1Department of Internal Medicine, Inha University Hospital, Inha University, Incheon, Korea.
2Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea.
3Department of Internal Medicine, Hallym University Medical Center, Hallym University, Anyang, Korea.
4Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University, Bucheon, Korea.
5Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon, Korea.
The clinical characteristics of elderly patients with AML differ from those of younger patients, resulting in poorer survival and treatment outcomes. We analyzed retrospectively the clinical data of AML patients 65 years old and above to describe patients' characteristics and treatment patterns, and to define meaningful prognostic factors of survival in the Korean population.
Basic patients' characteristics, clinical outcomes according to treatments, and prognostic factors associated with survival and treatment intensity were examined in a total of 168 patients diagnosed in 5 institutes between 1996 and 2012 as having AML.
Herein, 84 patients (50.0%) received high-intensity regimens (HIR), 18 (10.7%) received low-intensity regimens (LIR), and 66 (39.3%) received supportive care (SC) only. The median survival of all patients was 4.5 months; and median survival times with HIR, LIR, and SC were 6.8 months, 10.2 months, and 1.6 months, respectively. Median survival times with HIR and LIR were significantly longer than that with SC (
Even in elderly AML patients, an intensive treatment regimen could be beneficial with careful patient selection. Further prospective studies designed to identify specific prognostic factors are required to establish an optimal treatment strategy for elderly AML patients.
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The median age of patients is 65-70 years of at diagnosis . Intensive treatments such as high-dose chemotherapy and hematopoietic stem cell transplantation are effective in improving the survival of these patients . However, many patients are not eligible for these treatments owing to their advanced age, poor performance, or comorbidity. Furthermore, factors negatively influencing treatment outcomes, including adverse cytogenetic and molecular aberrations, antecedent hematologic disorders, and the incidence of fatal infection or bleeding, are more frequent in old age . As a result, the prognosis of elderly AML patients is very poor even with intensive treatment [3, 4, 5, 6, 7].
For these reasons, studies have been performed to identify optimal patient characteristics and optimal treatment regimens in elderly patients with AML. Specific parameters including clinical manifestations, laboratory values, and molecular and genetic markers have been suggested as prognostic or predictive factors .
In this study, we analyzed the clinical characteristics, treatment patterns, and outcomes of elderly AML patients (65 years old and above) treated at 5 Korean healthcare facilities. Prognostic factors were also analyzed to define the relationship among clinical parameters, treatment patterns, and patient survival.
Patients who were at least 65 years old and were diagnosed with AML between 1996 and 2012 were included in this study. Five institutes located in Gyeonggi province and Incheon city, Korea participated in this study, and a total of 168 cases were analyzed. The following clinical parameters were included in the analysis: age, gender, antecedent hematologic disorder, cytogenetic risk group classified according to the Southwest Oncology Group and Medical Research Council (SWOG/MRC) criteria, Eastern Cooperative Oncology Group (ECOG) performance status (ECOG-PS), Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), common blood cell count (CBC) test, lactate dehydrogenase (LDH), C-reactive protein (CRP), bone marrow (BM) blast percent, and other laboratory values that have been referred to as prognostic factors in past studies.
Treatment patterns were divided into 3 groups: high-intensity regimen (HIR), low-intensity regimen (LIR), and supportive care (SC) groups. Treatment for the HIR group consisted of anthracycline, high dose cytarabine and fludarabine; treatment for the LIR group consisted of low dose cytarabine, hypomethylating agent, arsenic trioxide and All-trans retinoic acid; and the treatment for the SC group included hydroxyurea or no active treatment.
Response criteria defined by the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in AML were used in this study .
Multivariate analyses of survival were performed using the Cox proportional hazard model. Overall survival (OS) was calculated by Kaplan-Meier survival curves and survival differences between subgroups were compared using log rank test. Independent-samples T test, chi-square test, and likelihood ratio test for trend were used to define the difference in clinical factors among the treatment groups. Statistical analysis was performed using the SPSS statistical software package (SPSS Inc., Chicago, IL).
Of the total of 168 patients, the number of male and female patients was 85 and 83, respectively. The median age was 70 years, and most patients had
Half of the patients (N=84, 50%) were treated with a HIR, and cytarabine with idarubicin was used mostly (N=76, 90.5%) among these patients. Further, 18 patients (10.7%) belonged to the LIR group and 66 patients (39.3%) to the SC group (Table 2). The response rate in the HIR group was 58.4% (N=49), with complete remission (CR) in 42.9% and partial remission (PR) in 15.5% of the patients. The response rate in the LIR group was 33.3% (CR: 5.6%, PR: 27.8%). Only 3 patients in the SC group achieved PR (Table 3). Response rates in the favorable, intermediate, and unfavorable cytogenetic risk groups were 30% (CR: 20%, PR: 10%), 35.8% (CR: 22.6%, PR: 13.2%), and 34.4% (CR: 21.8%, PR: 12.5%), respectively.
The median survival of all patients was 4.5 months (95% CI: 2.4-6.7 months) (Fig. 1A). Median survival rates in the favorable, intermediate, and unfavorable cytogenetic risk groups were 4.1 months (95% CI: 0.8-9.7 months), 5.0 months (95% CI: 1.6-8.4 months), and 4.5 months (95% CI: 2.4-6.7 months), respectively. There was no significant difference in the survival rates among the cytogenetic risk groups (
Multivariate analysis with age, ECOG-PS, risk group, HCT-CI, CBC count, creatinine (Cr) level, LDH level, CRP level, and BM blast percent was performed for all patients in each treatment group. Age over 70 years, ECOG-PS, Hb level, and Cr level were proven to be significant prognostic factors of survival for all patients (Table 4). ECOG-PS, Hb level, and CRP level were revealed as significant prognostic factors of survival in the HIR group (Table 5).
Improvement of survival due to advances in supportive care, chemotherapy regimens, and transplantation techniques has been observed in AML patients . However, elderly AML patients show poor prognosis because of characteristics associated with their age. Characteristics such as fragile medical condition leading to the restriction of active treatments, a higher incidence of treatment-related mortality, and a higher proportion of patients in the high-risk group, including those with high-risk cytogenetic or genetic profiles who may be refractory to treatment, were suggested as the causes of poor clinical outcomes in elderly AML patients . Survival of elderly AML patients has been reported to be only several months [3, 4, 5, 6, 7]. In our study, the median survival of elderly AML patients was 4.5 months, which was a result comparable to those obtained in other studies.
In this study, the median survival in the HIR and LIR groups was significantly longer than that in the SC group among all patients and in the intermediate-risk group. This significant difference among treatment groups was consistently observed even when meaningful prognostic factors such as ECOG-PS, Hb level, and CRP level were forced into the model (
Various prognostic or predictive models for elderly AML patients have been suggested to better predict clinical outcomes. Many factors, including age, PS, comorbidity, antecedent hematologic disorders, adverse cytogenetics, LDH level, blood cell counts, liver or kidney function, other laboratory values, and genetic profiles, have been reported as meaningful prognostic or predictive factors . In our multivariate analysis, age, ECOG-PS, Hb level, and Cr level were defined as prognostic factors (Table 4). Because of the higher incidence of treatment-related mortality in elderly AML patients, selecting the optimal treatment intensity is of primary importance in improving clinical outcomes. Intensive treatment could be helpful for selecting patients who are expected to tolerate it. In our study, ECOG-PS, Hb level, and CRP level were suggested to be prognostic factors for the outcomes of intensive treatment (Table 5). However, although other studies have shown significant differences among the survival of general AML patients classified into different cytogenetic risk groups according to the SWOG/MRC criteria, such differences were not observed (
Several phase III trials of intensive chemotherapy given to elderly AML patients reported CR rates of 30-50% after induction of treatment [9, 10, 11]. In our study, CR rate was 42.9% and the response rate was 58.4% in the HIR group. The patients with CR in this group had longer survival than non-CR patients (16.3 months vs. 3.2 months, respectively,
Even though this study has the limitation of a retrospective study, the results are worthy of notice. This study reports the practical aspects of treatment patterns and outcomes in elderly AML patients in 5 Korean institutes. It shows that clinical characteristics and outcomes in the Korean patients are similar to those in patients of western countries, and highlights the role of the same meaningful prognostic factors such as age, ECOG-PS, Hb level, Cr level, and CRP level. It also suggests that careful selection of patients receiving intensive chemotherapy could bring about better outcomes in elderly AML patients.
In the high-intensity regimen group, survival of the patients showing complete remission (CR) was significantly longer than that of patients who did not show CR (non-CR) (