderly” category (80
years or older) can attain a CR with intensive therapy,
but their chance of doing so is 30%, and only 7% of
treated patients are alive at one year. Similar numbers
hold for patients 70 years of age or older.9 Moreover,
long-term survival occurs in approximately 30% of
younger adults (or 45% of those entering a CR), com-
pared to only 5%–15% long-term DFS in adults over
the age of 60 years.2-4,15
Indications for Treatment
For 85%–95% of older AML patients, any therapy ul-
timately will be purely palliative. Treatment options
range from supportive care (blood and platelet transfu-
sions when needed, antibiotics to treat infections, and
growth factor support) to low-dose chemotherapy (e.g.,
hydroxyurea or low-dose cytarabine) or investigational
agents as part of clinical trials, and high-dose chemo-
therapy (anthracycline- or anthracenedione-based re-
mission induction therapy). Two trials have random-
ized older patients to receive either immediate remis-
sion induction chemotherapy with an anthracycline-
based regimen versus a less aggressive or palliative ap-
proach.16,17 Only one of these studies16 demonstrated a
survival advantage for patients receiving induction che-
motherapy (21 vs 11 weeks, P = 0.015), for a median
survival time only 16 days longer than the median amount
of time they spent hospitalized to receive therapy. Thus,
the decision of whether or not to offer remission induc-
tion therapy (on the part of physicians) or to receive it
(on the part of patients) is not straightforward.
In making this decision, older patients overesti-
mate the potential benefit they may derive from in-
tensive chemotherapy and may not recall all treat-
ment options. One study18 found that 74% of older
patients estimated their chance to be cured by re-
mission induction therapy to be ≥ 50%, and almost
90% estimated their chance of being alive in one
year to be ≥ 50%. In contradistinction, physicians
caring for these patients estimated the chance of cure
to be ≤ 10% almost 89% of the time. Nearly two-
thirds of patients did not recall being offered treat-
Hematology 2004
ments other than the one they chose, despite physi-
cian documentation of alternatives in all cases. Pa-
tients choosing to receive remission induction therapy
spent 79% of their days during the first 6 weeks of
the study period either hospitalized or being seen in
clinic, compared to 14% of days for patients choos-
ing less aggressive therapy or best supportive care.
Thus, treatment decisions should be based on indi-
vidual patient preferences after an informed discus-
sion has taken place that incorporates risk estimates
modified to a patient’s performance status, comorbid-
ities, and leukemia-specific risk factors, without us-
ing absolute cutoffs for prognostic factors or chrono-
logical age. For example, an active, “younger” older
adult with de novo AML and favorable cytogenetics
should be presented with different prognostic informa-
tion than a bed-bound septuagenarian with secondary
disease and complex cytogenetics. Ideally, this discus-
sion should include specifics about prognosis and treat-
ment-related complications, and the potential impact
therapy will have on a patient’s quality of life. When
available and clinically appropriate, older patients
should always be offered the opportunity to partici-
pate in clinical trials for up-front therapy.
Treatment Options
Remission induction therapy
As with younger AML patients, the backbone of remis-
sion induction in older adults consists of an anthracycline
(daunorubicin or idarubicin) or anthracenedione
(mitoxantrone) and cytosine arabinoside (Ara-C), a regi-
men that has not changed in over two decades. Typi-
cally, daunorubicin is given at a dose of 45 mg/m2/d × 3
days, or mitoxantrone or idarubicin are given at doses
of 12 mg/m2/d × 3 days, in combination with Ara-C,
which is administered as a continuous infusion at 100
or 200 mg/m2/d × 7 days (frequently referred to as 7+3
chemotherapy). While studies have compared different
anthracyclines and anthracenediones, varied doses and
schedules, and added additional agents with some im-
provement in CR rates, they have not demonstrated an
improvement in overall survival (OS) rates (Table
6).2,5,13,15,19-21 For example, a recent study from the ECOG
randomized older AML patients to remission induction
therapy with either daunorubicin, idarubicin, or
mitoxantrone along with a standard dose of Ara-C.9
The outcome was not significantly different, with CR
rates of 40%, 43%, and 46% and median survivals of
7.7, 7.5, and 7.2 months, respectively. Once a decision
has been made to initiate intensive chemotherapy, it
should not be delayed, as this may impact outcome.9,22
111
Table 6. Selected randomized studies defining remission induction therapy in older adults.

Remission Complete
Goal Induction Agents Remission Overall Survival Comments
Compare Anthracyclines and Anthracenediones
Lowenberg, 1998 2 M (8 mg/m2/d) + 47% 39 weeks (median) Early and post-induction death rates
A (100 mg/m2/d) 9% (5 years) were similar for both arms. Patients
vs. vs. vs. receiving mitoxantrone had a significantly
D (30 mg/m2/d) + 38% 36 weeks (median) higher rate of severe infections (25.1%
A (100 mg/m2/d) P = 0.07 6% (5 years) vs 18.6%) and a trend toward a longer
P = 0.23 duration of aplasia (22 vs 19 days).
AML Collaborative I (8-20 mg/m2/d) + 51% 33.6 weeks (median) Early induction failure tended to be higher
Group, 199819 A (100-200 mg/m2/d) with idarubicin, while late induction failure
vs. vs. vs. was lower. Myelosuppression was
D (45-50 mg/m2/d) + 46% 29.9 weeks (median) greater in patients receiving idarubicin.
A (100-200 mg/m2/d) P = ND P = 0.58
Archimbaud, 199920 I (8 mg/m2/d) + 45% 7 months (median) No difference between groups in degree
A (100 mg/m2/d) + 21% (2 years) of myelosuppression or in early death
E (100 mg/m2/d) rates.
vs. vs. vs.
M (7 mg/m2/d) + 50% 7 months (median)
A (100-200 mg/m2/d)+ P = 0.52 21% (2 years)
E (100 mg/m2/d) P = ND
Vary 7+3 Dose
Buchner, 199721 D (60 mg/m2/d) + 54% 16% (5 years) The 30 mg daunorubicin arm was closed
A (100 mg/m2/d) prematurely due to higher response rates
vs. vs. vs. in the 60 mg arm, resulting in 42 patients
D (30 mg/m2/d) + 42% 10% (5 years) receiving lower dose daunorubicin, and
A (100 mg/m2/d) P = 0.038 P = 0.11 130 patients receiving the higher dose.
Dillman, 199113 D (45 mg/m2/d) + 44% 11.0 weeks (median) This study has short overall survival times
A (100 mg/m2/d) compared to other studies in this patient
vs. vs. vs. population.
D (45 mg/m2/d) + 38% 9.6 weeks (median)
A (200 mg/m2/d) P = 0.68 P = 0.23
Add Agents
Goldstone, 200115 D (50 mg/m2/d) + 62% 12% (5 years) There were no significant differences in
A (100 mg/m2 q 12 hours)+ myelosuppression or other toxicities,
T (100 mg/m2 q 12 hours) neutrophils were slower to recover in the
vs. vs. vs. mitoxantrone arm. Patients receiving ADE
D (50 mg/m2/d) + 50% 8% (5 years) had higher rates of induction death (26%
A (100 mg/m2 q 12 hours) + P = 0.0021 P = 0.021 compared to 16% for DAT and 17% for
E (100 mg/m2/d) MAC)
vs. vs. vs.
M (12 mg/m2/d) + 55% 10% (5 years)
A (100 mg/m2/d P = 0.042 P = 0.1,2 0.23
Baer, 20025 D (60 mg/m2/d) + 46% 7 months (median) Because of concern about excessive
A (100 mg/m2/d)+ mortality on the ADEP arm (25 deaths vs
E (100 mg/m2/d) 12 on the ADE arm), it was closed early to
vs. vs. vs. to further accrual. Survival between the
D (40 mg/m2/d) + 39% 2 months (median) two arms was similar at one year.
A (100 mg/m2/d) +
E (60 mg/m2/d) + P = 0.008 P = 0.48
P (10 mg/kg/d)
Use Hematopoietic Growth Factors
Stone, 1995 3 D (45 mg/m2/d) + 54% 10.8 months Median duration of neutropenia was 15
A (200 mg/m2/d) (median) days in the GM-CSF arm and 17 days in
vs. vs. vs. placebo arm (P = 0.02). The duration of
D (45 mg/m2/d) + 51% 8.4 months hospitalization did not differ between the
A (200 mg/m2/d) + (median) arms; nor did the rates of life-threatening
GM-CSF (5 µg/kg/d) P = 0.61 P = 0.10 infection, or persistent leukemia.
Godwin, 199814 D (45 mg/m2/d) + 50% 9 months The duration of neutropenia was 15%
A (200 mg/m2/d) (median) shorter in the G-CSF arm compared to the
vs. vs. vs. placebo arm (P = 0.14). The duration of
D (45 mg/m2/d) + 41% 6 months hospitalization did not differ between the
A (200 mg/m2/d) + (median) arms; nor did the rates of life-threatening
G-CSF P = 0.89 P = 0.71 infection, or persistent leukemia.
Abbreviations: M, mitoxantrone; A, Ara-C (cytosine arabinoside); D, daunorubicin; I, idarubicin; E, etoposide; T, thioguanine; P, PSC-833;
GM-CSF, granulocyte macrophage colony stimulating factor; G-CSF, granulocyte colony stimulating factor; ND, not done
1 For comparison of DAT to ADE 2 For comparison of DAT to MAC 3 For comparison of ADE to MAC

112 American Society of Hematology

Hematopoietic growth factors
In the majority of AML patients, death results from
bleeding or infectious complications. This is particu-
larly true in older adults with AML. The utility of he-
matopoietic growth factors (HGF) for ameliorating the
myelosuppressive complications of AML therapy in
older adults has been studied extensively.3,14 These tri-
als were also designed to determine whether or not HGF
had detrimental effects due to inappropriate stimula-
tion of leukemic cell proliferation and thus resistance,
or whether they had beneficial effects in “priming” leu-
kemic cells to proliferate prior to the administration of
S-phase specific chemotherapy agents such as Ara-C.9,23
With the exception of one ECOG study that demon-
strated a CR rate and overall survival benefit in patients
randomized to the GM-CSF arm (compared to patients
receiving no growth factor support), these trials found
that while HGF are safe, reduce the duration of neutro-
penia (by a range of 2–6 days), and do not support
leukemia cell proliferation, they also do not reliably
improve the CR rate, the length of hospitalization, or
the induction death rate or prolong survival.
Post-remission chemotherapy
No randomized trial has ever demonstrated that any
amount of post-remission therapy in older AML pa-
tients provides better outcomes than no post-remission
therapy. That being said, the only studies demonstrat-
ing that long-term DFS is possible in older AML pa-
tients have included remission induction and post-re-
mission therapy. It is reasonable, then, to administer
post-remission therapy consisting of a repeat of remis-
sion induction therapy, single-agent Ara-C, or 2 days
of an anthracycline or anthracenedione (the same type
of drug given at the same doses as with remission in-
duction therapy) combined with 5 days of Ara-C, again
given at the same dose as with remission induction
therapy (frequently referred to as post-remission
therapy). There does not appear to be any additional
survival benefit attained from administering more than
1–2 cycles of post-remission therapy or in treating older
AML patients with maintenance therapy. In the Medi-
cal Research Council (MRC) AML 11 trial, 371 pa-
tients who entered a complete remission following
anthracycline- or anthracenedione-based remission in-
duction therapy were randomized to receive either 1
cycle of daunorubicin, Ara-C, and thioguanine (DAT) con-
solidation therapy, or DAT along with 3 additional cycles
of Ara-C–based consolidation therapy (for a total of 4
cycles of post-remission therapy).15 Of those randomized
to the long consolidation course, 61% were able to com-
plete all 4 cycles. Survival was similar at 5 years for pa-
tients randomized to the short and long consolidation arms.
Hematology 2004
Postremission bone marrow transplantation
An even more aggressive approach than induction
therapy followed by consolidation consists of bone
marrow transplantation. Nonmyeloablative allogeneic
bone marrow transplants take advantage of a graft-ver-
sus-leukemia effect using a less-intensive preparative
regimen with lower up-front mortality. The reduced
TRM and ability to perform these transplants in the
outpatient setting make them an appealing option for
the older AML patient with few comorbidities and an
adequate performance status. Preliminary studies that
include older AML patients have demonstrated that du-
rable complete remissions are attainable with this treat-
ment, though with limited follow-up. One study of 19
patients with myeloid malignancies (17 of whom had
advanced MDS or AML) and a median age of 64 years
(range, 60–70 years) demonstrated a 68% survival at a
median follow-up of 825 days following nonmyeloab-
lative transplantation.24 These early data have prompted
cooperative groups to explore the role of bone marrow
transplantation in older AML patients in first CR.
Newer approaches
Remission induction therapy for older adults with AML
is no panacea, with median and 5-year survival rates
resembling those of patients with advanced lung can-
cer.1 It is thus reasonable to consider investigational
agents for older AML patients as initial therapy, par-
ticularly those that may be associated with less TRM.
Potential targets for antileukemia therapy include spe-
cific signaling molecules required for the maintenance
of the leukemic state, such as tyrosine kinases;
overexpression of bcl-2, an anti-apoptosis signal; DNA
methylation, associated with suppression of regulatory
genes and with disease progression; indirect pathways
that maintain leukemogenesis, including angiogenesis
and drug resistance; and investigational agents with
mechanisms of action that differ from anthracyclines,
anthracenediones, and Ara-C, such as nucleoside ana-
logs, farnesyl transferase inhibitors (FTIs), and MDR
modulators, alone or in combination with standard thera-
pies.25-29 These approaches are discussed in more detail
in Section I. The efficacy of the FTI Zarnestra will be
examined in newly diagnosed AML patients over the
age of 70 years in the US cooperative group setting
(SWOG 0432). One recent trial from the Dutch-Bel-
gian Hemato-Onocology Cooperative Group (HOVON)
randomized predominantly older patients, most of whom
had a diagnosis of advanced MDS or AML, to Ara-C
and G-CSF or the same regimen plus fludarabine for 2
cycles followed by Ara-C and daunorubicin for 1 cycle.30
This study is typical of many novel combination trials
in older AML patients in that, while the CR rate was
113
improved in AML patients receiving fludarabine (95%
vs 71%, P = 0.046), survival was not impacted.
Supportive/palliative care
Intensive chemotherapy provides only marginal, if any,
survival benefit to older AML patients, so non-inten-
sive (or non-chemotherapy-based) approaches are rea-
sonable. We use the phrase aggressive supportive care
to emphasize that symptoms will be treated vigorously
and to distinguish this modality from hospice. Blood
and platelet transfusions should be administered to al-
leviate symptoms stemming from anemia and thromb-
ocytopenia, and antibiotics started when appropriate.
Low-dose chemotherapy should only be used in the set-
ting of leukocytosis and/or associated symptoms. Any
recommendations for the institution of neutropenic pre-
cautions (i.e., avoiding crowds, refraining from
ingestions of raw foods) must be balanced with the lack
of evidence supporting the benefit of these maneuvers
and the impact such restrictions will have on a patient’s
quality of life. Hospice services should be instituted
within 6 months of anticipated demise. While some
hospice organizations prohibit blood product transfu-
sions, we consider these to be palliative in this popula-
tion as they may result in improved quality of life in
terminal cancer patient populations.
REFERENCES
I. AML: Current Landscape and
Future Directions
1. Vardiman JW, Harris NL, Brunning RD. The World Health
Organization (WHO) classification of the myeloid neoplasms.
Blood. 2002;100:2292-2302.
2. Gilliland DG, Griffin JD. The role of FLT3 in hematopoiesis
and leukemia. Blood. 2002;100:1332-1342.
3. Poppe B, Vandesompele J, Schoch C, et al. Expression
analyses identify MLL as a prominent target of 11q23
amplification and support an etiologic role for MLL gain of
function in myeloid malignancies. Blood. 2004;103:229-235.
4. Kolitz JE, George SL, Dodge RK, Hoke E, Hurd DD. Dose
escalation studies of Ara-C (A), daunorubicin (D) and
etoposide (E) with and without multidrug resistance (MDR)
Modulation with PSC-833 (P in untreated adults with acute
myeloid leukemia (AML) [abstract]. Blood.
2001;98(Suppl):461a.
5. Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of
prolonged remission duration after high-dose cytarabine
intensification in acute myeloid leukemia varies by cytoge-
netic subtype. Cancer Res. 1998;58:4173-4179.
6. Byrd JC, Dodge RK, Carroll A, et al. Patients with
t(8;21)(q22;q22) and acute myeloid leukemia have superior
failure-free and overall survival when repetitive cycles of
high-dose cytarabine are administered. J Clin Oncol. 1999;
17:3767-3775.
7. Sanz MA, Martin G, Rayon C, et al for the PETHEMA Group.
A modified AIDA protocol with anthracycline-based
consolidation results in high antileukemic efficacy and
114
reduced toxicity in newly diagnosed PML/RARα-positive
acute promyelocytic leukemia. Blood. 1999;94:3015-3021.
8. Tallman MS, Nabhan C, Feusner JH, et al. Acute
promyelocytic leukemia: evolving therapeutic strategies.
Blood. 2002;99:759-767.
9. Fenaux P, Chastang C, Chevret S, et al. A randomized
comparison of all transretinoic acid (ATRA) followed by
chemotherapy and ATRA plus chemotherapy and role of
maintenance therapy in newly diagnosed acute promyelocytic
leukemia. Blood. 1999;94:1192-1200.
10. Diverio D, Rossi V, Avvisati G, et al. Early detection of
relapse by prospective reverse transcriptase-polymerase chain
reaction analysis of the PML/RAR alpha fusion gene in
patients with acute promyelocytic leukemia enrolled in the
GIMEMA-AIEOP multicenter “AIDA” trial. GIMEMA-
AIEOP Multicenter “AIDA” Trial. Blood. 1998;92:784-789.
11. Latagliata R, Petti MC, Fenu S, et al. Therapy-related
myelodysplastic syndrome-acute myelogenous leukemia in
patients treated for acute promyelocytic leukemia: an
emerging problem. Blood. 2002;99:822-824.
12. Soignet SL, Frankel SR, Douer D, et al. United States
multicenter study of arsenic trioxide in relapsed acute
promyelocytic leukemia. J Clin Oncol. 2001;19:3852-3860.
13. Sievers EL, Larson RA, Stadtmauer EA, Stey E, Lowenberg
B, Dombret H. Efficacy and safety of gemtuzumab
ozogamicin in patients with CD33-positive acute myeloid
leukemia in first relapse. J Clin Oncol. 2004;22:1087-1094.
14. Wadleigh M, Richardson PG, Zahrich D, et al. Prior
gemtuzumab ozogamicin exposure significantly increases the
risk of venoocclusive disease in patients who undergo
myeloablative allogeneic stem cell transplantation. Blood.
2003;102:1578-1582.
15. De Angelo DJ, Stone RM, Durrant S, Liu D, Baccarani M,
Schiffer CA, Amrein PC, Sherman ML. Gemtuzumab
ozogamicin (Mylotarg®) in combination with induction
chemotherapy for the treatment of patients with de novo acute
myeloid leukemia: two age-specific phase II trials [abstract].
Blood. 2003;102:100a.
16. Baer MR, George SL, Dodge RK, et al. Phase 3 study of the
multidrug resistance modulator PSC-833 in previously
untreated patients 60 years of age and older with acute
myeloid leukemia: Cancer and Leukemia Group B Study
9720. Blood. 2002;100:1224-1232.
17. List AF, Kopecky KJ, Willman CL, et al. Benefit of
cyclosporine modulation of drug resistance in patients with
poor-risk acute myeloid leukemia: a Southwest Oncology
Group study. Blood. 2001;98:3212-3220.
18. Marcucci G, Byrd JC, Guowei D, Klisovic MI, Kourlas PJ.
Phase I and pharmacodynamic studies of G3139, a Bcl-2
antisense oligonucleotide, in combination with chemotherapy
in refractory or relapsed acute leukemia. Blood.
2003;101:425-432.
19. Cortes J, Thomas D, Koller C, Giles F, Estey E, Faderl S.
Phase I study of bortezomib in refractory or relapsed acute
leukemias. Clin Cancer Res. 2004;10:3371-3376.
20. Lowenberg B, van Putten W, Theobald M, et al. Effect of
priming with granulocyte colony-stimulating factor on the
outcome of chemotherapy for acute myeloid leukemia. N
Engl J Med. 2003;349:743-752.
21. Silverman LR, Demalos EP, Peterson BL, et al. Randomized
controlled trial of azacitidine inpatients with the
myelodysplastic syndrome: a study of the Cancer and
Leukemia Group B. J Clin Oncol. 2002;20:2429-2440.
22. Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and
biological activity of the farnesyltransferase inhibitor
American Society of Hematology
 R115777 in adults with refractory and relapsed acute
leukemias: a phase I clinical-laboratory correlative trial.
Blood. 2001;97:3361-3369.
23. Lancet JE, Gojo I, Gotlib J, et al. Tipifarnib (ZARNESTRA)
in previously untreated poor-risk AML and MDS: interim
results of a phase 2 trial [abstract]. Blood. 2003;102:176a.
24. Fiedler W, Mesters R, Tinnefeld H, Loges S. A phase 2 clinical
study of SU5416 in patients with refractory acute myeloid
leukemia. Blood. 2003;102:2763-2767.
25. Stone RM, DeAngelo DJ, Klimek V, et al. Acute myeloid
leukemia patients with an activating mutation in FLT3
respond to a small molecule FLT3 tyrosine kinase inhibitor,
PKC412. Blood. First Edition Paper, prepublished online
September 2, 2004; DOI 10.1182/blood-2004-03-0891
26. Smith DB, Levis M, Beran M, Giles F, Kantarjian K. Single-
agent CEP 701, a novel FLT3 inhibitor, shows biologic and
clinical activity in patients with relapsed or refractory acute
myeloid leukemia. Blood. 2004;103:3669-3676.
27. DeAngelo D, Stone RM, Bruner RJ, et al. Phase I clincal
results with MLN518, a novel FLT3 antagonist: tolerability.
Pharmacokinetics and pharmacodynamics [abstract]. Blood.
2003;102:65a.
28. Wadleigh M, DeangeloDJ, Griffin JD, Stone RM. After
chronic myelogenous leukemia: tyrosine kinase inhibitors in
other hematologic malignancies. Blood. 2004; Epub 10.1182/
blood-2003-11-3896.
29. Karp JE, Gojo I, Pili R, Gocke CD, Greer J, Guo C. Targeting
vascular endothelial growth factor for relapsed and refractory
adult acute myelogenous leukemias: therapy with sequential
1-B-D- arabinofuransylcytosine, mitoxantrone, and
bevacizumab. Clin Cancer Res. 2004;10:3577-3585.
II. The Role of Autologous and Allogeneic (“Full”
and “Mini”) Stem Cell Transplantation in AML
1. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of
bone marrow as compared with peripheral blood cells from
HLA-identical relatives in patients with hematologic cancers.
N Engl J Med. 2001;344;175-181.
2. Zaucha JM, Gooley T, Bensinger WI, et al. CD34 cell dose in
granulocyte colony-stimulating factor-mobilized peripheral
blood mononuclear cell grafts affects engraftment kinetics
and development of extensive chronic graft-versus-host
disease after human leukocyte antigen-identical sibling
transplantation. Blood. 2001;98:3221-3227.
3. Champlin RE, Schmitz N, Horowitz MM, et al. Blood stem
cells compared with marrow as a source of hematopoietic cells
for allogeneic transplantation. Blood. 2000;95:3702-3709.
4. Schmitz N, Beksac M, Hasenclever D, et al. Transplantation of
mobilized peripheral blood cells to HLA-identical siblings
with standard-risk leukemia. Blood. 2002:100:761-767.
5. Cutler C, Kim HT, Hochberg E, et al. Sirolimus and
tacrolimus without methotrexate as graft-versus-host disease
prophylaxis after matched related donor peripheral blood
stem cell transplantation. Biol Blood Marrow Transplant.
2004;10:328-336.
6. Michallet M, Bilger K, Garban F, et al. Allogeneic hematopoi-
etic stem-cell transplantation after nonmyeloablative
preparative regimens: impact of pretransplantation and
posttransplantation factors on outcome. J Clin Oncol.
2001;19:3340-3349.
7. Stein AS, O’Donnell MR, Slovak ML, et al. Interleukin-2
after autologous stem-cell transplantation for adult patients
with acute myeloid leukemia in first complete remission. J
Clin Oncol. 2003;21:615-623.
8. Bertz H, Potthoff K, Finke J. Allogeneic stem-cell transplanta-
Hematology 2004
tion from related and unrelated donors in older patients with
myeloid leukemia. J Clin Oncol. 2003;21:1480-1484.
9. Tallman MS, Rowlings PA, Milone J, et al. Effect of post
remission chemotherapy before HLA identical sibling
transplantation for acute myelogenous leukemia in first
complete remission. Blood. 2000;96:1254-1258.
10. Bornhauser M, Storer B, Slattery JT, et al. Conditioning with
fludarabine and targeted busulfan for transplantation of
allogeneic hematopoietic stem cells. Blood. 2003;102:820-
826.
11. Couriel DR, Saliba RM, Giralt S, et al. Acute and chronic
graft-versus-host disease after ablative and nonmyeloablative
conditioning for allogeneic hematopoietic transplantation.
Biol Blood Marrow Transplant. 2004;10:178-185.
12. Jungbanss C, Marr KA, Carter RA, et al. Incidence and
outcome of bacterial and fungal infections following
nonmyeloablative compared with myeloablative allogeneic
hematopoietic stem cell transplantation: a matched control
study. Biol Blood Marrow Transplant. 2002;8:512-520.
13. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemo-
therapy compared with autologous or allogeneic bone
marrow transplantation in the management of acute myeloid
leukemia in first remission. N Engl J Med. 1998;339:1649-
1656.
14. Zittoun RA, Mandelli F, Willemze R, De Witte, T, et al.
Autologous or allogeneic bone marrow transplantation
compared with intensive chemotherapy in acute myelogenous
leukemia. N Engl J Med. 1995;332:217-223.
15. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, et al.
Karyotypic analysis predicts outcome of preremission and
post remission therapy in adult acute myeloid leukemia: a
Southwest Oncology Group/Eastern Cooperative Oncology
Group study. Blood. 2000;96:4075-4077.
16. Burnett AK, Goldstone AH, Stevens RMF, Hann IM, et al.
Randomized comparison of addition of autologous bone-
marrow transplantation to intensive chemotherapy for acute
myeloid leukaemia first remission: results of MRC AML 10
trial. Lancet. 1998;351:700-708.
17. Meloni G, Diverio D, Vignette M, et al. Autologous bone
marrow transplantation for acute promyelocytic leukemia in
second remission: prognostic relevance of pretransplant
minimal residual disease assessment by reverse-transcription
polymerase chain reaction of the PML/RARα fusion gene.
Blood. 1997;90:1321-1325.
18. Linker CA, Ries CA, Damon LE, et al. Autologous stem cell
transplantation for acute myeloid leukemia in first remission.
Biol Blood Marrow Transplant. 2000; 6:50-57.
19. Suciu S, Mandelli F, de Witte T, et al. Allogeneic compared
with autologous stem cell transplantation in the treatment of
patients younger than 46 years with acute myeloid leukemia
(AML) in first complete remission (CR1): an intention-to-treat
analysis of the EORTC/GIMEMA AML-10 trial. Blood.
2003;102:1232-1240.
20. Linker CA, Damon LE, Ries CA, Navarro WA, Case D, Wolf
JL. Autologous stem cell transplantation for advanced acute
myeloid leukemia. Bone Marrow Transplant. 2002;29:297-
301.
21. Reiffers J, Labopin M, Sanz M, et al. Autologous blood cell
vs marrow transplantation for acute myeloid leukemia in
complete remission: an EBMT retrospective analysis. Bone
Marrow Transplant. 2000;25:1115-1119.
22. Levine JE, Uberti JP, Ayash L, et al. Lowered-intensity
preparative regimen for allogeneic stem cell transplantation
delays acute graft-versus-host disease but does not improve
outcome for advanced hematologic malignancy. Biol Blood
115
 Marrow Transplant. 2003;9:189-197.
23. Sayer HG, Kroger M, Veyer J, et al. Reduced intensity
conditioning for allogeneic hematopoietic stem cell transplan-
tation in patients with acute myeloid leukemia: disease status
by marrow blasts is the strongest prognostic factor. Bone
Marrow Transplant. 2003;31:1089-1095.
24. Michallet M, Thomas X, Vernant JP, et al. Long-term outcome
after allogeneic hematopoietic stem cell transplantation for
advanced stage acute myeloblastic leukemia: a retrospective
study of 379 patients reported to the Societe Francaise de
Greffe de Moelle (SFGM). Bone Marrow Transplant.
2000;26:1157-1163.
25. Feinstein LC, Sandmaier BM, Maloney DG, et al. Allografting
after nonmyeloablative conditioning as a treatment after a
failed conventional hematopoietic cell transplant. Biol Blood
Marrow Transplant. 2003;9:266–272.
III. AML in Older Adults: Are We Listening?
1. Ries L, Eisner M, Kosary C, et al. SEER Cancer Statistics
Review, 1975-2001, National Cancer Institute. http://
seer.cancer.gov/csr/1975_2001/. Bethesda, MD: National
Cancer Institute; 2004.
2. Lowenberg B, Suciu S, Archimbaud E, et al. Mitoxantrone
versus daunorubicin in induction-consolidation chemotherapy
- the value of low-dose cytarabine for maintenance of
remission, and an assessment of prognostic factors in acute
myeloid leukemia in the elderly: final report. European
Organization for the Research and Treatment of Cancer and
the Dutch-Belgian Hemato-Oncology Cooperative Hovon
Group. J Clin Oncol. 1998;16:872-881.
3. Stone RM, Berg DT, George SL, et al. Granulocyte-macroph-
age colony-stimulating factor after initial chemotherapy for
elderly patients with primary acute myelogenous leukemia.
Cancer and Leukemia Group B. N Engl J Med.
1995;332:1671-1677.
4. 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.
5. Baer MR, George SL, Dodge RK, et al. Phase 3 study of the
multidrug resistance modulator PSC-833 in previously
untreated patients 60 years of age and older with acute
myeloid leukemia: Cancer and Leukemia Group B Study
9720. Blood. 2002;100:1224-1232.
6. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytoge-
netic abnormalities are predictive of induction success,
cumulative incidence of relapse and overall survival in adult
patients with de novo acute myeloid leukemia: results from
CALGB 8461. Blood. 2002;100:4325-4336.
7. 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;92:2322-2333.
8. Grimwade D, Walker H, Harrison G, et al. The predictive
value of hierarchical cytogenetic classification in older adults
with acute myeloid leukemia (AML): analysis of 1065
patients entered into the United Kingdom Medical Research
Council AML11 trial. Blood. 2001;98:1312-1320.
9. Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study
of three induction regimens and of priming with GM-CSF in
older adults with acute myeloid leukemia: a trial by the
Eastern Cooperative Oncology Group. Blood. 2004;103:479-
485.
10. Leith CP, Kopecky KJ, Godwin J, et al. Acute myeloid
116
leukemia in the elderly: assessment of multidrug resistance
(MDR1) and cytogenetics distinguishes biologic subgroups
with remarkably distinct responses to standard chemotherapy.
A Southwest Oncology Group study. Blood. 1997;89:3323-
3329.
11. Bauduer F, Ducout L, Dastugue N, Capdupuy C, Renoux M.
De novo and secondary acute myeloid leukemia in patients
over the age of 65: a review of fifty-six successive and
unselected cases from a general hospital. Leuk Lymphoma.
1999;35:289-296.
12. Estey E, Thall P, Beran M, Kantarjian H, Pierce S, Keating M.
Effect of diagnosis (refractory anemia with excess blasts,
refractory anemia with excess blasts in transformation, or
acute myeloid leukemia [AML]) on outcome of AML-type
chemotherapy. Blood. 1997;90:2969-2977.
13. Dillman RO, Davis RB, Green MR, et al. A comparative study
of two different doses of cytarabine for acute myeloid
leukemia: a phase III trial of Cancer and Leukemia Group B.
Blood. 1991;78:2520-2526.
14. Godwin JE, Kopecky KJ, Head DR, et al. A double-blind
placebo-controlled trial of granulocyte colony-stimulating
factor in elderly patients with previously untreated acute
myeloid leukemia: a Southwest oncology group study (9031).
Blood. 1998;91:3607-3615.
15. Goldstone AH, Burnett AK, Wheatley K, Smith AG,
Hutchinson RM, Clark RE. Attempts to improve treatment
outcomes in acute myeloid leukemia (AML) in older patients:
the results of the United Kingdom Medical Research Council
AML11 trial. Blood. 2001;98:1302-1311.
16. Lowenberg B, Zittoun R, Kerkhofs H, et al. On the value of
intensive remission-induction chemotherapy in elderly
patients of 65+ years with acute myeloid leukemia: a
randomized phase III study of the European Organization for
Research and Treatment of Cancer Leukemia Group. J Clin
Oncol. 1989;7:1268-1274.
17. Tilly H, Castaigne S, Bordessoule D, et al. Low-dose
cytarabine versus intensive chemotherapy in the treatment of
acute nonlymphocytic leukemia in the elderly. J Clin Oncol.
1990;8:272-279.
18. Sekeres MA, Stone RM, Zahrieh D, et al. Decision-making
and quality of life in older adults with acute myeloid leukemia
or advanced myelodysplastic syndrome. Leukemia.
2004;18:809-816.
19. A systematic collaborative overview of randomized trials
comparing idarubicin with daunorubicin (or other
anthracyclines) as induction therapy for acute myeloid
leukaemia. AML Collaborative Group. Br J Haematol.
1998;103:100-109.
20. Archimbaud E, Jehn U, Thomas X, et al. Multicenter
randomized phase II trial of idarubicin vs mitoxantrone,
combined with VP-16 and cytarabine for induction/
consolidation therapy, followed by a feasibility study of
autologous peripheral blood stem cell transplantation in
elderly patients with acute myeloid leukemia. Leukemia.
1999;13:843-849.
21. Buchner T, Hiddemann W, Wormann B, et al. Daunorubicin
60 instead of 30 mg/sqm improves response and survival in
elderly patients with AML [abstract]. Blood. 1997;90:583a.
22. Sekeres M, Rybicki L, Sobecks R, et al. The Time Interval
from Diagnosis of Acute Myeloid Leukemia (AML) in older
adults to start of remission induction therapy predicts survival
[abstract]. Blood. 2003;102:3257a.
23. Lowenberg B, van Putten W, Theobald M, et al. Effect of
priming with granulocyte colony-stimulating factor on the
outcome of chemotherapy for acute myeloid leukemia. N
American Society of Hematology
 Engl J Med. 2003;349:743-752.
24. Bertz H, Potthoff K, Finke J. Allogeneic stem-cell transplanta-
tion from related and unrelated donors in older patients with
myeloid leukemia. J Clin Oncol. 2003;21:1480-1484.
25. Stone R, Klimek V, DeAngelo D, et al. PKC412, an oral FLT3
inhibitor, has activity in mutant FLT3 acute myeloid leukemia
(AML): a phase II clinical trial [abstract]. Blood.
2002;100:316a.
26. Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic
activity of the farnesyltransferase inhibitor R115777 in adults
with refractory and relapsed acute leukemias: a phase 1
clinical-laboratory correlative trial. Blood. 2001;97:3361-
3369.
27. Giles FJ. The emerging role of angiogenesis inhibitors in
hematologic malignancies. Oncology (Huntingt). 2002;16:23-
29.
Hematology 2004
28. Silverman LR, Demakos EP, Peterson BL, et al. Randomized
controlled trial of azacitidine in patients with the
myelodysplastic syndrome: a study of the cancer and
leukemia group B. J Clin Oncol. 2002;20:2429-2440.
29. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a
novel FLT3 inhibitor, shows biologic and clinical activity in
patients with relapsed or refractory acute myeloid leukemia.
Blood. 2004;103:3669-3676.
30. Ossenkoppele GJ, Graveland WJ, Sonneveld P, et al. The
value of fludarabine in addition to ARA-C and G-CSF in the
treatment of patients with high-risk myelodysplastic syn-
dromes and AML in elderly patients. Blood. 2004;103:2908-
2913.
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