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 and J.-P. Gau2,*

1 Division of Hematology Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi 2 Division of Hematology, Department of Medicine, 3 Department of Pathology, 4 Division of Oncology, Department of Medicine and 5 Division of Transfusion Medicine, Department of Medicine, Taipai Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan

* 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; Email: jpgau{at}vghtpe.gov.tw


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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 comorbidities, elevated serum lactate dehydrogenase level (≥2x upper normal limit), extreme leukocytosis (≥100 x 109/l) and marked thrombocytopenia (≤20 x 109/l). Age was not an independent 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Acute myeloid leukemia (AML) occurs predominately in adults, and it afflicts the elderly more frequently than the young [1Go]. Epidemiologic surveillance shows that more than half of patients with AML are older than 60 years [2Go]. 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 [3Go–6Go]. However, with the selected nature of patients who enter trials, old-age patients constitute only roughly one-third of the total study population in large clinical trials of AML [7Go]. 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 patients [8Go–10Go]. 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 [9Go, 11Go]. Moreover, the adverse prognosis of AML in the elderly is also somewhat attributable to host-related factors that come with aging [7Go, 9Go, 12Go], and older patients may be less intensively treated compared with younger patients [13Go]. 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) [9Go, 12Go, 14Go]. Most of the prognostic 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 [11Go, 12Go]. 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 [15Go].

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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 [16Go] 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 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 [17Go]. Dyspoiesis was defined as 50% or more of the cells in any of the myeloid lineages being dysplastic in a pretreatment sample.

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 (>2x normal) and/or total bilirubin (≥2 mg/dl, with a predominance of 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.

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 [18Go]. Patients who failed to achieve CR after induction chemotherapy were classified according to types of failure: resistant disease, death during aplasia or indeterminate [18Go]. 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.

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
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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 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).


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Table 1. Patients’ characteristics

 
Treatment and CR rate
About one-third of patients received best supportive care only (n=69; 33.7%). Forty-nine patients (23.9%) underwent low-dose 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
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 PS score [PS ≥2 versus <2: hazard ratio (HR) 1.818; P=0.000), extreme leukocytosis (white blood cell count ≥100 x 109/l versus <10 x 109/l: HR 4.146; P=0.000), marked thrombocytopenia (platelets ≤20 x 109/l versus >20 x 109/l: HR 1.493; P=0.024), elevated lactate dehydrogenase (LDH) level (>2 x normal versus less: HR 1.499; P=0.033) and presence of comorbidities (at least one versus nil: HR 1.615; P=0.006).


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Table 2. Univariate analysis of prognostic factors affecting overall survival

 

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

 
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 high-risk 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).



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

 
Treatment and outcome for patients in the low-risk group
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, the duration of OS was independent of the type of management selected (Figure 2A, log-rank test).



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Figure 2. Kaplan–Meier estimates of overall survival (OS) in (A) low-risk and (B) high-risk patients treated with either intensive chemotherapy, low-dose 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.

 
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 low-dose 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 non-significant (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).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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 [19Go]. 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 decision [7Go, 20Go]. 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 [21Go]. On the other hand, Vey et al. [22Go] 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.

Other than the age factor, the clinical parameters identified here as poor risk indicators for old-age AML patients concur with various previous reports [3Go, 23Go–25Go]. 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 [11Go, 26Go]. 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 high-dose cytarabine as consolidation treatment [27Go, 28Go].

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 [9Go, 11Go, 29Go]. 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 [7Go, 11Go, 15Go, 29Go]. This could help explain the poor outcome of AML in the elderly population. Nevertheless, this would also mean the results of cytogenetic 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 [11Go, 29Go, 30Go]. 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 2x 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.

Received for publication January 10, 2005. Revision received April 28, 2005. Accepted for publication April 29, 2005.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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