from the Experts
How I Treat Older Patients With Acute Myeloid Leukemia
INTRODUCTION
Acute myeloid leukemia (AML) is a clonal
malignant proliferation of myeloid blast cells
affecting primarily older adults, with a median
age of onset of 68 years. The National Cancer
Institute’s Surveillance, Epidemiology, and
End Results program estimates 21,380 new
AML cases will have been diagnosed and
10,590 AML-related deaths will have occurred
in the United States in 2017.1 The main risk
factor for the development of AML is increas-
ing age, and although there rarely are other
identifiable predisposing factors, there is an
increasing number of AML cases after
exposure to chemotherapy or radiotherapy
(collectively referred to as “therapy-related
AML” [t-AML]). There also is a distinct high-
risk category of secondary AML (s-AML) after
antecedent hematological disorders, such as
myelodysplastic syndromes (MDS) or myelo-
proliferative neoplasms.2 Outcomes of AML in
older adults (aged >60 years) are dismal, with
survival rates reported to be <10% at 3 years
and <5% at 5 years.3,4 Therapeutic challenges
include both a more aggressive biology of the
disease as well as a patient that is more
susceptible to the toxic effects of chemother-
apy. Disappointingly, only 40% of patients
with AML who are aged >65 years are offered
chemotherapy within 3 months of diagnosis.
Moreover, elderly patients with AML who
receive treatment have a 33% lower risk of
AML-related death compared with their
untreated counterparts.5 Compared with
untreated elderly patients with AML, those
who are offered treatment tend to be younger,
are less likely to have s-AML, and are more
likely to have a good performance status (PS).
Furthermore, allogeneic hematopoietic stem
cell transplantation (HSCT) is feasible and can
offer a survival benefit for selected Medicare-
age patients.5 Although it generally is accepted
that older patients with AML can benefit from
2472
Martha Arellano, MD
treatment, there is clearly a need for risk- Department of Hematology and
Medical Oncology, Winship Cancer
adapted treatment strategies for elderly
Institute, Emory University,
patients with AML. We herein discuss 3 cases Atlanta, Georgia
that illustrate some of the complexities in
treatment planning, review the literature, and
Jennifer Wilkinson
highlight new treatments for older patients
Carlisle, MD
with AML. Hematology and Medical Oncology
Fellowship Training Program,
Emory University, Atlanta, Georgia
Clinical Cases
Case 1
An 81-year-old avid tennis player developed
rapidly progressive dyspnea on exertion and
fatigue. His complete blood count revealed
pancytopenia prompting bone marrow biopsy
and aspiration. His bone marrow was 90% cel-
lular with 40% myeloid blasts, dysplastic
changes, and complex cytogenetics (5q-, 18,
111q25, 122p11, and t[1;22]). His past medi-
cal history was significant for prostate cancer
diagnosed 6 years prior, which was treated
with radioactive seed implants; at presentation,
the patient had an undetectable prostate-
specific antigen level. He enrolled on a single-
arm phase 2 trial of azacitidine and a histone
deacetylase inhibitor. After 3 cycles, the patient
was taken off study after an episode of pneu-
monia and atrial fibrillation. He was switched to
decitabine and achieved complete remission
(CR) after 2 months. At the time of last follow-
up, the patient had completed 34 cycles of dec-
itabine and continued to play tennis.
Case 2
A 71-year-old man was referred with a new
diagnosis of AML after presenting with pancy-
topenia. He had low-risk prostate cancer diag-
nosed 3 years previously that was treated with
radiation. His bone marrow was 10% to 20%
cellular with 30% blasts and dysplastic ery-
throid precursors. Karyotype was normal male
and fluorescence in situ hybridization demon-
strated monosomy 20. His Eastern Coopera-
tive Oncology Group (ECOG) PS had recently
Cancer June 15, 2018

declined to 2. He received 8 cycles of decitabine (at a dose of
20 mg/m2/day for 5 days on 28-day cycles) on a clinical trial.
Physical therapy was initiated to improve his PS with the goal
of allogeneic HSCT. He achieved CR and after improvement in
his PS, the patient underwent allogeneic HSCT from a
matched unrelated donor after reduced intensity conditioning.
He developed gastrointestinal graft-versus-host disease but at
the time of last follow-up, 3.5 years after transplantation, the
patient was off all immunosuppression and continued to work.
Case 3
A 73-year-old woman presented to the emergency department
with a 3-week history of progressive dyspnea and was found
to have a white blood cell count of 86,200/lL with 68% blasts.
She underwent bone marrow biopsy with aspiration and initi-
ated treatment with hydroxyurea for cytoreduction. Her bone
marrow was 50% cellular with 63% myeloid blasts; AML fluo-
rescence in situ hybridization panel and cytogenetics were nor-
mal. Her ECOG PS had recently declined to 1. She received
induction with cytarabine and idarubicin (7 1 3 regimen), which
was complicated by neutropenic fever and severe mucositis,
precluding a bone marrow evaluation on day 14. Next-
generation sequencing for myeloid malignancies revealed a
biallelic mutation in CCAAT/enhancer binding protein a gene
(CEBPA). She achieved CR and went on to complete 4 cycles
of outpatient consolidation with intermediate-dose cytarabine.
At the time of last follow-up, 18 months after treatment, the
patient was doing well.
These cases refute the sense of nihilism regarding therapy in
elderly patients with AML that still exists in some areas outside
of the academic community and reinforce that the choice is no
longer induction versus no treatment, and that one treatment
does not fit all. Optimal outcomes depend on the careful selec-
tion of patients to identify which elderly patients might benefit
the most from the growing list of available AML treatments.
Below, we review assessment of disease and patient-related
factors as well as treatment advances, and present an algo-
rithm with which to guide the management of the older adult
with AML.
LITERATURE REVIEW
Risk Stratification
Disease-related factors
Cytogenetic abnormalities are crucial to guiding treatment deci-
sions because they remain the most important prognostic fac-
tor in AML. In fact, recurrent genetic abnormalities underlie the
recently updated World Health Organization classification of
myeloid neoplasms and acute leukemia.6 More unfavorable kar-
yotypes are noted among older patients (those aged 60 years)
(40%-50%) compared with younger patients (approximately
30%).7,8 Furthermore, older adults with AML are more likely to
express high levels of the multidrug resistance gene,9 making
elderly patients with AML more resistant to therapy. Grimwade
et al analyzed 1065 patients with a median age of 66 years
(range, 44-91 years) who were treated with intensive chemo-
therapy in the UK Medical Research Council (MRC) AML11 trial,
and outcomes were classified based on 3 cytogenetic risk
groups, which were similar across cooperative groups.8,10-12
Cancer June 15, 2018
INSIGHT from the Experts
The favorable-risk group included patients with the core-binding
factor leukemias and acute promyelocytic leukemia, with a 5-
year overall survival (OS) rate of 34%. Those in the
intermediate-risk category had a 5-year OS rate of 13%,
whereas the 5-year OS for patients with adverse cytogenetic
risk was 2%. In terms of disease response, AML with complex
cytogenetics (defined as 5 unrelated abnormalities in the
United Kingdom and more recently as 3 unrelated abnormali-
ties in the United States) has particularly dismal CR rates. In the
MRC AML11 trial, the CR rate was 26% for those with a com-
plex karyotype and 45% for patients with an adverse but non-
complex karyotype.8 A subsequent study of 635 adults aged
60 years demonstrated that 25% of patients with complex
karyotypes (3 abnormalities) achieved a CR compared with
a CR rate of 56% in the other cytogenetic risk groups
combined.13
Specific molecular abnormalities influence AML outcomes and
must be included in the initial risk assessment. The updated
National Comprehensive Cancer Network and European Leu-
kemiaNet AML risk stratifications include cytogenetic and
molecular abnormalities and are compared in Table 1.14,15
Examples of molecular abnormalities influencing cytogenetic
risk include mutant c-KIT, which is associated with a shorter
time to disease recurrence and decreased OS in patients with
t(8,21) and to a lesser extent in those with inv(16).16-18 In
patients with cytogenetically normal AML, internal tandem
duplication (ITD) in the fms-like tyrosine kinase 3 (FLT3) gene is
equivalent to the poor-risk cytogenetic group in terms of prog-
nosis.19-21 Conversely, mutation of nucleophosmin 1 (NPM1)
in the absence of a FLT3 mutation confers a favorable progno-
sis20 as does a double allelic mutation in CEBPA in patients
with cytogenetically normal AML.22,23 Not surprisingly, in the
prior European LeukemiaNet categorization, older patients had
worse outcomes when compared with younger patients
within each risk group.24,25 Moreover, older patients are more
likely to fall into the poor-risk molecular category, with higher
rates of adverse runt-related transcription factor 1 (RUNX1),
additional sex combs-like 1 (ASXL1), and TP53 mutations, and
lower rates of favorable mutations compared with younger
patients.26
Broad panel-based mutational analyses recently have defined
distinct genetic profiles that correspond to clinical subgroups
of AML, including t-AML, s-AML, and de novo AML. Among a
cohort of 42 patients aged  60 years with de novo AML, 33%
had mutations commonly found in s-AML, such as ASXL1,
SRSF2, and STAG2. Within the same cohort, 21% had TP53
mutations, whereas the remainder had mutations associated
with de novo AML (ie, RUNX1, NPM1, RAS, DNA methyltrans-
ferase 3 alpha [DNMT3A], and isocitrate dehydrogenase [IDH]
1/IDH2).27 Of particular importance are the TP53 gene muta-
tions, which lead to loss of important tumor suppressor func-
tions including DNA repair programs and cell cycle arrest.28
Most often, TP53 mutations are noted in patients with AML
with a complex karyotype or t-AML.29 In a study of patients
newly diagnosed with AML, TP53-mutated AML was associ-
ated with a lower CR rate (41% vs 57%) and OS rate (9% vs
24% at 2 years) irrespective of age or the type of treatment
received (high-intensity vs low-intensity chemotherapy).30 The
list of prognostically relevant molecular abnormalities
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 INSIGHT from the Experts

TABLE 1. Updated AML Risk Classification From the NCCN and ELN

Risk Category NCCN Cytogenetics15 NCCN Molecular15 ELN Genetic Abnormality14

Favorable Core binding factor: Normal cytogenetics: NPM1 t(8;21); RUNX1-RUNX1T1

inv(16), t(16;16), mutation in the absence Inv(16) or t(16;16); CBFB-MYH11
t(8;21), or t(15;17) of FLT3-ITD or isolated biallelic Mutated NPM1 without FLT3-ITD
(double) CEBPA mutation or with FLT3-ITDlow*
Biallelic mutated CEBPA
Intermediate Normal cytogenetics Core-binding factor with KIT Mutated NPM1 and FLT3-ITDhigh*
18 alone, t(9;11), mutation Wild-type NPM1 without FLT3-ITD
other nondefined T(9;11); MLLT3-KMT2A
Cytogenetic abnormalities not classified
as favorable or adverse
Poor (NCCN) Complex (3 clonal Normal cytogenetics: with T(6;9); DEK-NUP214
Adverse (ELN) chromosomal FLT3-ITD mutation T(v;11q23.3); KMT2A rearranged
abnormalities) TP53 mutation T(9;22); BCR-ABL1
Monosomal karyotype: Inv(3) or t(3;3); GATA2,MECOM(EVI1)
-5, 5q-, -7, 7q-, -5 or del (5q); -7;-17/abn(17p)
11q23- non t(9;11) Complex karyotype, monosomal karyotype
inv(3), t(3;3) Wild-type NPM1 and FLT3-ITDhigh
t(6;9) Mutated RUNX1
t(9;22) Mutated ASXL1
Mutated TP53
Abbreviations: AML, acute myeloid leukemia; ASXL1, additional sex combs-like 1; CBFB-MYH11, core-binding factor beta subunit-smooth muscle myosin
heavy chain 11; CEBPA, CCAAT/enhancer binding protein alpha; DEK-NUP214, DEK-nucleoporin 214; ELN, European LeukemiaNet; FLT3-ITD, fms-like tyrosine
kinase 3 internal tandem duplication; GATA2, GATA-binding protein 2; MECOM(EVI1), MDS1 and EVI1 complex locus; MLLT3-KMT2A, MLLT3-lysine methyl-
transferase 2A; NCCN, National Comprehensive Cancer Network; NPM1, nucleophosmin 1; RUNX1, runt-related transcription factor 1; RUNX1T1, RUNX1
translocation partner 1.
*FLT3-ITD “low” indicates an allelic ratio <0.5, whereas “high” indicates an allelic ratio 0.5 using semiquantitative DNA fragment analysis by taking the
ratio of the area under the curve “FLT3-ITD” divided by area under the curve “FLT3-wild-type.”

continues to grow and supports the standard use of myeloid
panel sequencing during the workup of AML. Well-
documented genetic abnormalities also provide potential tar-
gets for therapy and may aid in the detection of minimal resid-
ual disease.31
Patient-related factors
Clinical trials in elderly patients with AML have focused on
patients aged 60 to 80 years who have an ECOG PS between 0
and 2. Sadly, this leaves the patients who are aged >80 years
and considered unfit unrepresented, and further complicates
the application of clinical trial data to the individual patient. In
the early 1990s, high AML induction mortality in the elderly
became a focus and led to investigations into lower intensity
therapies, recognizing that some older adults should be treated
differently from fit younger adults.32 Furthermore, chronologi-
cal age cannot adequately account for the variety of factors,
including physical fitness, medical comorbidities, and cognitive
function, that appear to significantly impact an individual’s abil-
ity to tolerate induction and consolidation therapy.33
The decision to treat and how to treat AML in the elderly
should not rely solely on PS and chronological age but ideally
should include comprehensive assessments that define
degrees of frailty and predict tolerance to treatment and the
likelihood of benefiting from intensive approaches. Comorbid-
ities can be assessed using the Hematopoietic Cell Transplan-
tation–Specific Comorbidity Index, in which higher scores
correlate with worse outcomes in transplantation patients34
and are independent predictors of early death in elderly
patients with AML.35,36 In a single-institution prospective
cohort study of consecutive adults aged 60 years undergoing
induction, pretreatment impairments in cognition and objective
physical function using the Short Physical Performance Battery
Protocol and Score Sheet (timed 4-meter walk, chair stands,
and standing balance) were significantly associated with
worse OS.37 Klepin et al have championed comprehensive
geriatric assessment in patients with AML as a way to identify
vulnerable patients in order for the field at large to consider
more supportive therapy and find additional ways to improve
quality of life.33 Polypharmacy is common in older adults and
has been associated with reduced functional capacity38 and
increased mortality in those undergoing induction chemother-
apy for AML.39 Given that some patient-related factors, such
as PS and polypharmacy, are modifiable, we recommend dedi-
cated efforts to preemptively address these factors at the time
of AML diagnosis.
Treatment Options
Newly diagnosed AML in the fit elderly
Induction chemotherapy
Since the 1980s, the backbone of induction chemotherapy in
the United States has been the “7 1 3” regimen, consisting of
continuous infusion of cytarabine for 7 days and an anthracy-
cline for 3 days.40,41 This regimen led to remissions in only 40%
to 60% of older adults compared with 60% to 80% of younger
adults.42 Numerous subsequent studies tested modifications in
the dose of cytarabine, the dose or type of anthracycline, or the
addition of novel agents.43-46 The Acute Leukemia French

2474 Cancer June 15, 2018


Association-9801 study evaluated remission induction in
patients aged 50 to 70 years using either high doses of daunoru-
bicin (at a dose of 80 mg/m2/day for 3 days), high-dose idarubi-
cin (IDA4; at a dose of 12 mg/m2/day for 4 days), or standard-
dose idarubicin (IDA3; at a dose of 12 mg/m2/day for 3 days).
There were no significant differences noted with regard to the
OS, event-free survival, or rate of disease recurrence, but CR
rates were significantly higher for the groups treated with IDA3
and IDA4 compared with the high-dose daunorubicin group
(83%, 78%, and 70%, respectively, in the IDA3, IDA4, and dau-
norubicin arms).47 Trials in younger adults (aged 18-60 years)
demonstrated that high-dose daunorubicin (90 mg/m2) led to
better OS compared with daunorubicin at a dose of 45 mg/m2,
and no difference was noted between high-dose daunorubicin
and IDA.48,49 In patients aged >60 years, daunorubicin at a
dose of 90 mg/m2 in the first induction cycle was tolerated as
well and led to higher response rates (CR rate of 64% vs 54%)
when compared with conventional dose daunorubicin (45 mg/
m2/dose), but did not improve OS.50 Subsequently, the UK
NCRI AML17 trial51 demonstrated no difference in any out-
come when comparing daunorubicin at a dose of 60 mg/m2 ver-
sus 90 mg/m2 for induction in patients with AML who were
aged 16 to 72 years. Outside of a clinical trial, we routinely use
idarubicin at a dose of 12 mg/m2 for induction in older adults.
Alternatively, daunorubicin at a dose of 60 mg/m2 is a reason-
able anthracycline choice.
Until very recently, induction options were limited to regimens
that have been around since the 1980s. Fortunately, with the
recent approval by the US Food and Drug Administration (FDA)
of CPX-351 injection for adults with newly diagnosed high-risk
AML (t-AML or AML with myelodysplasia-related changes),
we now have a new option.52 This medication repackages the
2 classic chemotherapy agents cytarabine and daunorubicin in
a 5:1 molar ratio within a liposomal formulation and is given for
induction at a dose of 100 U/m2 on days 1, 3, and 5.53 The treat-
ment of older adults (aged 60-75 years) with newly diagnosed
high-risk AML revealed significantly improved OS (median OS
of 9.56 months vs 5.95 months) when compared with standard
7 1 3 therapy. Grade 3 to 5 adverse events were similar to
those noted with the standard 7 1 3 regimen.53 Landmark sur-
vival analyses at the time of allogeneic HSCT are encouraging
for the use of CPX-351 as a possible bridge to successful trans-
plantation for a very poor-risk subgroup of patients with
AML.54 Currently, we use CPX-351 for patients with t-AML or
s-AML and continue to use the 7 1 3 regimen in those with de
novo AML. As clinical experience expands with an ongoing trial
in patients at high risk of induction mortality,55 CPX-351 may
become more broadly used. The recent reapproval of gemtuzu-
mab ozogamicin (discussed below) adds the option of adding
gemtuzumab ozogamicin to the 7 1 3 regimen in older patients
with non–high-risk, de novo AML. Table 2 shows recently
approved medications in AML.52,56-58
Postremission therapy
The need for additional chemotherapy to sustain initial remis-
sion in patients with AML has been recognized since the
1970s and 1980s.59,60 A trial comparing consolidation or pro-
longed maintenance with no further therapy was stopped pre-
maturely after interim analysis because all the patients in the
Cancer June 15, 2018
INSIGHT from the Experts
“no further therapy” arm had developed disease recurrence by
a median of 4 months.61 The choice of consolidation therapy
should be guided by baseline risk assessment using cytoge-
netic and molecular markers, along with reassessment of
patient fitness. In younger adult patients with favorable-risk
disease, consolidation chemotherapy may lead to lasting
remissions, whereas for those with poor-risk disease, alloge-
neic stem cell transplantation may provide the only possibility
of cure. However, to the best of our knowledge, there is no
clear evidence to support postremission therapy, except for
transplantation, among older adults with AML. Given the sig-
nificant morbidity and mortality related to allogeneic transplan-
tation, further risk stratification of intermediate-risk patients
remains a very active area of research to avoid both overtreat-
ment and undertreatment.
High-dose cytarabine (HiDAC) became a standard consolida-
tion regimen for patients aged 60 years with favorable-risk
AML in first complete remission based on the Cancer and Leu-
kemia Group B (CALGB) trial, which evaluated 3 cytarabine
doses (3 g/m2 twice daily on days 1, 3, and 5 [HiDAC] vs 400
mg/m2/day for 5 days vs 100 mg/m2/day for 5 days). Each regi-
men was intended for 4 consolidation cycles. There was a
higher probability of continuous CR at 4 years in the HiDAC
group compared with the groups receiving lower doses of
cytarabine (44% vs 24% and 29%, respectively).62 The benefit
of HiDAC was more evident within the patients with core-
binding factor AML when compared with the other cytogenetic
groups.63 Unfortunately, <50% of patients aged 60 years
were able to receive the intended number of cycles of HiDAC
due to increased toxicity, and age subsequently was capped at
60 years after an interim analysis demonstrated no benefit for
HiDAC among patients aged >60 years.62 Lowering the cytara-
bine dose (1.5-2 g/m2 daily for 6 days) may be better tolerated
in older patients.64 Subsequent data from MRC AML15 sug-
gest that, for consolidation, intermediate-dose cytarabine at a
dose of 1.5 g/m2 may be equivalent to 3 g/m2 and 2 consolida-
tion cycles may be equivalent to 3. However, this was noted
among younger patients who received 2 induction cycles.65
Our group uses 4 intermediate-dose cytarabine consolidation
cycles for older patients (aged >60 years) with favorable-risk
AML. For fit older adults with intermediate-risk AML, we use
up to 3 cycles of intermediate-dose cytarabine while the
patients are undergoing transplantation workup. Donor source,
match, and comprehensive patient assessments are consid-
ered when deciding who should proceed to transplantation in
first CR and for whom transplantation should be reserved in
case of disease recurrence. We use alternative regimens (clini-
cal trial, hypomethylating agents [HMAs]) or fewer cycles of
intermediate-dose cytarabine for patients with unfavorable-
risk AML as a bridge to transplantation.
For patients with unfavorable/high-risk disease, allogeneic
HSCT leads to improved OS.10 A landmark analysis of patients
aged <60 years with AML and high-risk cytogenetics in first
complete remission demonstrated that patients who received
allogeneic transplantation experienced superior 5-year OS
compared with patients who received continued consolidation
chemotherapy (48% vs 18%, respectively; P 5 .004).66 How-
ever the morbidity and mortality ascribed to allogeneic trans-
plantation cannot be taken lightly in elderly patients with AML.
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 INSIGHT from the Experts

TABLE 2. Medications Approved by the FDA for AML in 2017

Therapeutic Specific Common and/or

(Brand Name) Target Approved Indication Dose/Regimen Serious Side Effects

Midostaurin FLT3 Adults with newly diagnosed 50 mg orally twice daily on d 8 to 21 of Febrile neutropenia,
(Rydapt)56 AML and FLT3 mutationa each cycle of induction with device-related infection,
cytarabine and daunorubicin and on and mucositis
d 8 to 21 of each cycle of consolida-
tion with high-dose cytarabine
Enasidenib IDH2 Adults with recurrent or 100 mg orally daily until disease Hyperbilirubinemia,
(Idhifa)57 refractory AML and IDH2 progression differentiation syndrome
mutationa (fever, dyspnea, effusions,
and edema)
CPX-351 NA Adults with newly diagnosed Induction: daunorubicin 44 mg/m2 and Hemorrhage, cardiotoxicity,
(Vyxeos)52 therapy-related or cytarabine 100 mg/m2 on d 1, 3, and 5; copper overload, and
MDS-related AML consolidation: daunorubicin 29 mg/m2 hypersensitivity reactions
and cytarabine 65 mg/m2 liposome on
d 1 and 3
Gemtuzumab CD33 Adults with newly diagnosed Combination induction: 3 mg/m2 on d 1, 4, Neutropenia, hepatotoxicity,
ozogamicin CD33-positive AML; adults or and 7 with daunorubicin and veno-occlusive disease,
(Mylotarg)58 children aged  2 y with cytarabine; single induction: 6 mg/m2 and hemorrhage
recurrent/refractory on d 1 and 3 mg/m2 on d 8, continued
CD33-positive AML for up to 8 courses of 2 mg/m2 once
every 4 wk; recurrent/refractory
AML: 3 mg/m2 on d 1, 4, and 7
Abbreviations: AML, acute myeloid leukemia; FDA, US Food and Drug Administration; FLT3, fms-like tyrosine kinase 3; IDH2, isocitrate dehydrogenase 2;
MDS, myelodysplastic syndromes; NA, not applicable.
a
Mutation must be documented by an FDA-approved test.

The advent of intermediate-intensity and reduced-intensity
conditioning regimens has allowed more older adults to suc-
cessfully undergo transplantation, thereby attaining the benefi-
cial graft-versus-leukemia effect while minimizing toxicities
related to transplantation.67,68 In fact, a large study by the Cen-
ter for International Blood and Marrow Transplant Research
demonstrated similar outcomes in younger and older adults
with AML and MDS who underwent allogeneic transplantation
after reduced intensity conditioning.68 The choice of graft
donor, graft source, and conditioning regimen for the older
adult with AML recently was reviewed.69,70 A large meta-
analysis including 749 patients aged >60 years with AML sup-
ports the use of reduced-intensity allogeneic HSCT for elderly
patients with AML, with a 3-year recurrence-free survival rate
of 35%.71 The limited numbers of patients aged >70 years,
with the oldest patient reported as being 74 years, precluded a
meaningful analysis of transplantation outcomes in the group
of patients aged >70 years. These results argue against using
age alone to exclude allogeneic transplantation as a potentially
curative approach in elderly patients with AML. Outcomes
may be improved by the careful selection of patients for this
approach.72
Newly diagnosed AML in the unfit elderly
Previously, treatment options for older adults who were not
considered fit for induction chemotherapy were limited to sup-
portive care with transfusions and hydroxyurea or referral to
hospice. Supportive care alone for older adults with AML was
associated with a median survival of 1 month during the
1990s.4 For patients desiring treatment, several low-intensity
and intermediate-intensity regimens may offer disease stabiliza-
tion, prolonged survival, and improved quality of life. Low-dose
cytarabine (LDAC) treatment was established after a random-
ized study demonstrated higher rates of CR (18% vs 1%) and
OS (4 months vs 3 months) compared with hydroxyurea in a
population of unfit older adults.73 LDAC given at a dose of 20
mg subcutaneously twice daily for 10 days on a cycle of 4 to 6
weeks was found to be well tolerated; unfortunately, patients
with adverse cytogenetics derived no benefit in remission or
survival.73 Gemtuzumab ozogamicin, a humanized monoclonal
antibody targeting CD33 conjugated to calicheamicin, a cyto-
toxic antibiotic, initially was approved in 2001 for patients aged
60 years who were diagnosed with AML74 and was with-
drawn in 2010 due to toxicity.75 In a phase 2 trial of adults aged
>75 years with newly diagnosed AML, the median OS was 4.9
months in the group treated with gemtuzumab ozogamicin ver-
sus 3.6 months among individuals treated with best supportive
care.76 Single-agent use in patients with recurrent disease dem-
onstrated a CR rate of 26% after 1 cycle.77 Subsequent ran-
domized phase 3 data showed the clinical benefit both when
gemtuzumab ozogamicin was used as monotherapy78 or when
it was added to induction chemotherapy at a lower dose of 3
mg/m2.79 Given the improved toxicity profile when used at
lower doses, gemtuzumab ozogamicin recently was reap-
proved by the FDA for adults with newly diagnosed and recur-
rent/refractory, CD33-positive AML (Table 2).52,56-58
The HMAs azacitidine and decitabine, which initially were
developed as antimetabolites, were shown to target leukemo-
genic epigenetic changes.80 Both currently are approved by
the FDA for MDS and commonly are used off label for less

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intensive therapy or refractory disease in patients with AML.
Trial experience with azacitidine in patients with AML began
with the AZA-MDS-001 phase 3 study, which included patients
with higher-risk MDS with up to 30% blasts, which by World
Health Organization criteria includes AML with >20% blasts.81
Subjects were randomized in a 1:1 ratio to azacitidine at a dose
of 75 mg/m2 per day for 7 days per 28-day cycle or to 1 of 3 con-
ventional care options (supportive care, LDAC, or intensive
chemotherapy). Post hoc analysis of the patients with AML
demonstrated CR rates of 18% among 55 patients treated
with azacitidine for a median of 8 cycles, compared with a CR
rate of 16% among 58 patients treated with conventional ther-
apy for a median of 5.5 cycles (LDAC in 20 patients), 2.5 cycles
(intensive chemotherapy in 11 patients), or best supportive
care (27 patients). Despite similar CR rates, the azacitidine
group had a significantly higher median survival of 24.5 months
compared with 16 months for patients treated with conven-
tional therapy.81 Two studies from the Austrian Azacitidine
Registry showed that azacitidine-treated patients with AML
had a median OS of approximately 9 to 10 months.82,83 A sub-
sequent international phase 3 trial included 488 patients aged
65 years with newly diagnosed AML. Subjects were random-
ized 1:1 to azacitidine or a preselected conventional regimen
(induction chemotherapy, LDAC, or best supportive care). The
median OS was 10.4 months for the azacitidine group (95%
confidence interval [CI], 8.0-12.7 months) versus 6.5 months
for the conventional care group (95% CI, 5.0-8.6 months).84
Initial phase 1 studies of decitabine in patients with AML dem-
onstrated promising CR/CR with incomplete hematologic
recovery (CRi) rates of 18% to 32%.85-87 Three phase 2 studies
established the effectiveness of decitabine in older adults.
Drawing on MDS literature, Cashen et al used decitabine at a
dose of 20 mg/m2/day for 5 days every 4 weeks in adults with a
median age of 74 years. The median OS was 7.7 months for all
patients and 14 months for responders. The CR rate was 24%
after a median of 4.5 cycles.88 A European study treated 227
elderly patients with AML with decitabine at a dose of 15 mg/
m2 every 8 hours for 3 days on a 6-week cycle and demon-
strated a CR in 13% and a partial response/CRi in 12%.89 Blum
et al treated 53 patients with a median age of 74 years with
decitabine at a dose of 20 mg/m2/day for 10 days, with the
cycle length reduced to 5 days if a response was observed.90
The CR rate was 47% and the median survival was 12.7
months after a median of 3 cycles of decitabine. The longer
treatment cycles were found to lead to increased febrile neu-
tropenia but not mortality.90 However, interim results of an
ongoing randomized phase 2 study comparing 10-day versus
5-day decitabine as frontline therapy in elderly patients with
AML who were ineligible for induction demonstrated no signifi-
cant difference in remission or survival outcomes between the
2 regimens (CR/pathologic CR/CRi rate of 51% for 5-day vs
41% for 10-day; P value was not significant).91 Ten-day decita-
bine may be particularly beneficial for the treatment of patients
with TP53-mutated AML based on a recent study of 116
patients with either AML or MDS who were treated with deci-
tabine at a dose of 20 mg/m2 for 10 days per monthly cycle.
Enhanced exome, gene panel, and serial sequencing were
used to evaluate mutation clearance, and patients with classi-
cally worse prognostic markers actually were found to have
Cancer June 15, 2018
INSIGHT from the Experts
higher rates of temporary mutation clearance. Response in
patients with unfavorable cytogenetic risk was 67% versus
34% in those with favorable or intermediate risk, and
responses among patients with TP53 mutations were 100%
(all 21 patients) versus 41% for patients with wild-type TP53.92
An international phase 3 trial of decitabine at a dose of 20 mg/
m2/day for 5 days in 4-week cycles versus physician choice of
either LDAC at a dose of 20 mg/m2 subcutaneously once daily
for 10 days in 4-week cycles or best supportive care was per-
formed.93 The study included 485 patients with a median age
of 73 years, 63% of whom had intermediate-risk and 36% of
whom had poor-risk cytogenetics. The primary endpoint of OS
did not reach statistical significance; the median OS for
patients receiving decitabine was 7.7 months (95% CI, 6.2-9.2
months) after a median of 4 cycles of decitabine compared
with 5.0 months (95% CI, 4.3–6.3 months) for patients treated
with LDAC or best supportive care (P 5 .108).93 Ad hoc analy-
sis of more mature data demonstrated a statistical survival
benefit. However, concerns about the lower dose of LDAC and
not meeting prespecified endpoints may have precluded
approval for AML in the United States.94 Despite lacking FDA
approval for AML, HMAs remain commonly used and currently
are under active investigation, especially for combination ther-
apy. To the best of our knowledge, the precise mechanism(s)
of HMAs are not fully elucidated,95 but novel studies have sug-
gested they may be used at lower and longer doses as an
“epigenetic primer.”96,97 Reversing aberrant methylation of
tumor suppressor genes may sensitize leukemic cells to cyto-
toxic therapy.98 This is especially relevant for AML that is asso-
ciated with mutations in TET2, IDH1 and IDH2, ASXL1, and
DNMT3A, which encode proteins involved in epigenetic
regulation of transcription.99
The selection of lower intensity treatment options relies on the
assessment of disease characteristics/prior therapy, PS, and
patient wishes. If patients have a very poor premorbid PS,
remain fully dependent despite treatment of acute complica-
tions and attempts at rehabilitation, or clearly do not want treat-
ment, then either best supportive care or hospice is indicated.
For unfit patients, HMAs are offered; for those who received
prior HMAs (for MDS), we often used LDAC. The reapproval of
gemtuzumab ozogamicin adds complexity to this choice, with
practice patterns still emerging; nevertheless, patient comorbid
conditions, side effect profiles, and logistic details can inform a
practical choice.
Salvage therapy for patients with
recurrent/refractory disease
Unfortunately, the majority of older adults with AML will
develop disease recurrence and die of their disease. The prog-
nosis for patients with recurrent disease is dismal, with <10%
of these individuals surviving long term.100 To our knowledge,
there is no standard salvage regimen for patients with recur-
rent AML, and much of the data regarding treatment options
are derived from small and/or single-institution studies, which
have inherent limitations. Enrollment in clinical trials is critical.
Outside of clinical trials, frequently used regimens combine an
anthracycline/anthracenedione with other active agents. The
addition of granulocyte colony-stimulating factor (G-CSF) to
regimens can accelerate time to neutrophil recovery,101 but
2477
 INSIGHT from the Experts

TABLE 3. Selected Salvage Regimens for Recurrent/Refractory AML

No. of Patients
(Recurrent/ Median Age, Complete Median OS,
Regimen Refractory AML) Years Response Months Study

Mitoxantrone and etoposide (ME) 61 (20/21) 47 43% NA Ho 1988102

36 (27/9) 58 34% NA Trifilio 2012103
Mitoxantrone, etoposide, and IDAC (MEC) 32 (18/14) 24 66% 9 Amadori 1991104
74 (30/28) 37 55% NA Spadea 1993105
29 (23/6) 54 59% NA Trifilio 2012103
Fludarabine, cytarabine, and G-CSF (FLAG) 69 (NA) 63 81% >16 Estey 1994101
65 (21 early/44 late)a 47 81%/30% 17/3 Jackson 2001106
41 (19/11) 53 56% 11 Carella 2001107
Fludarabine, cytarabine, G-CSF, and 32 (NA) 59 53% <12 de la Rubia 2002108
idarubicin (FLAG-IDA)
46 (36/10) 41 52% 11 Pastore 2003109
Cladribine, ARA-C, and G-CSF (CLAG) 58 (8/50) 45 50% 8.5 Wrzesien-Kus 2003110
Cladribine, ARA-C, G-CSF, and 114 (39/75) 45 53% 9 Wierzbowska 2008111
mitoxantrone (CLAG-M)
Abbreviations: AML, acute myeloid leukemia; ARA-C, cytosine arabinoside; G-CSF, granulocyte colony-stimulating factor; IDAC, intermediate-dose ARA-C;
NA, not available; OS, overall survival.
a
Patients in group 1 experienced late recurrence  6 months after first-line chemotherapy, whereas patients in group 2 either experienced an early disease
recurrence <6 months after stopping chemotherapy or were refractory to first-line chemotherapy.

does not improve outcomes. Table 3 shows a summary of
selected salvage regimens.102-111
Mutation-specific targeted therapies
Despite years of intense study in the field, to our knowledge
no therapies were approved by the FDA for AML between
2001 and 2016.112 Fortunately, there have been 2 recent
approvals of targeted therapies for AML, namely FLT3 and
IDH2. A focus on the poor prognostic FLT3-ITD led to the
development of several FLT3 inhibitors.113-115 Midostaurin
was approved by the FDA in April 2017 for newly diagnosed
adults with FLT3-positive AML in combination with standard
7 1 3 induction and cytarabine consolidation.56 Approval was
based on an international, randomized, placebo-controlled
phase 3 trial (CALGB 10603) published in June 2017.116 Of the
717 patients randomized and stratified according to the sub-
type of FLT3 mutation (point mutation in the tyrosine kinase
domain or low- or high-ratio ITD), 360 were assigned to the
midostaurin group. The primary endpoint was OS, which was
found to be significantly longer in the group treated with mid-
ostaurin compared with the placebo group (75 months vs 26
months; hazard ratio for death, 0.78 [1-sided P 5 .009]), with a
consistent benefit noted across the FLT3 mutation subgroups.
The most common grade 3/4 adverse reactions were febrile
neutropenia, device-related infection, and mucositis.116 It is
interesting to note that the trial only included adults aged 18 to
59 years. Despite lacking data in the elderly, we offer this treat-
ment to patients aged >60 years with close monitoring for
toxicity.
In August 2017, the FDA granted approval for enasidenib, an
IDH2 inhibitor for adults with recurrent or refractory AML who
were found to have an IDH2 mutation based on a companion
assay.57 The 2 common IDH2 mutations, R140 and R172, both
lead to accumulation of the metabolite (R)-2-hydroxyglutarate,
leading to hematopoietic differentiation block, and enasidenib
suppresses (R)-2-hydroxyglutarate in both mutation sub-
types.117 Approval was based on a multicenter, open-label
phase 1/2 trial that included 199 patients with recurrent/refrac-
tory AML, 62% of whom were aged 65 years. In the popula-
tion of patients with recurrent/refractory AML, the overall
response rate was 40.3% and the median OS was 9.3 months.
Grade 3 and 4 toxicities included indirect hyperbilirubinemia
(12%) and IDH inhibitor-associated differentiation syndrome
(7%).118 Differentiation syndrome can be deadly and patients
present with fever; dyspnea; pulmonary infiltrates; pleural or
pericardial effusions; rapid weight gain or peripheral edema;
lymphadenopathy; bone pain; and hepatic, renal, or multiorgan
dysfunction and should be treated with systemic corticoste-
roids (Table 2).52,56-58 Targeted agents provide an opportunity
to intervene based on disease biology and possibly eliminate
minimal residual disease, and warrant further study in the older
patient with AML.
Promising therapies and ongoing clinical trials
In an effort to fast-track new therapies desperately needed for
AML, specifically in the elderly population, the Leukemia and
Lymphoma Society is leading the Beat AML Master Trial. Up to
500 newly diagnosed patients aged 60 years will undergo
rapid genomic testing that will direct patients to a relevant tar-
geted therapy arm with correlative studies.119 Information
regarding the numerous other therapeutic trials in elderly
patients with AML can be obtained at ClinicalTrials.gov.

2478 Cancer June 15, 2018


Figure 1. Acute myeloid leukemia (AML) treatment algorithm for the older adult. ARA-C indicates cytosine arabinoside; APL, acute
promyelocytic leukemia; FLT3, fms-like tyrosine kinase 3; MRD, minimal residual disease; NextGen, next-generation; s-AML, second-
ary acute myeloid leukemia; t-AML, therapy-related acute myeloid leukemia.
DISCUSSION
The landscape of AML treatment is changing. Although the
recently approved induction and targeted therapies offer new
hope for patients who receive this life-threatening diagnosis,
they add additional considerations to an already complex dis-
ease. The classic (albeit simplified) algorithm of induction, fol-
lowed by consolidation (with or without transplantation)
versus hospice is no longer sufficient. Instead, significant
advances including broad panel-based genetic assessment,
more focus on modifiable patient-related factors, and
improved supportive care are moving the field forward, espe-
cially for elderly patients with AML.
The unique circumstances of each patient (disease related
and patient related) need to be thoughtfully considered when
developing a treatment plan (Fig. 1.). The diagnosis of AML
is, frankly, sudden and scary. Patients and their support sys-
tems often are very fearful and can face a wide knowledge
gap in understanding the disease and its many attendant
complications. Often the urge to feel proactive in the face of
cancer can lead to an understandable but sometimes danger-
ous push to “do everything possible.” We must be especially
prudent when caring for the elderly patient with AML to
ensure that we use all available data when building a treat-
ment plan and that all safety and supportive care measures
are available to these patients as we embark on treatments
that may do more harm than good. For example, in the
patient in case 1, clinicians may consider induction therapy
when sitting across the clinic room from a very functional
and fit patient who wants a chance at cure. However, trial
experience demonstrating dismal outcomes for induction
Cancer June 15, 2018
INSIGHT from the Experts
therapy in octogenarians regardless of PS, the paucity of
transplantation data in this age group, and the potential for
long-lasting remissions with reduced intensity therapies
allowed this patient an option that improved his quality life
and prolonged his survival.
Case 2 highlights the importance of comprehensive patient
assessment, not just to define prognosis but also to identify
opportunities to intervene with regard to modifiable factors,
such as physical deconditioning and managing polypharmacy.
The 71-year-old patient had poor-risk disease and was unfit for
induction; therefore, hypomethylating therapy was initiated
along with physical therapy. It took a compelling explanation by
his physician to explain that although the process of improving
his physical fitness may be painful due to arthritis, it potentially
could make life-saving treatment possible down the road. At
his age, complications related to induction therapy were likely
to make the patient much weaker and possibly preclude sub-
sequent consolidation with transplantation. Conversely, the
patient in case 3 had an excellent PS with no medical comor-
bidities, which is fortunate because she had proliferative dis-
ease with a white blood cell count of 86,200/lL. She required
cytoreduction and was able to complete induction therapy; her
favorable-risk disease may be cured, although follow-up was
short.
The care of the older adult with AML requires a comprehensive
approach and a constant reevaluation of the risks and potential
benefits of all available treatments. Along with pharmaceutical
and hospital-based interventions, support from family and
skilled providers (nursing, physical therapy, occupational ther-
apy, home health aides, nutritionists, and transportation) is
2479

essential. Clinical trials for disease-specific and best supportive
therapy should be strongly encouraged to continue to improve
the care of patients with AML.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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men in patients with refractory and relapsed acute myeloid leukemia of Oncology Fellowship Training Program,
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Jennifer Wilkinson Carlisle, MD
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University in St. Louis in St. Louis,
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