Pretreatment prognostic factors and treatment outcome in elderly patients with de novo acute myeloid leukemia

Original article

Annals of Oncology 16: 1366– 1373, 2005 doi:10.1093/annonc/mdi259 Published online 14 June 2005

Pretreatment prognostic factors and treatment outcome in elderly patients with de novo acute myeloid leukemia C.-C. Chen1,2, C.-F. Yang3, M.-H. Yang4, K.-D. Lee1, W.-K. Kwang3, J.-Y. You2, Y.-B. Yu2, C.-H. Ho2, C.-H. Tzeng5, W.-K. Chau2, H.-C. Hsu2 & J.-P. Gau2* 1

Division of Hematology Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi; 2Division of Hematology, Department of Medicine, Department of Pathology, 4Division of Oncology, Department of Medicine and 5Division of Transfusion Medicine, Department of Medicine, Taipai Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan

3

Received 10 January 2005; revised 28 April 2005; accepted 29 April 2005

Introduction Acute myeloid leukemia (AML) occurs predominately in adults, and it afflicts the elderly more frequently than the young [1]. Epidemiologic surveillance shows that more than half of patients with AML are older than 60 years [2]. For old-age patients with AML, the complete remission (CR) rate after induction therapy ranges from  40% to 50%, and <10% of these patients are expected to be alive at 3 years [3– 6]. However, with the selected nature of patients who enter trials, oldage patients constitute only roughly one-third of the total study population in large clinical trials of AML [7]. The overall outcome appears far more disappointing when considered in the context of the whole population of elderly AML patients. Accumulating evidence indicates that AML in older patients is biologically different from that occurring in younger

*Correspondence to: Dr J.-P. Gau, Division of Hematology, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan. Tel: + 886-2-28712121, ext. 3866; Fax: + 886-2-28757523; E-mail: [email protected] q 2005 European Society for Medical Oncology

patients [8– 10]. For example, older patients with AML tend to have more unfavorable cytogenetics and a higher rate of multidrug resistance gene expression, which might contribute significantly to their poor clinical outcome [9, 11]. Moreover, the adverse prognosis of AML in the elderly is also somewhat attributable to host-related factors that come with aging [7, 9, 12], and older patients may be less intensively treated compared with younger patients [13]. Taking all these issues into account, it seems reasonable to designate elderly AML patients as an unique and independent entity. Treatment guidelines and predictive prognostic models for AML patients developed from large randomized trials may not be suitable for the elderly. Although the outcome of elderly AML is generally poor, the prognosis may vary among different subgroups. A number of previous studies focusing on elderly patients with AML have identified several factors indicating favorable clinical outcome. These include relatively young age (e.g. 55–65 years), preserved organ function, lacking expression of MDR, favorable cytogenetics, de novo leukemia and good performance status (PS) [9, 12, 14]. Most of the prognostic

Downloaded from http://annonc.oxfordjournals.org/ at Ritsumeikan University on June 10, 2015

Background: Elderly patients with acute myeloid leukemia (AML) generally have an unfavorable clinical course and are under-represented in clinical trials. The aim of this study was to analyze the prognosis and treatment outcome of elderly AML patients. Patients and methods: We studied 205 AML patients aged 65 years or older at our hospital. Prior to study initiation, we designated 13 variables to be analyzed for their impact on complete remission (CR) rate and overall survival (OS). Results: Induction regimen (standard chemotherapy) and good performance status (PS) (Eastern Cooperative Oncology Group PS 0– 1) independently influenced the achievement of CR. Multivariate analysis also determined five poor prognostic factors for OS: poor PS (score 2 – 4), presence of _ 2 upper normal limit), extreme leukocomorbidities, elevated serum lactate dehydrogenase level (> _ 100  109/l) and marked thrombocytopenia (< _ 20  109/l). Age was not an independent cytosis (> contributing factor in terms of either CR attainment or OS duration. Low-risk patients, who possessed one or less non-leukocytosis poor prognostic factor, had significantly longer disease-free survival and OS than their high-risk counterparts. Conclusions: Elderly AML patients should be risk-stratified at diagnosis. Anthracycline-based induction chemotherapy would be the best therapeutic option for such patients. Key words: AML, elderly, prognosis, treatment

1367 Table 1. (Continued)

Table 1. Patients’ characteristics n (%)

Characteristic

Range

65–91

Albumin (g/dl)

Median

74

Characteristic

Median

Age (years)

Sex Male

165 (80.5)

Female

40 (19.5)

FAB classification 4 (2.0)

M1

47 (22.9)

M2

84 (41.0)

M4

24 (11.7)

M5

20 (9.8)

M6

7 (3.4)

M7

4 (2.0)

Unclassified

15 (7.3)

Presence of dyspoietic features Yes

31 (15.1)

No

163 (79.5)

Not recorded

11 (5.4)

Cytogenetic studies Favorable

4 (2.0)

Intermediate

66 (32.2)

Unfavorable

27 (13.2)

Not evaluated

108 (52.7)

ECOG PS 0–1

105 (51.2)

2–4

97 (47.3)

Not recorded

3 (1.5)

WBC (109/l) Range

0.4–322.8

Median

10.9

6.2

Range

2.1–5.0

Median

3.5

a

Determination of co-morbidity was based on the hepatic, renal and cardiac function of the patients. FAB, French–American– British; ECOG PS, Eastern Cooperative Oncology Group performance status; WBC, white blood cell count; LDH, lactate dehydrogenase.

models proposed are not without significant disadvantages. First, detection of MDR expression is not readily accessible in most patient-based service hospitals. Secondly, delayed availability of karyotypic analysis often hinders treatment planning, as many experts agree that cytogenetic data is the most critical independent determinant in the decision-making of therapeutic option for elderly AML patients [11, 12]. Such delay might impose adverse effects on these patients. A recently completed phase III study from Eastern Cooperative Oncology Group (ECOG) demonstrated that delaying induction therapy in older patients with AML resulted in a lower CR rate [15]. The aim of this study was to analyze the survival of elderly AML patients seen at our institute during the last decade. Most of these patients would have been excluded in prospective randomized trials because of old age and poor general condition; however, they might be more representative of the real patient population that hematologists face during daily practice. By delineating the important prognostic factors from various pretreatment parameters, we stratified elderly AML patients into two risk groups, and successfully developed a model that could facilitate accurate prediction of outcome and serve as a guide for treatment selection.

Hemoglobin (g/dl) Range

3.1–13.6

Median

7.6

Platelet (109/l) Range

4–1476

Median

43

LDH (U/l) Range

111–3950

Median

383

Comorbiditya No

143 (69.8)

At least one

60 (29.3)

Missing data

2 (1.0)

Uric acid (mg/dl) Range

1.5–21.7

Patients and methods Patients and diagnosis All patients 65 years of age or older diagnosed as having AML at Taipei Veterans General Hospital between January 1991 and December 2003 were screened. The diagnosis of AML was based on morphological picture, immunophenotypical analysis, and cytochemical studies and French– American– British criteria [16] were used for AML subtype classification. Central review was organized and the diagnosis had to be made upon the agreement of two or more hematologists/hematopathologists at our institute. We excluded patients with preceding clonal hematological diseases such as myeloproliferative disorders, myelodysplasic syndromes (MDS), multiple myeloma, lymphoproliferative disorders, aplastic anemia or paroxysmal nocturnal hemoglobinuria, or patients who previously received chemo- or radiotherapy for solid tumors. Patients with morphologic evidence of dyspoiesis but lacking an antecedent diagnosis of MDS and devoid of previously unexplained persistent cytopenia in the peripheral blood, however, were allowed. Patients with acute promyelocytic

Downloaded from http://annonc.oxfordjournals.org/ at Ritsumeikan University on June 10, 2015

M0

n (%)

1368 leukemia, treated differently and apparently having a superior outcome, were also excluded.

Pretreatment work-up Pretreatment baseline characteristics were recorded for evaluation. Cytogenetic studies using conventional G-banding method were performed in about half of the patients. They were categorized into favorable, intermediate and unfavorable groups according to Southwest Ongology Group (SWOG) criteria [17]. Dyspoiesis was defined as 50% or more of the cells in any of the myeloid lineages being dysplastic in a pretreatment sample.

Therapy and outcome The treatment of each patient was individualized and categorized into three major groups: anthracycline-based standard chemotherapy (conventional 7-3 or 5-2 protocols), low-dose cytarabine and best supportive care. The 7-3 protocol consisted of continuous infusion of cytarabine at the dose of 200 mg/m2/day for seven consecutive days and a 3-day course of bolus anthracycline using either daunomycin at a dose of 45 mg/m2/day or idarubicin at a dose of 10–12 mg/m2/day. The 5-2 protocol consisted of similar regimen with reduced duration to 5 and 2 days, respectively. In the low-dose group, patients received continuous infusion of cytarabine at the dose of 20–30 mg/m2/day for 10–14 days, for each course. Patients receiving only supportive care without chemotherapy and patients receiving hydroxyurea and/or leukapheresis to control hyperleukocytosis were all included in the best supportive care group. The final decision of treatment for each patient was made by the attending physicians after taking patient’s willingness, preference and clinical condition into consideration. Response to remission induction therapy was evaluated according to SWOG criteria [18]. Patients who failed to achieve CR after induction chemotherapy were classified according to types of failure: resistant disease, death during aplasia or indeterminate [18]. Overall survival (OS) was measured from the date of diagnosis until death from any cause, with observation ending at the date of last contact for patients last known to be alive.

Treatment and CR rate About one-third of patients received best supportive care only (n = 69; 33.7%). Forty-nine patients (23.9%) underwent lowdose cytarabine induction chemotherapy, with a mean of 1.23 courses for each patient. Eighty-six patients (41.9%) received standard treatment, with a mean of 1.53 courses for each pateint. In all, 40 patients achieved CR, including one patient whose CR occurred spontaneously following an episode of infection. The overall CR rate was 28.9% for patients receiving chemotherapy. Thirty-four patients (39.5%) achieved CR after standard chemotherapy, while there were only five remissions (10.2%) among those receiving low-dose cytarabine induction. The mean number of courses of chemotherapy to CR were 1.20 and 1.29 for patients receiving standard chemotherapy and low-dose treatment, respectively. Nine induction deaths (10.4%) occurred in the standard treatment arm, compared with only one (2%) in the low-dose group. We compared various parameters for their influence on the CR rate (complete data not shown). On multivariate analysis, only two factors were statistically important: the regimen of induction therapy [odds ratio of induction failure for low-dose cytarabine when compared with standard chemotherapy: 6.77; 95% confidence interval (CI) 2.33 –19.68; P = 0.000], and the PS of patients (odds ratio of induction failure, PS 2–4 versus PS 0–1: 5.46; 95% CI 1.9 –15; P = 0.001). Neither age, cytogenetic risk group nor other clinical data were relevant to the probability of CR attainment.

Overall survival Statistical analysis The variables of OS were estimated by the Kaplan–Meier method. Differences between groups were calculated using the log-rank test for univariate analysis. Cox’s proportional hazards model was used to test independent prognostic factors. All calculations were performed using the Statistical Package of Social Sciences software, version 11.5 (SPSS, Inc., Chicago, IL, USA).

Results Patients’ characteristics Two hundred and five AML patients older than 65 years of age were eligible for this study. Their baseline characteristics were shown in Table 1. Since retired veterans constituted roughly 70% of all patients in our institute, the sex

All variables were subjected to univariate analysis for prognostic significance on OS (Table 2, log-rank test). As a result, we excluded cytogenetic data (which were available in only about half of the patients) and tested six pretreatment parameters in multivariate analysis using the Cox proportional hazard model (Table 3). It was determined that five variables were independent adverse prognostic factors: poorer ECOG _ 2 versus <2: hazard ratio (HR) 1.818; PS score [PS > P = 0.000), extreme leukocytosis (white blood cell count > _ 100  109/l versus <10  109/l: HR 4.146; P = 0.000), _ 20  109/l versus marked thrombocytopenia (platelets < 9 >20  10 /l: HR 1.493; P = 0.024), elevated lactate dehydrogenase (LDH) level (>2  normal versus less: HR 1.499; P = 0.033) and presence of comorbidities (at least one versus nil: HR 1.615; P = 0.006).

Downloaded from http://annonc.oxfordjournals.org/ at Ritsumeikan University on June 10, 2015

The designated presence of comorbidities hinged on the function of three major organs: liver, kidney and heart. Renal function impairment was defined as an estimated creatinine clearance <40 ml/min. Hepatic dysfunction was defined as increased serum levels of alanine transaminase _ 2 mg/dl, with a predominance of (>2 normal) and/or total bilirubin (> direct hyperbilirubinemia). Abnormal cardiac function was defined as clinical evidences of congestive heart failure, at least New York Heart Association functional class II or higher.

distribution between these AML patients was somewhat biased. There were 165 men and 40 women. The median age of these patients was 74 years (range 65 –91). The most common subtype was M2 leukemia (41%). Cytogenetic studies were performed in 97 patients (47.3%). By SWOG criteria, only four out of the 97 patients (4.1%) had favorable cytogenetics, either t(8;21) (three cases) or inv(16) (one case), while most patients (n = 66; 68%) had intermediate-risk cytogenetics. As of 30 November 2004, the median follow-up period was 88 days (range 3–1058).

1369

Table 2. Univariate analysis of prognostic factors affecting overall survival Factors

n (%)a

Overall survival (days) Mean

Projected 6-month survival rate (%)

P valueb

95% CI

Age 65–69 years

37 (18.0)

184

107–261

32.4

Reference

70–74 years

79 (38.5)

234

173–295

35.4

0.2515

75–79 years > _ 80 years

49 (23.9)

189

137–241

38.8

0.7568

40 (19.5)

144

93–196

22.5

0.4679

165 (80.5)

197

160–234

33.3

40 (19.5)

206

133–278

32.5

Yes

31 (16.0)

204

130–278

32.5

No

163 (84.0)

198

159–236

32.3

Sex Male Female

0.8081

Presence of dyspoietic features

0.6747

4 (4.1)

227

100–354

75.0

0.0178

Intermediate

Favorable

66 (68.1)

292

215–370

43.9

0.0000

Unfavorable

27 (27.8)

86

55–116

11.1

Reference

0–1

105 (52.0)

271

217–325

46.7

2–4

97 (48.0)

121

93–149

18.6

<10

98 (48.8)

228

182–273

39.8

Reference

10–49.9

55 (27.4)

201

139–264

34.5

0.3982

50–99.9 > _ 100

22 (10.9)

248

119–376

40.9

0.9491

26 (12.9)

43

23–62

3.8

0.0000

122 (60.7)

194

153–234

32.0

79 (39.3)

213

154–272

36.7

ECOG PS

0.0000

WBC (109/l)

Hemoglobin (g/dl) < _8 >8 Platelets (109/l) < _ 20

0.5881

0.0783 49 (23.9)

145

102–187

26.5

156 (76.1)

216

175–256

35.3

LDH (U/l) < _ 2 normal

117 (57.9)

243

197–289

41.9

>2 normal

85 (42.1)

140

96–184

21.2

143 (70.0)

222

181–263

37.1

At least one

60 (30.0)

147

92–202

23.3

Uric acid (mg/dl) < _7

125 (61.6)

212

174–250

39.2

78 (38.4)

179

117–240

21.8

84 (41.6)

181

132–229

27.4

118 (58.4)

213

168–258

37.3

>20

0.0002

Comorbidity No

>7 Albumin (g/dl) < _ 3.4 >3.4

0.0099

0.1788

0.3037

Regimen of induction CT

a

Intensive CT

86 (42.2)

255

195–315

44.2

Reference

Low dose Ara-C

49 (24.0)

174

129–219

30.6

0.1186

Nil

69 (33.8)

144

97–190

20.3

0.0026

Percentage of patients with available data. Log-rank test. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; WBC, white blood cell count; LDH, lactate dehydrogenase; CT, chemotherapy; Ara-C, cytarabine. b

Downloaded from http://annonc.oxfordjournals.org/ at Ritsumeikan University on June 10, 2015

Cytogenetic studies

1370 Table 3. Multivariate analysis of pretreatment prognostic factors affecting overall survival Hazard ratio

95% CI for exp(b)

P valuea

70–74 versus 65– 69 years

0.729

0.474–1.121

0.150

75–79 versus 65– 69 years

0.880

0.545–1.420

0.600

> _ 80 versus 65 –69 years

1.264

0.764–2.094

0.362

1.818

1.303–2.538

0.000

10–49.9 versus <10

1.055

0.711–1.565

0.792

50–99.9 versus <10

0.741

0.422–1.299

0.295

> _ 100 versus <10

4.146

2.422–7.099

0.000

1.493

1.055–2.112

0.024

1.499

1.033–2.176

0.033

1.615

1.146–2.274

0.006

Factors Age

ECOG PS 2–4 versus 0–1 WBC (109/l)

Platelets (109/l)

LDH _ 2 >2 normal versus < Comorbidity > _ 1 versus 0 a

Cox’s proportional hazard model. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; WBC, white blood cell count; LDH, lactate dehydrogenase.

Pretreatment risk stratification for elderly patients with AML We then stratified elderly patients with AML into two risk groups according to these prognostic factors. Patients were considered to be in the low-risk group if they had none or only one of the following adverse factors: poorer ECOG PS, marked thrombocytopenia, elevated serum LDH level or presence of comorbidity. These patients had a median disease-free survival (DFS) of 275 days and a median OS of 197 days, with a projected 1-year survival rate of 30.3%. Patients with extreme leukocytosis and patients with more than one adverse factors were all categorized into the highrisk group. They fared rather poorly, with a median DFS and OS of 108 and 54 days, respectively. Their projected 1-year survival rate was 5%. Kaplan –Meier estimated OS and DFS curves for patients in the two risk groups are shown in Figure 1 (P = 0.0000 and 0.0305, respectively, log-rank test).

the duration of OS was independent of the type of management selected (Figure 2A, log-rank test).

Treatment and outcome for patients in the high-risk group High-risk patients receiving standard chemotherapy had superior CR rates (11/31; 35.5%), although this took place at the cost of more induction deaths (19.4%). On the other hand, only one out of 25 patients (4%) achieved CR after low-dose cytarabine induction, and one (4%) induction death occurred after such treatment. As shown in Figure 2B, patients treated with either intensive chemotherapy or lowdose cytarabine all had a longer OS when compared with those received best supportive care only (P = 0.0380 and 0.0097, respectively, log-rank test). The difference between intensive therapy or low-dose treatment, however, was nonsignificant (P = 0.8044, log-rank test). There was no discrepancy between 7-3 and 5-2 regimen groups in terms of CR rate or OS (data not shown).

Treatment and outcome for patients in the low-risk group

Discussion

We looked further into the impact of different treatment choices on CR rate and OS of patients in the two risk groups. For low-risk patients, standard chemotherapy resulted in higher CR rates than did low-dose cytarabine (50% versus 16.7%; P = 0.009, Fisher’s exact test). The comparison of CR rate between 7-3 and 5-2 regimen was statistically non-significant. Three aplasia deaths occurred after 7-3 induction, but none occurred in the other two regimens. However,

How to treat elderly patients with AML has remained a topic of debate [7, 12]. In the famous EORTC prospective randomized trial reported 16 years ago, the median survival in intensively treated patients was twice as long as those receiving a palliative approach [19]. In that study, the patient number was relatively small and thus not prognostically stratified. More recently, prognostic factors, especially age and cytogenetics, have been advocated as the major determinants in therapeutic

Downloaded from http://annonc.oxfordjournals.org/ at Ritsumeikan University on June 10, 2015

< _ 20 versus >20

1371 A 1.0

Probability

0.8

0.6

0.4 P = 0.0000

0.2

Low-risk (n =99) 0.0

0

200

400

600 OS (days)

800

1000

1200

1.0

Probability

0.8

0.6

0.4 P = 0.0305 Low-risk (n =27)

0.2 High-risk (n =12) 0.0 0.0

200

400

600 DFS (days)

800

1000

1200

Figure 1. Kaplan–Meier estimates of (A) overall survival (OS) and (B) disease-free survival (DFS) for elderly AML patients according to riskstratification (log-rank test). Patients in the low-risk group had both significantly longer DFS and OS than their high-risk counterparts.

decision [7, 20]. However, it seems that the decision to give a patient chemotherapy or not cannot be based solely on age. Experience from M. D. Anderson demonstrated that traditionally available chemotherapy was generally not indicated in patients aged 80 years or over with AML [21]. On the other hand, Vey et al. [22] suggested that patients aged more than 75 years should not be excluded from intensive chemotherapy regimens. In our study, age played a minor role, if any, in determining the type of treatment. It did not exert a significant impact on the achievement of CR, nor did it influence the OS. We believe the discrepancies with other previous reports lie in what age is looked at. As we demonstrated, it was the functional status of the patients that predicted the outcome rather than the chronological age. In our AML patients, those aged 75 or older with a good PS and the absence of comorbidities would actually do better than those younger but with poorer general condition, if all other disease-related parameters were similar.

Downloaded from http://annonc.oxfordjournals.org/ at Ritsumeikan University on June 10, 2015

B

High-risk (n =101)

Other than the age factor, the clinical parameters identified here as poor risk indicators for old-age AML patients concur with various previous reports [3, 23 –25]. These adverse prognostic factors can be classified into two major categories: patient-related and disease-related. Comorbidity and PS are host-related factors, while increment of serum LDH level, extreme leukocytosis and marked thrombocytopenia indicate clinical aggressiveness of leukemia per se. After using pretreatment parameters to establish risk stratification, we found the influence of different treatment modalities on clinical outcome within each risk group. In the low-risk group, patients treated with anthracycline-based standard chemotherapy had higher CR rate and hence a possibly improved quality of life when compared with patients managed by low-dose cytarabine. However, the success of treatment in the low-risk patients could not be demonstrated in OS. Part of that might be attributable to the excellent supportive care for patients without chemotherapy or not achieving CR, although it was more likely the result of inadequate post-remission therapy. Concern about toxicity might result in the use of less intensive protocols or even no consolidation therapy at all. Patients who achieved CR ultimately died from leukemic relapse. This phenomenon was demonstrated in subgroup comparison between UK MRC AML10 and AML11 trials, as old patients with favorable cytogenetics had a CR rate similar to that of younger patients, but their relapse rate was significantly higher [11, 26]. On the other hand, unlike young AML patients, the effect of consolidation therapy was rather unsatisfactory. Early studies did show that patients aged 60 years or older were unlikely to benefit from highdose cytarabine as consolidation treatment [27, 28]. For high-risk patients, our data demonstrated that standard chemotherapy should be the treatment of choice. While all chemotherapeutic regimens produced a longer OS when compared with supportive care alone, the CR rate achieved by low-dose therapy was rather unsatisfactory. Although the induction death rate was higher, the improved CR rate and possibly resultant better quality of life among CR patients suggested that induction with standard regimen was definitely worthwhile for the high-risk elderly AML patients. Cytogenetic change was not tested as a covariate for predicting OS in our study, mainly because karyotyping was not covered by the insurance in our country during the study period. Therefore, we could not obtain a sufficient number of patients for a valid multivariate analysis. Most hematologists consider karyotype a critical parameter in determining the choice of treatment or in predicting clinical outcome of elderly AML patients [9, 11, 29]. However, unlike young patients with AML, the proportion of the old-age AML patients possessing intermediate and adverse cytogenetics is extraordinarily high. Most studies demonstrate that elderly AML patients with these chromosomal changes accounted for >90% of those karyotyped [7, 11, 15, 29]. This could help explain the poor outcome of AML in the elderly population. Nevertheless, this would also mean the results of cytogenetic

1372 A

1.0 Low-risk group

Probability

0.8

Intensive C/T vs Supportive P = 0.1887 LD AC vs Supportive P = 0.7596 Intensive C/T vs LD AC

0.6

P = 0.1794

0.4

0.2 Intensive C/T (n = 47) LD AC (n =23) 0

200

400

Supportive (n = 29) 800 1000

600

1200

OS B

1.0 High-risk group LD AC (n =25)

Probability

0.8

Intensive C/T vs Supportive P = 0.0380 LD AC vs Supportive P = 0.0097

0.6

Intensive C/T vs LD AC

P = 0.8044

0.4

0.2 Intensive C / T (n =37) Supportive (n =39) 0.0

0

100

200

300 400 OS (days)

500

600

700

Figure 2. Kaplan–Meier estimates of overall survival (OS) in (A) low-risk and (B) high-risk patients treated with either intensive chemotherapy, lowdose cytarabine (LD AC), or best supportive care (log-rank test). (A) In low-risk patients, the duration of OS was not significantly different among the three treatment groups. (B) In high-risk patients, those receiving chemotherapy had better survival than those given best supportive care. However, the difference in OS duration was not statistically significant between intensive treatment arm and low-dose therapy arm. C/T, chemotherapy.

studies almost automatically categorize patients into intermediate- or high-risk groups. If we take a closer look at some large trials of elderly AML, the difference of clinical outcome between patients within the two groups is actually not as great as that between patients with favorable and intermediate cytogenetics [11, 29, 30]. The prognostic stratification of karyotyping would therefore not be as important in elderly AML patients as it is in the young. From our results, we believe that old-age patients with AML should not be excluded from receiving standard chemotherapy. There is a fair chance of these patients achieving CR, which could be translated into probably improved quality of life and, in high-risk patients, prolonged OS. However, for those entering CR, more effective post-remission chemotherapy might be

warranted to better improve their chance of long-term survival. With the advent and progress of newer therapeutic modalities such as non-myeloablative stem cell transplantation and target therapies, it is hopeful that safer and more effective consolidation therapy for elderly AML patients in CR status could emerge and drastically improve their clinical outcome. In conclusion, poor PS, elevated serum LDH level more than 2 normal, presence of comorbidity, extreme leukocytosis and marked thrombocytopenia are pretreatment poor prognostic indicators for AML patients aged 65 years or older. Induction chemotherapy with anthracycline-based standard regimen is the best therapeutic option for elderly AML patients, as it would result in higher CR rate for them, and prolong OS in the high-risk subpopulation.

Downloaded from http://annonc.oxfordjournals.org/ at Ritsumeikan University on June 10, 2015

0.0

1373

References 16.

17.

18.

19.

20. 21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

Downloaded from http://annonc.oxfordjournals.org/ at Ritsumeikan University on June 10, 2015

1. Rathnasabapathy R, Lancet JE. Management of acute myelogenous leukemia in the elderly. Cancer Control 2003; 10: 469– 477. 2. Brincker H. Estimate of overall treatment results in acute nonlymphocytic leukemia based on age-specific rates of incidence and of complete remission. Cancer Treat Rep 1985; 69: 5–11. 3. Anderson JE, Kopecky KJ, Willman CL et al. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood 2002; 100: 3869–3876. 4. Dombret H, Chastang C, Fenaux P et al. A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 1995; 332: 1678–1683. 5. Godwin JE, Kopecky KJ, Head DR et al. A double-blind placebocontrolled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (9031). Blood 1998; 91: 3607– 3615. 6. Lowenberg B, Suciu S, Archimbaud E et al. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy—the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol 1998; 16: 872– 881. 7. Hiddemann W, Kern W, Schoch C et al. Management of acute myeloid leukemia in elderly patients. J Clin Oncol 1999; 17: 3569–3576. 8. Harousseau JL. Acute myeloid leukemia in the elderly. Blood Rev 1998; 12: 145– 153. 9. Leith CP, Kopecky KJ, Godwin J et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997; 89: 3323–3329. 10. Hamblin TJ. Disappointments in treating acute leukemia in the elderly. N Engl J Med 1995; 332: 1712– 1713. 11. 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. 12. Estey EH. How I treat older patients with AML. Blood 2000; 96: 1670–1673. 13. Mayer RJ, Davis RB, Schiffer CA et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994; 331: 896–903. 14. Pinto A, Zagonel V, Ferrara F. Acute myeloid leukemia in the elderly: biology and therapeutic strategies. Crit Rev Oncol Hematol 2001; 39: 275– 287. 15. Rowe JM, Neuberg D, Friedenberg W et al. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults

with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood 2004; 103: 479–485. Bennett JM, Catovsky D, Daniel MT et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103: 620–625. Slovak ML, Kopecky KJ, Cassileth PA et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075–4083. Cheson BD, Cassileth PA, Head DR et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990; 8: 813–819. Lowenberg B, Zittoun R, Kerkhofs H et al. On the value of intensive remission-induction chemotherapy in elderly patients of 65 + years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol 1989; 7: 1268–1274. Harousseau JL. Acute myeloid leukemia in the elderly. Blood Rev 1998; 12: 145–153. DeLima M, Ghaddar H, Pierce S, Estey E. Treatment of newlydiagnosed acute myelogenous leukaemia in patients aged 80 years and above. Br J Haematol 1996; 93: 89– 95. Vey N, Coso D, Bardou VJ et al. The benefit of induction chemotherapy in patients age > or = 75 years. Cancer 2004; 101: 325–331. Ferrara F, Mirto S, Serum LDH. value as a predictor of clinical outcome in acute myelogenous leukaemia of the elderly. Br J Haematol 1996; 92: 627–631. Geller RB, Zahurak M, Hurwitz CA et al. Prognostic importance of immunophenotyping in adults with acute myelocytic leukaemia: the significance of the stem-cell glycoprotein CD34 (My10). Br J Haematol 1990; 76: 340 –347. Goldstone AH, Burnett AK, Wheatley K et al. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 2001; 98: 1302–1311. Grimwade D, Walker H, Oliver F et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998; 92: 2322–2333. Mayer RJ, Davis RB, Schiffer CA et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994; 331: 896 –903. Schiller G, Lee M. Long-term outcome of high-dose cytarabinebased consolidation chemotherapy for older patients with acute myelogenous leukemia. Leuk Lymphoma 1997; 25: 111–119. Wahlin A, Markevarn B, Golovleva I, Nilsson M. Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia. Br J Haematol 2001; 115: 25–33. Buchner T, Urbanitz D, Hiddemann W et al. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol 1985; 3: 1583–1589.