Hematology 2010 Luger 62 9

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Treating the Elderly Patient with Acute Myelogenous

Leukemia

Selina M. Luger 1

1Hematologic Malignancies and Stem Cell Transplant Program, Hematology-Oncology Division, University of

Pennsylvania Medical Center, Philadelphia, PA

Decisions regarding the optimal treatment of acute myelogenous leukemia in the elderly patient requires the

consideration of multiple factors. Population-based studies have demonstrated that, for all age groups, aggressive

therapy results in improved survival and quality of life when compared with palliative care. The optimal induction and

postremission regimen for older patients has yet to be determined. Furthermore, not all patients are candidates for

such therapy. Consideration of patient and disease-related factors can help to determine the appropriateness of

intensive therapy in a given patient. For those patients for whom aggressive induction therapy does not seem to be in

their best interest, novel agents are being investigated that will hopefully address the issues of induction death and

early relapse associated with these patient populations.

How Is Acute Myeloid Leukemia in the Elderly

Different?Acute myeloid leukemia (AML) presents at all ages, but is mainly a

disease of the elderly, with a median age of 69 years in the white US

population.1 In the Swedish Acute Leukemia Registry, 68% of

patients diagnosed with AML since 1973 were over age 60 years;

between 1997 and 2005, 75% was aged 60 years or more.2

Prognosis worsens every decade beginning at age 30 to 40.1,3 A

report by the German Acute Myeloid Leukemia Cooperative Group

looked at patients 16 to 85 years of age enrolled in two consecutive

trials in 1992 and 1999 with no upper age limit who had AML. 4 In a

multivariate analysis of prognostic factors, age Ն 60 years was a

statistically significant poor prognostic factor for complete remis-

sion (CR), overall survival (OS), remission duration, and relapse-free survival (RFS). Population-based studies have reported 3- and

5-year survival rates of only 9% to 10% and 3% to 8%, respectively,

in patients over age 60, compared with 5-year survival rates of up to

50% for younger patients.2,5,6 Poorer outcome has traditionally been

considered to be the result of less intensive therapy in this

population, concurrent comorbidities, a higher likelihood of under-

lying hematopoietic disorders, and biologically poor risk disease.

Moreover, because of the perception that older adults are less likely

to do well with standard therapy, clinicians are less likely to treat

these patients aggressively or refer them to centers that do so. As

such, lower levels of aggressive treatment may compound underly-

ing prognostic differences associated with patient factors and

disease biology.

In a retrospective analysis of 968 adults with AML in five

Southwest Oncology Group (SWOG) trials to understand the nature

of how AML changes with age, differences were noted in perfor-

mance status (PS), presenting white blood cell (WBC) count,

percentage marrow blasts, expression of multidrug resistance (MDR),

and karyotype.7 (Table 1). When compared with disease in patients

younger than age 56, those age Ն 56 are are more likely to have

unfavorable cytogenetics and less likely to have favorable cytogenet-

ics. Differences in disease biology are also apparent. For example,

in an analysis of oncogenic pathway dysresgulation in 425 patients

with AML, there is a statistically significant difference in the

expression of E2F and PI3 (phosphoinositide 3) kinase activation,

but a higher probability of RAS, TNF (tumor necrosis factor), Src,

and EPI (extrinsic pathway inhibitor) pathway activation.8 In

younger patients, a similar profile is of poor prognostic significance

and portends for decreased sensitivity to anthracycline.

What Is the Standard Therapy for the Older Patient

With AML?The combination of an anthracycline and cytarabine (3ϩ7), with or

without other agents, is considered the standard induction regimen

for patients under age 60, followed by consolidation therapy that

often uses high-dose cytarabine.9–11 As noted previously, the use of

the standard 3ϩ7 regimen in elderly patients does not yield results

similar to those seen in younger patients. Recent studies have,

therefore, focused on dose intensification of anthracyclines and/or

postremission therapy (Table 2).

In a recently published cooperative group study, Lowenberg et al 12

reports the results of a comparison of induction therapy with

daunorubicin (DNR) at a dose of 45 mg/m2 or 90 mg/m2 in 813

patients over age 60 with previously untreated AML. Although CR

rates were improved in the group that received the higher dose of

DNR (64% vs 54%, Pϭ .002), there was no significant difference in

the two induction groups with respect to OS and event-free survival

(EFS). Thirty-day mortality was 11% to 12% in both groups.

Two-year probabilities of relapse after CR and death during CR for

the standard versus intensified DNR groups were 61% versus 54%

for relapse and 10% versus 16% for death. Exploratory post-hoc

analysis of patients aged 60 to 65 (n ϭ 299), however, demonstrated

a difference in the two dose groups with respect to CR (51% vs

73%), 2-year EFS (14% vs 29%, Pϭ .002), and 2-year OS (23% vs

38%, P Ͻ .001). In the subgroup with core binding factor

abnormalities (n ϭ 33), escalated dose was associated with in-

creased CR and decreased risk of disease progression or death (CR,

74% vs 93%; disease-free survival [DFS], 31% vs 62%).

Although the study by Lowenberg et al12 would suggest that

intensification of DNR leads to superior CR rates with no difference

in toxicity, the use of high-dose DNR by the French Cooperative

CHALLENGES IN ACUTE MYELOID LEUKEMIA

62 American Society of Hematology



Group in ALFA (Acute Leukemia French Association)-9801 did not

demonstrate similar results.13 In their study, DNR at 80 mg/m2 /day

was compared with standard or high-dose idarubicin (IDA) during

induction therapy of patients ages 50 to 70. Neither high-dose DNR

nor high-dose IDA demonstrated any clinically relevant superiority

over standard dose IDA in this population of patients. Multivariate

analysis revealed age Ͼ 60 orϽ 60 to be of prognostic significance

for OS, but not for CR or EFS. WBCs and cytogenetics significantly

influenced EFS and OS in multivariate analysis. Although the

superiority of higher dose anthracycline as induction is not clearly

established by these trials, they do demonstrate that there is no

increased toxicity with these regimens. In addition, dose-reduced

anthracycline led to inferior CR rates in the Lowenberg study, and

survival was not as good in certain subgroups of patients. As such,

although there is no clear evidence that dose intensification is

needed, there does not seem to be any reason to attenuate doses of

anthracycline in patients over age 60. Doses of DNR at 60 mg/m2 or

IDA at 12 mg/ 2 for 3 days together with cytarabine would be

appropriate to use.

In the National Cancer Research Institute (NCRI) AML 14 trial,

randomizations were conducted of anthracycline dose and cytara-

bine dose in induction, the use of an MDR modulator (PSC 833) in

induction, and a number of postremission courses. 14 No benefit was

seen to any of the interventions tested. The PSC 833 arm was closed

prematurely because of an increased early death rate because of

infection. A randomized trial by the Eastern Cooperative Oncology

Group (ECOG) similarly showed no benefit to the addition of the

MDR modulator zosuquidar to induction therapy with DNR 45

mg/m2 and cytarabine.15 The question of whether the short infusion

time of zosuquidar in this study inadequately blocked the polyglyco-

protein pump has been raised by a subsequent study. 16 A review of

sequential SWOG studies that differed by the addition of cyclospo-

rine to DNR and cytarabine demonstrated that CR rates were the

same with and without cyclosporine (38% vs 44%), with a median

OS of 6 months versus 7 months and an RFS of 14 months versus 8

months.17 The lack of benefit of these agents suggests that they are

either not effective at inhibiting MDR or that MDR inhibition, even

if effective, cannot overcome the drug resistance.

Clofarabine, an agent that was initially approved for use with

patients with acute lymphoblastic leukemia, has recently been

studied in patients with relapsed and refractory AML, as well as

untreated elderly patients with AML.18-20 Results of phase II trials

are encouraging. The upcoming phase III ECOG trial for elderly

patients with AML will randomize patients to induction therapy

with DNR and cytarabine versus single-agent clofarabine.

Once CR has been obtained, there is no standard postremission

strategy in these patients. No prospective randomized study has ever

established the benefit of postremission therapy in older adults;

however, all large studies of AML have included postremission

therapy, presumably because of the concern that patients are all

destined to relapse without postremission therapy. Cycles of

high-dose cytarabine, which is felt to be of benefit in younger

patients, has not been demonstrated to be of benefit in this age group

and is thought to be too toxic.21 Single cycles of high-dose

cytarabine have, however, been well tolerated in cooperative group

studies.13,22 Recent studies of gemtuzumab, as well as studies of

interleukin-2 as postremission therapy, have not demonstrated any

benefit.23,24 In the EORTC-GIMEMA (European Organization for

Research and Treatment of Cancer-Gruppo Italiano Malattie eMatologiche dell’Adulto) AML 13 trial, in which postremission

therapy was randomized between two cycles of intensive intrave-

nous therapy versus oral therapy, no difference in DFS was

demonstrable between the two groups.25,26 The median DFS was 9

months for the noninfusional therapy versus 10.4 months for the

intravenous regimen and 3-year DFS 13 versus 21% ( P ϭ .15).

Although no OS benefit was seen, the only patients who enjoyed

prolonged DFS had received postremission chemotherapy. This

study also offered autologous hematopoetic stem cell transplant

(HSCT) as a postremission therapy, and no benefit was demon-

strated to HSCT.23 Of the 61 patients with AML in CR in this study

who underwent stem cell harvest after first consolidation, 33 of 61

patients had HSCT with a median 3-year OS of 39% and a DFS of

28% for the 33 patients who underwent HSCT and a DFS of 21% forthe 61 patients who underwent stem cell harvest.

Although randomized trials have not been done to unequivocally

establish the need for consolidation therapy, randomized trials have

Table 1. Patientand disease characteristics at presentation of AML, by

age

<56 years 56-65 66-75 >75 year

PS 0 (%) 35 29 27 18

PS<2 (%) 84 75 73 68

PS >2 (%) 2 10 7 14

FavorableKaryotype (%)

16 5 5 4

IntermediateKaryotype (%)

45 55 55 44

Unfavorable

Karyotype (%)

33 38 39 50

MDR+ (%) 33 62 61 57

MDR indicates multidrug resistance. Adapted fromAppelbaum et al.7

Table 2. Intensive regimens for elderly AML

Study

Age (range)

Number

Induction and postremission treatment

regimens and randomizations

CR

ED

Survival

HOVON12,23

67(60-83)

N=813

INDUCTION

Ara-C 200 + DNR (45 vs 90)

Followed by

Ara-C 1000 mg/ m2 x 6 days

POSTREMISSION

Allogeneic HSCT or

GO x 3 cycles or No further treatment

CR

54% vs 64%

ED

12% vs 11%

2 yr DFS 30%

ALFA-980113

60 (50-70)

N=478

INDUCTION

DNR 80 x3d vs. IDA 12 x 3d vs 4d + Ara-C

+/- followed by

MTZ + Ara-C

POSTREMISSION

Ara-C 1 g/ m2 q 12 h x 4 d + induction

anthracycline x 2d +/- IL-2

CR

70% vs 83% vs 78%

ED

8% vs 3% vs 6%

OS 17 mo.

2 yr EFS 23.5%

2 yr OS 38%

AML14 14

67(44-88)

N=1273

INDUCTION

DAT x 2 courses +/- PSC-833

(Ara-C 100 vs 200 mg/m2/day)

POSTREMISSION

MTZ + Ara-C

+/- followed by ICE

54% CR

18% ED

5 yr DFS 13%

ALFA 9803 28

72(65-85)

N=429

INDUCTION

DNR45 or IDA 9 x 4 d + Ara-C

+/- followed by

MTZ + Ara-C

POSTREMISSION

Ara-C 60 mg/ m2 q 12 h x 5 day + anthracycline x

1 d, monthly x 6mo vs

Ara-C 200 mg/ m2 x 7d + anthracycline x 4 d

57% CR

10% ED

OS 12 mo

2 yr OS 27%

4 yr OS 12%

AML HD98-B 29

65(61-78)

N=329

INDUCTION

IDA 12 + Ara-C x 2 cycles +/- ATRA

POSTREMISSION

Ara-C + MTZ + IE(IV) vs oral IE (po)

q mo x 12 mo

46% CR

OS 22.3 mo(IEiv) vs 14.3

mo (IEpo)

4 yr OS 24%

AML-1326

67(61-80)

n=757

INDUCTION

MICE x 1-2 cycles

+/- GCSF

POSTREMISSION

mini-ICE (IV) vs Infusional mini-ICE

x 2 cycles vs 1 cycle +HSCT

57% CR

DFS 1 yr

3 yr DFS 21%

3 yr OS 32%

HOVON indicates Stichting Hemato-Oncologie voor Volwassenen Nederland; ED,

early death; Ara-C, cytarabine; GO, gemtuzumab ozogamicin; MTZ, mitoxantrone;

IL-2, interleukin-2; DAT, daunorubicin, cytarabine, 6-thioguanine; ATRA, tretinoin;

ICE, idarubicin, cytarabine, etoposide; IE, idarubicin, etoposide; MICE, mitox-

antrone, etoposide, cytarabine.

Hematology 2010 63



evaluated duration and types of postremission therapy. The AML 11

trial demonstrated that there was no benefit when four cycles, rather

than 1 cycle, of moderate intensity postremission therapy were given.27

In the ALFA 9803 trial comparing a cycle of intensive consolidation

versus 6 months of lower dose therapy, prolonged consolidation was

associated with improved OS (56% vs 37%) and DFS (28% vs 17%).28

Repeated courses of low-intensity chemotherapy were also associated

with shorter hospitalization and fewer transfusions. Age, AML type,

and cytogenetics were associated with longer DFS. In the AML HD98

study, in which patients who achieved a CR and after one intensiveconsolidation were randomized to either a second intensive consolida-

tion with IDA/etoposide or mild oral maintenance with the same drugs,

there was a lower relapse rate and superior survival in the group that

received the more intensive therapy (median survival 22.3 vs 14.3

months).29 In addition to supporting the use of high-dose consolidation,

this study suggests that more than one cycle of consolidation was

superior when this regimen was used. Like other studies in the elderly,

only 29% of the initial patient cohort was randomized after first

consolidation. Moreover, only 2 of 96 randomized patients had

high-risk cytogenetics, highlighting the selection bias in many of these

trials. One of the other major issues for studies of postconsoldation is

that many patients do not receive their assigned therapy, making the

trials difficult to interpret. Until there is a randomized trial demonstrat-

ing that there is no benefit to postremission therapy, I feel that it should

be offered to those patients who achieve a CR and are able to tolerate it.

Recent analyses have further tried to elucidate the prognostic

importance of cytogenetics and molecular prognostic factors in

elderly patients. As in younger patients, core binding factor

abnormalities have a more favorable prognosis. In a retrospective

French study of 147 patients who received at least one dose of

induction chemotherapy, 60 had t(8;21) and 87 had inversion (16).

There was an 88% CR rate and a 10% 8-week early death rate. 30

With a median follow-up of 48 months, the 5-year probability of OS

and leukemia-free survival (LFS) was 31% and 27%, respectively.

On multivariate analysis, high WBC count, poor PS, and del(9q)

were of negative impact, and trisomy 22 and intensive consolida-

tion—when compared with maintenance therapy—were of positive

impact. Despite a CR rate of 88%, median LFS was only 18 months.

In the t(8;21) group, the difference in survival following intensive

consolidation was statistically significant when compared with

maintenance (not yet reached vs 10 months). In a recent analysis of

the impact of NPM1 (nucleophosmin) mutation in elderly patients

in 148 patients Ն 60 years of age, with de novo cytogenetically

normal AML enrolled onto CALGB (Cancer and Leukemia Group

B) 9720 and 10201, those patients with NPM1 mutations have a

higher CR (84 vs 48) and longer 3-year DFS (DFS 23 vs 10) and OS

(35 vs 8). In multivariate analysis, this was particularly true in

patientsՆ 70 years of age (CR 87% vs 39%, DFS 30% vs 7%, and

OS 49% vs 5%). Several investigators have suggested that, in

determining therapy for older patients with AML, it would be

appropriate to wait for results of cytogenetic and perhaps molecular

studies before discussing therapeutic options.31

Overall, these studies demonstrate that results of intensive therapy

in elderly patients remain poor. Although CR rates of 40% to 80%

can be achieved, in highly selected populations, long-term survival

is poor. Even in patients with favorable cytogenetics who have 80%

CR rates, relapse rates are high. As such, novel strategies are

needed. With the use of reduced-intensity conditioning regimens,

allogeneic transplantation has become a valid option. Recent reports

have suggested that age, at least up to 70, does not impact outcome

of reduced-intensity transplant and that reduced intensity transplan-

tation may yield better outcomes than chemotherapy in patients

aged 60 to 70. Retrospective registry studies have demonstrated that

age does not appear to be a factor in transplant outcome. In a

retrospective analysis of 629 reduced-intensity allogeneic trans-

plants reported to the French transplant registry, outcomes (OS,

transplant-related mortality, and acute graft-versus-host disease

[GVHD]) in patients over age 65 were comparable with those for

patients who were between ages 60 and 65.32 Two-year OS was 48%

vs 47% for the two age groups. Similarly, data from the Center for

International Blood and Marrow Transplant Research (CIBMTR)on 1080 patients undergoing reduced-intensity conditioning trans-

plant for AML or myelodysplastic syndrome (MDS) demonstrated

no difference in nonrelapse mortality, grade 2 to 4 GVHD, chronic

GVHD, or relapse, when patients ages 60 to 64 or over age 65 were

compared with patients aged 40 to 59.33 Although 2-year survival

rates were lower in patients over age 60, 2-year survival rates were

greater than 30% in all age groups, and multivariate analysis

revealed no significant impact of age on DFS or OS. In a prospective

study of the feasibility of transplant in patients over age 50 at M.D.

Anderson who entered CR, outcome for those patients who

underwent an allogeneic transplant with reduced-intensity condition-

ing had a superior RFS and OS when compared with those who

received postremission chemotherapy.34 A retrospective analysis of

over 1,000 elderly patients with AML in first CR who underwentHSCT or chemotherapy demonstrated improved OS and DFS in the

HSCT group.35 Further prospective studies are needed.

Who Should Not Receive Intensive Therapy?Selection criteria commonly used for inclusion into clinical studies

have a major impact on reported outcome. Furthermore, the

interpretation of clinical trials must be done with caution, in that not

only are eligibility criteria different, but also investigator choice and

patient preference clearly influence patient inclusion. In an analysis

by the Swedish of 9729 patients diagnosed with AML in Sweden

since 1973, the proportion of older patients who were considered

eligible for intensive remission induction therapy decreased from

92% in those aged 60 to 64 years to 80%, 67%, 45%, 23%, and 4%

in those aged 65 to 69, 70 to 74, 75 to 79, 80 to 84, and 85ϩ years,

respectively.2 Importantly, this report found that early death rates

were improved with intensive treatment, compared with palliation

alone. This was seen in all age groups and all PS levels. For

example, within patients age 76 to 89, with a PS of Ͼ 2, those who

received intensive treatment had a 36% early death rate, compared

with 52% for those who received palliation alone. The assessment

of eligibility for intensive therapy is, however, quite subjective, and

the reason that certain patients within the cohort received intensive

therapy whereas others did not is not available in this report. An

analysis was done within the six Swedish health care regions among

patients age 70 to 79 years.2,36 Percentage of patients who were

deemed candidates for intensive therapy differed by region, prob-

ably because of physician and patient preferences, because baseline

characteristics of the patients seem no different. In those regions in

which only 40% of patients were felt to be eligible for intensive

therapy, there was a 16% early death rate with intensive treatment,

compared with 27% with palliation only. The early death rate was

similar in those regions wherein 75% of patients were felt to be

eligible for intensive treatment. When comparing regions where

only 40% versus 75% were treated intensively, CR rates with

intensive treatment were 41% and 49%, respectively, and CR rates

for the entire group in the region was 19% versus 37%. Given the

lower proportion of patients who received intensive therapy in those

regions, the 2-year OS was decreased at 24% versus 50% and 5-year

OS was 1% versus 13%. Furthermore, although PS is more




predictive for early death rate than age, long-term survival may be

achieved in patients with initial poor PS. Based on their report, they

state that standard intensive treatment decreased early death rates in

most patients up to age 80.

The MRC (Medical Research Council) AML 11 trial allowed for the

use of cytogenetic data to identify prognostic groups in older adults

who were treated with intensive therapy on study.37 More recently,

investigators have become interested in developing tools to allow us

to discriminate between patients who are likely to benefit from

intensive chemotherapy versus those who should be candidates for

less aggressive therapy (Table 3).

Patients are now being considered “unfit for intensive therapy” and

more appropriate for alternative or investigational therapy if there is

either a high risk of early mortality or a poor chance of long-term

DFS. In a retrospective analysis by Wheatley of the patients in the

AML 11 trial, five risk factors were identified in AML patients that

were weighted according to the values of their multivariate coeffi-

cients and used to define three subgroup risk classifications that

were then able to be validated in the more recent MRC AML 14

trial.38 Cytogenetic group, age, WBC count, PS, and de novo vs

secondary AML were all found to be highly significant. Good,

standard, and poor risk groups had a 1-year survival of 53%, 43%,

and 16%, respectively (P Ͻ .0001). In a retrospective analysis by

Kantarjian et al39 of 998 patients aged 60 or older who received

intensive therapy at M.D. Anderson Cancer Center, a multivariate

analysis was performed to calculate a prognostic score. They

identified prognostic risk factors: age (Ն 75 years), unfavorable

cytogenetics, poor PS (Ͼ 2), Ն 12-month history of antecedent

hematologic disorder (AHD), lactate dehydrogenase (LDH) Ͼ 600,

elevated creatinine, and treatment outside a laminar flow room.

Three risk subgroups were defined based on the number of poor

prognostic factors. Those with none of the adverse risk factors have

an expected CR rate of Ͼ 60%, induction mortality of 10%, and

1-year survival over 50%. A poor risk group with more than or equal

to three poor prognostic risk factors had CR, induction mortality,

and 1-year survival rates of Ͻ 20%, Ͼ 50%, and Ͻ 10%, whereas

those in an intermediate risk group had rates of 50%, 30%, and 30%,

respectively. Several reports have focused on the impact of comor-

bidities on decision making in AML. A refined Hematopoetic Cell

Transplantation Comorbidity Index (HCTCI) has been found to be

useful in identifying patients who are not candidates for intensive

therapy.40 Malfuson et al41 analyzed 416 patients treated on the

ALFA 9803 multicenter trial to identify independent prognostic

factors that would impact on OS. Based on their analysis, theypropose that, in those patients with unfavorable cytogenetics and the

presence of two poor prognostic factors (age Ն 75 years, PS Ն 2,

and WBC count Ն 50 ϫ 109 /L), the OS is only 19% at 12 months,

and these patients should, therefore, not be considered for standard

chemotherapy.

In a recent analysis of the AML 96 trial of 909 patients with a

median age of 67, univariate and multivariate analyses identified

karyotype, NPM1 mutation status, WBC count, and LDH of

independent prognostic significance for OS, DFS, and relapse.42

Although favorable and poor cytogenetic risk groups had markedly

different OS, those patients with intermediate risk karyotype could

be subdivided based on CD34 expression, along with the abovemen-

tioned factors identified on multivariate analysis, allowing for thedesignation of four groups: (1) favorable cytogenetics, (2) interme-

diate cytogenetic with favorable features, (3) intermediate cytogenet-

ics with adverse risk features, and (4) poor risk cytogenetics, with

3-year OS of 39.5%, 30%, 10.6%, and 3.3%, respectively. These

scoring systems can be used to identify patients who are likely to

respond to standard therapy, as well as those who are not likely to

benefit and should therefore be considered for alternate or investiga-

tional therapy.

What Treatment Options Are Available for Patients

Who Are Not Candidates for Intensive Induction

Therapy?For those patients who are not considered to be candidates for

intensive induction therapy, one would hope to identify agents and

regimens that are more effective and less toxic to address the

concerns regarding early induction death, inadequate response rate,

and high risk of relapse. The NCRI AML 14 study was designed to

allow for randomization of patients between intensive and noninten-

sive therapy, but only eight patients agreed to randomization. 14,43 As

such, data available on novel agents comes from a variety of pilot

and phase II studies with differing eligibility criteria. When

evaluating the outcomes, it is important to also look at the

characteristics of patients who were ultimately enrolled. Table 4

reviews available data from some of these studies.

As part of the NCRI AML 14 study, 212 patients who were deemed

unfit for intensive treatment options by the local investigator were

randomized to receive supportive care alone with hydroxyurea or

cytarabine 20 mg twice daily by subcutaneous injection for 10 days

every 4 to 6 weeks.43 Outcome was improved for the low-dose (LD)

cytarabine arm when compared with supportive care with hydroxyu-

rea alone. CR was 18% versus 1%, and median survival was 575

days for those who achieved CR, compared with 66 days in

nonresponders. DFS for responders was 8 months. Survival benefit

was seen in all age groups, even those over age 75. As none of the

patients with adverse cytogenetics achieved a CR, no survival

benefit was, however, seen in that group. The early death rate was

39% at 8 weeks. Although no criteria were used to define unfit

patients, 78% were over age 70, 27% had secondary AML, 30% had

Table 3. Prognostic scoring in elderly AML

Prognostic Factors CR Rate (%) Early Death

Rate (%)

Overall Survival

Grimwade37

MRC

AML11trial

Cytogenetics

Good.:63

Standard: 53-63Poor:26

5yr (%)

Good:34

Standard :10-15

Poor : 2

Kantarjian39

MDACC

Age>=75

Karotype

ECOG PS>2

AHD >12 mo No laminar flow

Good.: >60

Standard: 50Poor: <20

Good 10

Standard:30

Poor: >50

1 yr. (%)

Good. :>50

Standard: 30

Poor: <10

LDH

Creatinine

Malfuson 41

ALFA

9803, n=418

Cytogenetics

Age>=75

PS>=2

WBC>=50X109/l

1yr (%)

Poor:19

Others: 58

Giles40

MDACCHematopoietic celltransplantation

comorbidity index

(HCTCI)

Good:64Standard:43

Poor:42

Good:3

Standard:11Poor:29

Good:45 wks

Standard:31wksPoor:19 wks

Wheatley 38

AML14

Cytogenetics

Age

WbcPS

De novovs

secondary AML

1/3 year OS(%)

Good: 60/29

Standard: 48/27Poor:30/9

Rollig42

AML 96CD34Wbc

Age

LDH NPM1

Cytogenetics

3 yrOS(%)

Good: 30-40Standard:10.6

Poor: 3.3

MDACCindicatesM.D. Anderson CancerCenter.

Hematology 2010 65



PS Ն 2, 27% had heart disease, 49% had other comorbidities, and

59% had a poor risk score by the Wheatley Risk Index. 38 Based on

this study, LD cytarabine became the standard of care for the

treatment of patients felt to be unfit for intensive chemotherapy,

although one could argue that it should not be given to those with

poor risk cytogenetics.

The DNA methyltransferase inhibitors have been the subject of several

recent studies. In a multicenter phase II study of 55 patients over age 60

with untreated AML, decitabine was administered for 5 days monthly

until disease progression.44 With a median of three cycles, the overall

response rate was 24%, median survival was 7.7 months, and 30-day

mortality was 7%. Responses were seen in all cytogenetic risk groups,

as well as in those patients with prior MDS. An alternate schedule of

decitabine was reported by Blum et al.45,46 Patients received an initial

one totwo courses of 10days of decitabine, followed bya course over 3

to 5 days every 4 weeks for 1 year. Of the 53 patients with a median age

of 74, 36% had secondary AML, and 34% had a complex karyotype.

Eighteen patients had a HCTCI score of Ն 3. There was a 64%

response rate after a median of three cycles of therapy. CR occurred in

all subsets, regardless of age, karyotype, presenting WBC, and prior

AHD. One-year survival of poor risk patients was 30% (compared with

10% in patients with a similar Wheatley risk score in the AML 11

trial38).

In a study of azacitidine in AML with 20% to 30% blasts, patients

who were deemed unfit for standard induction chemotherapy were

randomized against either supportive care or LD cytarabine.47 OS

survival was superior in the azacitidine arm. There was a statisti-

cally significant difference seen in OS for patients with poor risk

cytogenetics in favor of azacitidine, compared with conventional

care regimens (12.3 vs 5.3 months, respectively, with 2-year OS of

38% vs 0%).

Gemtuzumab ozogamicin (GO) has been the subject of a recent

study by the EORTC and GIMEMA leukemia groups (AML 19).48

In this randomized multicenter study, 84 patients were randomized

to receive one of two schedules of GO at attenuated doses or best

supportive care. The proportion of patients either achieving a

response or maintaining stable disease was greater in patients who

receive GO at a dose of 6 mg/m2 on day 1 and 3 mg/m2 on day 8,

when compared with a schedule of GO 3 mg/m 2 on days 1, 3, and 5

(63% vs 38%, respectively). Results of the comparison with patients

who were randomized to standard care are not yet available, and a

phase III trial is ongoing.

Clofarabine has been studied as an agent in elderly patients withAML. In a phase II study of the agent in 112 patients over age 60

with untreated AML with at least one unfavorable baseline prognos-

tic factor, there was a 46% response rate.49 The median age of the

patients was 71. Twenty-two percent of patients had a baseline PS of

2, 47% had a prior hematologic disorder (AHD) or secondary AML,

55% had an unfavorable karyotype, and 62% were Ն age 70.

Overall response rate (ORR) was 395 for patients Ն 70, 32% for PS

2, 51% for patients with AHD, 54% for intermediate karyotype and

42% for unfavorable karyotype, and 38% for patients with three risk

factors. Median DFS was 37 weeks, and median OS was 41 weeks

for all patients, 59 weeks for patients with CR/complete remission

with incomplete platelet recovery (CRp), and 72 weeks for patients

with CR. Early death rate (within 60 days) was 16%.

In two consecutive European studies of 106 untreated older patients

with AML who were considered unfit for chemotherapy, partici-

pants were given four to six 5-day courses of clofarabine. 18,50 In the

UWCM (University of Wales College of Medicine)-001 study,

patients who were either over age 70 (68%) or over age 60, with a

PS of 2 or cardiac comorbidity, were treated with clofarabine for 5

days every 28 days for 2 to 4 courses. In the BIOV-121 study,

patients were treated for 5 days every 4 to 6 weeks for up to six

courses. All patients were age Ն 65 and deemed unfit for chemo-

therapy. Overall, 36% of patients had a PS Ն 2, 30% had adverse

risk cytogenetics, 46% had Wheatley poor risk disease, and 65%

were age Ն 70. The ORR was 48%, and the median OS was 19

weeks for all and 45 weeks for those who attained a CR/complete

remission with incomplete blood count recovery (CRi). Responses

were seen in patients with adverse cytogenetics (44% ORR),

patients with secondary AML (31%), and patients age Ն 70 (49%).

The death rate within 30 days was 18%.

A novel agent, laromustine (VNP40101M), a sulfonylhydrazine alky-

lating agent, has been studied in 85 patients with poor risk AML ageՆ

60 years.51 Patients received one to two cycles of laromustine at a dose

of 600 mg/m2, followed by one cycle of cytarabine. Seventy-eight

percent of patients were age Ն 70, 47% had an adverse karytype, 41%

had a PS of 2, 77% had pulmonary disease, 73% had cardiac disease,

and 3% had hepatic disease. All patients with unfavorable karyotype or

ECOG PS had at least one other risk factor at the time of enrollment.

Seventy-five percent of patients had Ն 3 risk factors. The ORR was

32% and was similar in patients over age 70 (32%), with a PS of 2

(32%), with baseline pulmonary or cardiac dysfunction (27%–34%).

There was a 14% 30-day mortality. OS was 3.2 months (12.4 months

for those with CR/CRp), and 1-year survival was 21% (52% for those

with CR/CRp).

These phase II studies are encouraging, in that responses are seen in

all poor risk categories, and early death rates are acceptable.

Randomized trials are needed. Although randomized trials of

intensive versus nonintensive therapy have not been successful, the

ongoing AML 16 trial was designed to randomize patients who are

considered not fit for intensive treatment to LD cytarabine versus

Table 4. Novel therapeutic regimens

Author/Regimen Number

Age (Range)

Eligibility CR/ED

Cashen44

Decitabine 20mg/m2 x 5 d

n=55median age 74(61-87)

>=60Intermediate/poor risk

cytogeneticsECOG PS <=2

25% CR 2% CRi30d ED 7%

Blum45,46

Decitabine 20mg/m2 x 10 d

n=53Median age74(60-85)15% >= age 80

Unfit for intensive therapy 47% CR 17% CRi30d ED 2%

Kantarjian49

Clofarabine30 mg/m2 x 5 d

N=129Median age71(60-88)

>=70ECOG PS2AHD

Int/Hi risk karyotype

38% CR 8% CRp30d ED 9.8%

Burnett18,50

Clofarabine30 mg/m2 x 5 d

n=106Median age 71(60-84)

UWCM-001>=70WHO>2

Cardiac disease

BIOV-121>=65Unfit for intensive chemo

CR+ CRi 48%30d ED18%

Schiller 51

Laromustine600 mg/m2

n=85

Median age72(60-87)

>=60Unfavorable karyotypeECOG=2Age >=70Cardiac, pulmonary,

hepatic comorbidities

CR 23%CRp 8%30d ED 14%

Int indicates intermediate; Hi, high; UWCM, University of Wales College of Medi-

cine; WHO, World Health Organization; chemo, chemotherapy; CRi, completeremission with incomplete blood count recovery; ED, early death; CRp, complete

remission with incompleteplatelet recovery.




LD cytarabine with GO, LD cytarabine with arsenic trioxide or

tipifarnib, or LD clofarabine.52 The arsenic arm has been closed

because of ineffectiveness with CR/CRi of 29%, compared with

24% and a 12-month OS of 27%, compared with 41%. The other

arms continue to accrue patients.

Approach to the Elderly Patient With AMLAML is a disease of the elderly, with the majority of patients over age

60. As our population ages, that percentage will only increase.

Unfortunately, the standard regimens that are successful in treating

younger patients will AML are not as beneficial in the majority of older

patients with the disease. Figure 1 outlines my approach to the elderly

patient with AML. Understanding of the disease biology, as well as the

prognostic factors associated with the host, allows us to betterdetermine which patients are likely to benefit from standard therapy

and which require alternative approaches. Objective scoring systems

are being developed that allow us to define patients unfit for intensive

chemotherapy on the basis of increased risk of induction death, low

response rate, and/or low long-term DFS. Optimal induction and

postremission therapy for patients appropriate for intensive therapy

have yet to be defined, again, because results are not satisfactory with

our current regimens, even in those patients who do not have definable

poor prognostic factors. When compared with young patients with

similar disease-related features, outcomes are inferior. For patients who

are not candidates for intensive therapy because of comorbid condi-

tions, low-intensity therapies appear to be superior to palliative care

alone. Whenever possible, patients should be enrolled in clinical trials

that will allow us to address these issues.

DisclosuresConflict-of-interest disclosure: The author declares no competing

financial interests.

Off-label drug use: Use of gemtuzumab ozogamicin, clofarabine,

and decitabine.

CorrespondenceSelina M. Luger, MD, Professor of Medicine, and Director,

Leukemia Program, Hospital of the University of Pennsylvania,

Perelman Center for Advanced Medicine, 3400 Civic Center Blvd.,

Philadelphia, PA 19104; Phone: (215) 614-1847; Fax: (215) 615-

5888; e-mail: [email protected]

References1. Surveillance Epidemiology and End Results (SEER) Program.

Limited use-data (1973–2004). National Cancer Institute D,

Surveillance Research Program, Cancer Statistics Branch.

SEER Web site. http:// www.seer.cancer.gov. Accessed April

2007.

2. Juliusson G, Antunovic P, Derolf A, et al. Age and acute

myeloid leukemia: real world data on decision to treat and

outcomes from the Swedish Acute Leukemia Registry. Blood .

2009;113:4179– 4187.

3. Pulte D, Gondos A, Brenner H, Pulte D, Gondos A, Brenner H.

Improvements in survival of adults diagnosed with acute

myeloblastic leukemia in the early 21st century. Haemato-

logica. 2008;93:594– 600.

4. Buchner T, Berdel WE, Haferlach C, et al. Age-related risk

profile and chemotherapy dose response in acute myeloid

leukemia: a study by the German Acute Myeloid Leukemia

Cooperative Group. J Clin Oncol. 2009;27:61–69.

5. Lerch E, Espeli V, Zucca E, et al. Prognosis of acute myeloid

leukemia in the general population: data from southern Switzer-

land. Tumori. 2009;95:303–310.

6. Alibhai SM, Leach M, Minden MD, et al. Outcomes and quality

of care in acute myeloid leukemia over 40 years. Cancer .2009;115:2903–2911.

7. Appelbaum F, Gundacker H, Head DR, et al. Age and acute

myeloid leukemia. Blood . 2006;107:3481–3485.

8. Rao AV, Valk PJ, Metzeler KH, et al. Age-specific differences

in oncogenic pathway dysregulation and anthracycline sensitiv-

ity in patients with acute myeloid leukemia. J Clin Oncol.

2009;27:5580–5586.

9. Appelbaum FR, Baer MR, Carabasi MH, et al. NCCN practice

guidelines for acute myelogenous leukemia. Oncology. 2000;14:

53–61.

10. Dohner H, Estey EH, Amadori S, et al. Diagnosis and

Non-M3 AML

Age > 80 Age 60-79

Poor PS, comorbidities, unfavorable

karyotype+ poor prognostic factors

Good PS, good /intermediate karyotype

Clinical trial/low intensity therapy

Clinical trial for all patients preferable

Induction therapy with standard dose anthracycine and

cytarabine

Postremission therapy with 1 or 2 cycles of

intermediate or high dose cytarabine containing regimen

Complete Remission

Consideration of RIC transplant

Figure 1. My approach to the patient over age 60 with AML.

Hematology 2010 67



management of acute myeloid leukemia in adults: recommenda-

tions from an international expert panel, on behalf of the

European LeukemiaNet. Blood . 2010;115:453– 474.

11. Morra E, Barosi G, Bosi A, et al. Clinical management of

primary non-acute promyelocytic leukemia acute myeloid

leukemia: Practice Guidelines by the Italian Society of Hematol-

ogy, the Italian Society of Experimental Hematology, and the

Italian Group for Bone Marrow Transplantation. Haemato-

logica. 2009;94:102–112.

12. Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leuke-

mia. N Engl J Med . 2009;361:1235–1248.

13. Pautas C, Merabet F, Thomas X, et al. Randomized study of

intensified anthracycline doses for induction and recombinant

interleukin-2 for maintenance in patients with acute myeloid

leukemia age 50 to 70 years: results of the ALFA-9801 study.

J Clin Oncol. 2010;28:808– 814.

14. Burnett AK, Milligan D, Goldstone A, et al. The impact of dose

escalation and resistance modulation in older patients with

acute myeloid leukaemia and high risk myelodysplastic syn-

drome: the results of the LRF AML 14 trial. Br J Haematol.

2009;145:318–332.

15. Cripe LD, Uno H, Paietta EM, et al. Zosuquidar, a novel

modulator of P-glycoprotein, does not improve the outcome of

older patients with newly diagnosed acute myeloid leukemia: a

randomized, placebo-controlled, trial of the Eastern Coopera-

tive Oncology Group (ECOG 3999). Blood . 2010 Aug 17.

[Epub ahead of print]

16. Lancet J, Gotlib J, Wetzler M, et al. Phase I/II study of the

P-glycoprotein (Pgp) inhibitor zosuquidar administered by

continuous infusion (CIV) with daunorubicin (DNR) and

cytarabine (ARA-C) as primary therapy in older patients with

Pgp-positive acute myeloid leukemia (AML) [abstract]. Blood .

2007;110.

17. Chauncey TR, Gundacker H, Shadman M, et al. Sequential

phase II Southwest Oncology Group studies (S0112 and S0301)

of daunorubicin and cytarabine by continuous infusion, without

and with ciclosporin, in older patients with previously untreated

acute myeloid leukaemia. Br J Haematol. 2009;148:48 –58.

18. Burnett A, Russell N, Kell J, et al. European development of

clofarabine as treatment for older patients with acute myeloid

leukemia considered unsuitable for intensive chemotherapy

[abstract]. J Clin Oncol. 2010;28.

19. Faderl S, Erba HP, Claxton DF, et al. Clofarabine produces

durable remissions in older patients with AML with unfavor-

able prognostic factors and multiple comorbidities [abstract

4155]. Blood . 2009;114.

20. Faderl S, Ravandi F, Huang X, et al. A randomized study of

clofarabine versus clofarabine plus low-dose cytarabine as

front-line therapy for patients aged 60 years and older with

acute myeloid leukemia and high-risk myelodysplastic syn-

drome. Blood . 2008;112:1638 –1645.

21. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremis-

sion chemotherapy in adults with acute myeloid leukemia.

N Engl J Med . 1994;331:896 –903.

22. 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

Cooperataive Oncology Group. Blood . 2004;103:479– 485.

23. Lowenberg B, Beck J, Graux C, et al. Gemtuzumab ozogamicin

as postremission treatment in AML at 60 years of age or more:

results of a multicenter phase 3 study. Blood . 2010;115:2586–

2591.

24. Baer MR, George SL, Caligiuri MA, et al. Low-dose interleu-

kin-2 immunotherapy does not improve outcome of patients

age 60 years and older with acute myeloid leukemia in first

complete remission: Cancer and Leukemia Group B Study

9720. J Clin Oncol. 2008;26:4934– 4939.

25. Jehn U, Suciu S, Thomas X, et al. Non-infusional vs intrave-

nous consolidation chemotherapy in elderly patients with acute

myeloid leukemia: final results of the EORTC-GIMEMA

AML-13 randomized phase III trial. Leukemia. 2006;20:1723–

1730.26. Thomas X, Suciu S, Rio B, et al. Autologous stem cell

transplantation after complete remission and first consolidation

in acute myeloid leukemia patients aged 61–70 years: results of

the prospective EORTC-GIMEMA AML-13 study. Haemato-

logica. 2007;92:389 –396.

27. Goldstone A, Burnett A, Wheatley K, Smith AG, Hutchinson

M, Clark R. Attemps to improve treatment outcomes in acute

myeloid leukemia (AML) in older patients: the results of the

United Kingdon Medical Research Council AML11 trial.

Blood . 2001;98:1302–1311.

28. Gardin C, Turlure P, Fagot T, et al. Postremission treatment of

elderly patients with acute myeloid leukemia in first complete

remission after intensive induction chemotherapy: results of the

multicenter randomized Acute Leukemia French Association

(ALFA) 9803 trial. Blood . 2007;109:5129 –5135.

29. Schlenk RF, Frohling S, Hartmann F, et al. Intensive consolida-

tion versus oral maintenance therapy in patients 61 years or

older with acute myeloid leukemia in first remission: results of

second randomization of the AML HD98-B treatment trial.

Leukemia. 2006;20:748–750.

30. Prebet T, Boissel N, Reutenauer S, et al. Acute myeloid

leukemia with translocation (8;21) or inversion (16) in elderly

patients treated with conventional chemotherapy: a collabora-

tive study of the French CBF-AML intergroup. J Clin Oncol.

2009;27:4747–4753.

31. Sekeres MA, Elson P, Kalaycio ME, et al. Time from diagnosis

to treatment initiation predicts survival in younger, but not

older, acute myeloid leukemia patients. Blood . 2009;113:28–

36.

32. Chevallier P, Blaise D, Milpied N, et al. Reduced intensity

conditioning (RIC) allogeneic stem cell transplantation for

patients agedϾϭ60 years: a retrospective study of 629 patients

from the Societe Francaise De Greffe De Moelle et de therapie

cellulaire (SFGM-TC). Blood . 2009;114:84– 85.

33. Rollig C, Thiede C, Gramatzki M, et al. A novel prognostic

model in elderly patients with acute myeloid leukemia: results

of 909 patients entered into the prospective AML96 trial.

Blood . 2010;116:971–978.

34. Estey E, de Lima M, Tibes R, et al. Prospective feasibility

analysis of reduced-intensity conditioning (RIC) regimens for

hematopoietic stem cell transplantation (HSCT) in elderly

patients with acute myeloid leukemia (AML) and high-risk

myelodysplastic syndrome (MDS). Blood . 2007;109:1395–

1400.

35. Kurosawa S, Yamaguchi T, Uchida N, et al. Comparison of

allogeneic hematopoietic cell transplantation and chemo-

therapy as post-remission strategy in elderly patients with

non-M3 AML in CR1: retrospective analysis with 1036 patients

[abstract 524]. Blood . 2009;114.

36. Juliusson G, Billstrom R, Gruber A, et al. Attitude towards

remission induction for elderly patients with acute myeloid

leukemia influences survival. Leukemia. 2006;20:42– 47.

37. 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.

38. Wheatley K, Brookes CL, Howman AJ, et al. Prognostic factor

analysis of the survival of elderly patients with AML in the

MRC AML11and LRF AML14 trials. Br J Haematol. 2009;145:

598–605.

39. Kantarjian H, O’Brien S, Cortes J, et al. Results of intensive

chemotherapy in 998 patients age 65 years or older with acutemyeloid leukemia or high-risk myelodysplastic syndrome:

predictive prognostic models for outcome. Cancer . 2006;106:

1090–1098.

40. Giles FJ, Borthakur G, Ravandi F, et al. The haematopoietic

cell transplantation comorbidity index score is predictive of

early death and survival in patients over 60 years of age

receiving induction therapy for acute myeloid leukaemia. Br J

Haematol. 2007;136:624– 627.

41. Malfuson JV, Etienne A, Turlure P, et al. Risk factors and

decision criteria for intensive chemotherapy in older patients

with acute myeloid leukemia. Haematologica. 2008;93:1806–

1813.

42. Rollig C, Aulitzky WE, Bodenstein H, et al. Risk stratification

and prognostic factors in elderly AML patients—updatedresults of 909 patients entered into the prospective AML96 trial

[abstract 329]. Blood . 2009;114.

43. Burnett AK, Milligan D, Prentice AG, et al. A comparison of

low-dose cytarabine and hydroxyurea with or without all-trans

retinoic acid for acute myeloid leukemia and high-risk myelo-

dysplastic syndrome in patients not considered fit for intensive

treatment. Cancer . 2007;109:1114 –1124.

44. Cashen AF, Schiller GJ, O’Donnell MR, et al. Multicenter,

phase II study of decitabine for the first-line treatment of older

patients with acute myeloid leukemia. J Clin Oncol. 2010;28:

556–561.

45. Blum W, Garzon R, Klisovic RB, et al. Clinical response and

miR-29b predictive significance in older AML patients treated

with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A.

2010;107:7473–7478.

46. Blum W, Klisovic R, Liu S, et al. Preliminary results of a phase

II study of low dose decitabine as a single agent in older

patients (age Ͼϭ60) with previously untreated acute myeloid

leukemia (AML) [abstract 2957]. Blood . 2008;112.

47. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine

prolongs overall survival compared with conventional careregimens in elderly patients with low bone marrow blast count

acute myeloid leukemia. J Clin Oncol. 2010;28:562–569.

48. Amadori S, Suciu S, Selleslag D, et al. Randomized trial of two

schedules of low-dose gemtuzumab ozogamicin as induction

monotherapy for newly diagnosed acute myeloid leukaemia in

older patients not considered candidates for intensive chemo-

therapy. (A phase II study of the EORTC and GIMEMEA

leukaemia groups (AML-19).) Br J Haematol. 2010;149:376–

382.

49. Kantarjian HM, Erba HP, Claxton D, et al. Phase II study of

clofarabine monotherapy in previously untreated older adults

with acute myeloid leukemia and unfavorable prognostic

factors. J Clin Oncol. 2010;28:549 –555.

50. Burnett AK, Baccarani M, Johnson P, et al. A phase II study(biov-121) of clofarabine monotherapy first line in patients

aged 65 years or older with acute myeloid leukemia for whom

standard intensive chemotherapy is not considered suitable

[abstract 425]. Blood . 2006;108.

51. Schiller GJ, O’Brien SM, Pigneux A, et al. Single-agent

laromustine, a novel alkylating agent, has significant activity in

older patients with previously untreated poor-risk acute my-

eloid leukemia. J Clin Oncol. 2010;28:815–821.

52. Russell NH, Hills RK, Hunter AE, et al. Low dose ara-C versus

low dose ara-C and arsenic trioxide: the UK NCRI AML16

“pick a winner” comparison [abstract 486]. Blood . 2009;114.

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