Original Paper Acta Haematol 2015;133:300–309 DOI: 10.1159/000362777
Received: December 3, 2013 Accepted after revision: April 9, 2014 Published online: December 2, 2014
Selection of Elderly Acute Myeloid Leukemia Patients for Intensive Chemotherapy: Effectiveness of Intensive Chemotherapy and Subgroup Analysis Dae Sik Kim a Ka Won Kang a Eun Sang Yu a Hong Jun Kim a Jung Sun Kim a Se Ryeon Lee a Yong Park a Hwa Jung Sung a Soo Young Yoon b Chul Won Choi a Byung Soo Kim a a
Division of Oncology and Hematology, Department of Internal Medicine, and b Department of Laboratory Medicine, Korea University Medical Center, Seoul, South Korea
Abstract Background: Despite the advances in acute myeloid leukemia (AML) treatment, the prognosis of elderly patients remains poor and no definitive treatment guideline has been established. In the present study, we aimed to evaluate the effectiveness of intensive chemotherapy in elderly AML patients and to determine which subgroup of patients would be most responsive to the therapy. Methods: We retrospectively analyzed 84 elderly patients: 35, 19, and 30 patients were administered intensive chemotherapy, low-dose chemotherapy, and supportive care, respectively. Results: Among those who received intensive chemotherapy, there were 17 cases of remission after induction chemotherapy; treatment-related mortality was 22.9%. The median overall survival was 7.9 months. Multivariate analysis indicated that the significant prognostic factors for overall survival were performance status, fever before treatment, platelet count, blast count, cytogenetic risk category, and intensive chemotherapy. Subgroup analysis showed that intensive chemotherapy was markedly effective in the relatively younger pa-
© 2014 S. Karger AG, Basel 0001–5792/14/1333–0300$39.50/0 E-Mail [email protected] www.karger.com/aha
tients (65–70 years) and those with de novo AML, better-tointermediate cytogenetic risk, no fever before treatment, high albumin levels, and high lactate dehydrogenase levels. Conclusions: Elderly AML patients had better outcomes with intensive chemotherapy than with low-intensity chemotherapy. Thus, appropriate subgroup selection for intensive chemotherapy is likely to improve therapeutic outcome. © 2014 S. Karger AG, Basel
Introduction
Acute myeloid leukemia (AML) is the most common type of adult leukemia. AML generally has a poor prognosis, and the only curative treatment is intensive chemotherapy. However, treatment-related mortality and the risk of complications are very high, which limits the therapeutic options. The proportion of elderly AML patients (i.e. ≥65 years of age) has increased over time because both the prevalence and median age of AML patients have increased [1]. Furthermore, the incidence of AML increases with age; the median age at diagnosis was 67 years in the USA [2]. Approximately 45.9 and 54.1% of AML patients are diagnosed at 1 × 109/l and >100 × 109/l, respectively, and 5% residual bone marrow blasts after induction therapy who survived 60 days after induction therapy were considered to have experienced induction failure. Early death was defined as death from any cause within 60 days from the first day of treatment.
Patients We retrospectively analyzed 84 patients aged ≥65 years with newly diagnosed AML who were treated at the Korea University Medical Center between January 2003 and April 2012. AML was defined as the presence of >20% bone marrow myeloblasts according to the World Health Organization (WHO) classification, and additional morphological, immunohistochemical and cytogenetic analyses were performed by a specialist from the Department of Laboratory Medicine. Patients with therapy-related AML, AML with myelodysplasia-related changes, and de novo AML were also included. Patients with acute promyelocytic leukemia were excluded because of the differences in treatment and prognosis. The patients were divided into 3 risk groups on the basis of
Statistical Analysis All analyses were performed using the IBM Statistical Package for Social Sciences (SPSS) version 20.0. Differences in variables between the 3 groups were compared by the Kruskal-Wallis test. Overall survival was calculated by the Kaplan-Meier method and compared by the log-rank test. Univariate analyses of prognostic factors were performed using the log-rank test with the following variables: sex, age, performance status, Charlson risk index, prior heart disease, hemoglobin, white blood cell (WBC) count, blast count, platelet count, presence/absence of fever before treatment, CRP levels, LDH levels, bone marrow fibrosis, WHO classification, cytogenetic risk category, and type of induction treatment. Factors showing a significant effect in the univariate analysis were entered into the multivariate analysis. The Cox proportional hazards method was used for multivariate analysis and included sex, age, performance status, comorbidities, WBC count, blast count, plate-
Elderly AML Patients for Intensive Chemotherapy
Acta Haematol 2015;133:300–309 DOI: 10.1159/000362777
Patients and Methods
301
Downloaded by: University of Tokyo 157.82.153.40 - 5/22/2015 2:56:24 PM
spectively [2]. During the past 50 years, the number of patients aged ≥65 and ≥85 years has doubled and more than quadrupled, respectively [1, 3]. However, elderly AML patients have a poorer prognosis than younger AML patients [4, 5]. This is thought to be due to advanced age itself as well as increased incidences of unfavorable prognostic factors, poor performance status, increased organ dysfunction and comorbidities, unfavorable karyotype, and secondary AML. Cytarabine and anthracycline combination therapy has been the standard induction chemotherapy for decades. However, many elderly AML patients have been treated with conservative management or low-intensity chemotherapy and not with intensive chemotherapy owing to the poor response to intensive chemotherapy and high incidences of complications and mortality. Low-intensity treatments involving subcutaneous cytarabine, 5-azacytidine, and decitabine do not confer any overall survival benefit, and the complete remission rate remains low [4–8]. Clofarabine is considered an intermediate-intensity treatment option for elderly AML patients, but no large-scale randomized phase III trial has been performed [9]. Some studies have reported the outcomes of intensive chemotherapy in elderly AML patients and demonstrated that elderly AML patients have a low complete response (CR) rate, short overall survival, and a high mortality rate [10–13]. Therefore, the treatment of elderly AML patients is generally decided on a patient-specific basis. Furthermore, no definitive treatment guideline has been established. In the present study, we aimed to evaluate the efficacy of intensive chemotherapy for elderly AML patients and identified prognostic factors. Subgroup analysis was also performed to identify which patients would benefit most from intensive chemotherapy.
Table 1. Patient demographics and baseline characteristics
Patients Age, years Median Range Sex Male Female ECOG PS 0–1 2–4 Charlson risk index 0 points ≥1 points Heart disease No Yes WHO classification De novo Secondary Cytogenetic riskc category Better to intermediate Poor Fever at diagnosis No Yes Fibrosis No Yes
Total
Supportive care group
Low-dose chemo- Intensive chemo- p value therapy group therapy group
84
30 (35.7)
19 (22.6)
35 (41.7)
71 65 – 82
72 66 – 79
75 66 – 82
69 65 – 81
49 (58.3) 35 (41.7)
16 (53.3) 14 (46.7)
10 (52.6) 9 (47.4)
23 (65.7) 12 (34.3)
34 (40.5) 50 (59.5)
6 (20) 24 (80)
7 (36.8) 12 (63.2)
21 (60) 14 (40)
41 (48.8) 43 (51.2)
14 (46.7) 16 (53.3)
7 (36.8) 12 (63.2)
20 (57.1) 15 (42.9)
75 (89.3) 9 (10.7)
27 (90) 3 (10)
17 (89.5) 2 (10.5)
29 (87.9) 4 (12.1)
0.003a 0.306b 0.001b 0.379b 0.853b 0.351b 69 (82.1) 15 (17.9)
23 (76.7) 7 (23.3)
16 (84.2) 3 (15.8)
30 (85.7) 5 (14.3) 0.521b
63 (75) 21 (25)
22 (73.3) 8 (26.7)
13 (68.4) 6 (31.6)
28 (80) 7 (20) 0.127b
49 (58.3) 35 (41.7)
14 (46.7) 16 (53.3)
12 (63.2) 7 (36.8)
23 (65.7) 12 (34.3)) 0.713b
62 (73.8) 22 (26.2)
22 (73.3) 8 (26.7)
13 (68.4) 6 (31.6)
27 (77.1) 8 (22.9)
Values are numbers of patients with percentages in parentheses unless otherwise indicated. Low-dose chemotherapy: cytarabine (20 mg/day subcutaneously for 21 days); intensive chemotherapy: idarubicin (12 mg/m2/day, intravenous bolus for 3 days) and cytarabine (100 mg/m2/day, continuous intravenous infusion for 7 days). PS = Performance status. a Kruskal-Wallis test. b Linear-by-linear association. c Cytogenetic risk: better: inv(16) or t(16;16), t(8;21), t(15;17); intermediate: normal, +8 alone, t(9;11), others; poor: complex (≥3 clonal chromosomal abnormalities), monosomal karyotype, –5, 5q–, –7, 7q–, 11q23–non t(9:11), inv(3), t(3;3), t(6;9), t(9;22).
Results
Patient Characteristics In total, 84 patients were analyzed. The median age was 71 years (range 65–82); 23% of patients were aged ≥75 years. The patients were divided into 3 treatment groups: patients who received intensive chemotherapy 302
Acta Haematol 2015;133:300–309 DOI: 10.1159/000362777
(i.e. idarubicin plus cytarabine), patients who received low-dose chemotherapy (i.e. low-dose cytarabine), and patients who received best supportive care. There were no significant differences between the 3 groups in any of the variables except for age and performance status. Patients in the intensive chemotherapy group were relatively younger and had better performance status. The Charlson risk index was applied to estimate the comorbidities [14]. According to the Charlson risk index, a greater proportion of the intensive chemotherapy group was classified as low risk, but there were no significant differences between the 3 groups. The presence of heart disease, Kim /Kang /Yu /Kim /Kim /Lee /Park / Sung /Yoon /Choi /Kim
Downloaded by: University of Tokyo 157.82.153.40 - 5/22/2015 2:56:24 PM
let count, presence/absence of fever before treatment, CRP levels, WHO classification, and cytogenetic risk category. The level of significance was set at p < 0.05.
Table 2. Baseline laboratory results
Total
Supportive care Low-dose chemo- Intensive chemo- p value group therapy group therapy group
44 (52.4) 40 (47.6)
19 (63.3) 11 (36.7)
10 (52.6) 9 (47.4)
15 (42.9) 20 (57.1)
46 (54.8) 38 (45.2)
19 (63.3) 11 (36.7)
11 (57.9) 8 (42.1)
16 (45.7) 19 (54.3)
0.101a
Hb
Received: December 3, 2013 Accepted after revision: April 9, 2014 Published online: December 2, 2014
Selection of Elderly Acute Myeloid Leukemia Patients for Intensive Chemotherapy: Effectiveness of Intensive Chemotherapy and Subgroup Analysis Dae Sik Kim a Ka Won Kang a Eun Sang Yu a Hong Jun Kim a Jung Sun Kim a Se Ryeon Lee a Yong Park a Hwa Jung Sung a Soo Young Yoon b Chul Won Choi a Byung Soo Kim a a
Division of Oncology and Hematology, Department of Internal Medicine, and b Department of Laboratory Medicine, Korea University Medical Center, Seoul, South Korea
Abstract Background: Despite the advances in acute myeloid leukemia (AML) treatment, the prognosis of elderly patients remains poor and no definitive treatment guideline has been established. In the present study, we aimed to evaluate the effectiveness of intensive chemotherapy in elderly AML patients and to determine which subgroup of patients would be most responsive to the therapy. Methods: We retrospectively analyzed 84 elderly patients: 35, 19, and 30 patients were administered intensive chemotherapy, low-dose chemotherapy, and supportive care, respectively. Results: Among those who received intensive chemotherapy, there were 17 cases of remission after induction chemotherapy; treatment-related mortality was 22.9%. The median overall survival was 7.9 months. Multivariate analysis indicated that the significant prognostic factors for overall survival were performance status, fever before treatment, platelet count, blast count, cytogenetic risk category, and intensive chemotherapy. Subgroup analysis showed that intensive chemotherapy was markedly effective in the relatively younger pa-
© 2014 S. Karger AG, Basel 0001–5792/14/1333–0300$39.50/0 E-Mail [email protected] www.karger.com/aha
tients (65–70 years) and those with de novo AML, better-tointermediate cytogenetic risk, no fever before treatment, high albumin levels, and high lactate dehydrogenase levels. Conclusions: Elderly AML patients had better outcomes with intensive chemotherapy than with low-intensity chemotherapy. Thus, appropriate subgroup selection for intensive chemotherapy is likely to improve therapeutic outcome. © 2014 S. Karger AG, Basel
Introduction
Acute myeloid leukemia (AML) is the most common type of adult leukemia. AML generally has a poor prognosis, and the only curative treatment is intensive chemotherapy. However, treatment-related mortality and the risk of complications are very high, which limits the therapeutic options. The proportion of elderly AML patients (i.e. ≥65 years of age) has increased over time because both the prevalence and median age of AML patients have increased [1]. Furthermore, the incidence of AML increases with age; the median age at diagnosis was 67 years in the USA [2]. Approximately 45.9 and 54.1% of AML patients are diagnosed at 1 × 109/l and >100 × 109/l, respectively, and 5% residual bone marrow blasts after induction therapy who survived 60 days after induction therapy were considered to have experienced induction failure. Early death was defined as death from any cause within 60 days from the first day of treatment.
Patients We retrospectively analyzed 84 patients aged ≥65 years with newly diagnosed AML who were treated at the Korea University Medical Center between January 2003 and April 2012. AML was defined as the presence of >20% bone marrow myeloblasts according to the World Health Organization (WHO) classification, and additional morphological, immunohistochemical and cytogenetic analyses were performed by a specialist from the Department of Laboratory Medicine. Patients with therapy-related AML, AML with myelodysplasia-related changes, and de novo AML were also included. Patients with acute promyelocytic leukemia were excluded because of the differences in treatment and prognosis. The patients were divided into 3 risk groups on the basis of
Statistical Analysis All analyses were performed using the IBM Statistical Package for Social Sciences (SPSS) version 20.0. Differences in variables between the 3 groups were compared by the Kruskal-Wallis test. Overall survival was calculated by the Kaplan-Meier method and compared by the log-rank test. Univariate analyses of prognostic factors were performed using the log-rank test with the following variables: sex, age, performance status, Charlson risk index, prior heart disease, hemoglobin, white blood cell (WBC) count, blast count, platelet count, presence/absence of fever before treatment, CRP levels, LDH levels, bone marrow fibrosis, WHO classification, cytogenetic risk category, and type of induction treatment. Factors showing a significant effect in the univariate analysis were entered into the multivariate analysis. The Cox proportional hazards method was used for multivariate analysis and included sex, age, performance status, comorbidities, WBC count, blast count, plate-
Elderly AML Patients for Intensive Chemotherapy
Acta Haematol 2015;133:300–309 DOI: 10.1159/000362777
Patients and Methods
301
Downloaded by: University of Tokyo 157.82.153.40 - 5/22/2015 2:56:24 PM
spectively [2]. During the past 50 years, the number of patients aged ≥65 and ≥85 years has doubled and more than quadrupled, respectively [1, 3]. However, elderly AML patients have a poorer prognosis than younger AML patients [4, 5]. This is thought to be due to advanced age itself as well as increased incidences of unfavorable prognostic factors, poor performance status, increased organ dysfunction and comorbidities, unfavorable karyotype, and secondary AML. Cytarabine and anthracycline combination therapy has been the standard induction chemotherapy for decades. However, many elderly AML patients have been treated with conservative management or low-intensity chemotherapy and not with intensive chemotherapy owing to the poor response to intensive chemotherapy and high incidences of complications and mortality. Low-intensity treatments involving subcutaneous cytarabine, 5-azacytidine, and decitabine do not confer any overall survival benefit, and the complete remission rate remains low [4–8]. Clofarabine is considered an intermediate-intensity treatment option for elderly AML patients, but no large-scale randomized phase III trial has been performed [9]. Some studies have reported the outcomes of intensive chemotherapy in elderly AML patients and demonstrated that elderly AML patients have a low complete response (CR) rate, short overall survival, and a high mortality rate [10–13]. Therefore, the treatment of elderly AML patients is generally decided on a patient-specific basis. Furthermore, no definitive treatment guideline has been established. In the present study, we aimed to evaluate the efficacy of intensive chemotherapy for elderly AML patients and identified prognostic factors. Subgroup analysis was also performed to identify which patients would benefit most from intensive chemotherapy.
Table 1. Patient demographics and baseline characteristics
Patients Age, years Median Range Sex Male Female ECOG PS 0–1 2–4 Charlson risk index 0 points ≥1 points Heart disease No Yes WHO classification De novo Secondary Cytogenetic riskc category Better to intermediate Poor Fever at diagnosis No Yes Fibrosis No Yes
Total
Supportive care group
Low-dose chemo- Intensive chemo- p value therapy group therapy group
84
30 (35.7)
19 (22.6)
35 (41.7)
71 65 – 82
72 66 – 79
75 66 – 82
69 65 – 81
49 (58.3) 35 (41.7)
16 (53.3) 14 (46.7)
10 (52.6) 9 (47.4)
23 (65.7) 12 (34.3)
34 (40.5) 50 (59.5)
6 (20) 24 (80)
7 (36.8) 12 (63.2)
21 (60) 14 (40)
41 (48.8) 43 (51.2)
14 (46.7) 16 (53.3)
7 (36.8) 12 (63.2)
20 (57.1) 15 (42.9)
75 (89.3) 9 (10.7)
27 (90) 3 (10)
17 (89.5) 2 (10.5)
29 (87.9) 4 (12.1)
0.003a 0.306b 0.001b 0.379b 0.853b 0.351b 69 (82.1) 15 (17.9)
23 (76.7) 7 (23.3)
16 (84.2) 3 (15.8)
30 (85.7) 5 (14.3) 0.521b
63 (75) 21 (25)
22 (73.3) 8 (26.7)
13 (68.4) 6 (31.6)
28 (80) 7 (20) 0.127b
49 (58.3) 35 (41.7)
14 (46.7) 16 (53.3)
12 (63.2) 7 (36.8)
23 (65.7) 12 (34.3)) 0.713b
62 (73.8) 22 (26.2)
22 (73.3) 8 (26.7)
13 (68.4) 6 (31.6)
27 (77.1) 8 (22.9)
Values are numbers of patients with percentages in parentheses unless otherwise indicated. Low-dose chemotherapy: cytarabine (20 mg/day subcutaneously for 21 days); intensive chemotherapy: idarubicin (12 mg/m2/day, intravenous bolus for 3 days) and cytarabine (100 mg/m2/day, continuous intravenous infusion for 7 days). PS = Performance status. a Kruskal-Wallis test. b Linear-by-linear association. c Cytogenetic risk: better: inv(16) or t(16;16), t(8;21), t(15;17); intermediate: normal, +8 alone, t(9;11), others; poor: complex (≥3 clonal chromosomal abnormalities), monosomal karyotype, –5, 5q–, –7, 7q–, 11q23–non t(9:11), inv(3), t(3;3), t(6;9), t(9;22).
Results
Patient Characteristics In total, 84 patients were analyzed. The median age was 71 years (range 65–82); 23% of patients were aged ≥75 years. The patients were divided into 3 treatment groups: patients who received intensive chemotherapy 302
Acta Haematol 2015;133:300–309 DOI: 10.1159/000362777
(i.e. idarubicin plus cytarabine), patients who received low-dose chemotherapy (i.e. low-dose cytarabine), and patients who received best supportive care. There were no significant differences between the 3 groups in any of the variables except for age and performance status. Patients in the intensive chemotherapy group were relatively younger and had better performance status. The Charlson risk index was applied to estimate the comorbidities [14]. According to the Charlson risk index, a greater proportion of the intensive chemotherapy group was classified as low risk, but there were no significant differences between the 3 groups. The presence of heart disease, Kim /Kang /Yu /Kim /Kim /Lee /Park / Sung /Yoon /Choi /Kim
Downloaded by: University of Tokyo 157.82.153.40 - 5/22/2015 2:56:24 PM
let count, presence/absence of fever before treatment, CRP levels, WHO classification, and cytogenetic risk category. The level of significance was set at p < 0.05.
Table 2. Baseline laboratory results
Total
Supportive care Low-dose chemo- Intensive chemo- p value group therapy group therapy group
44 (52.4) 40 (47.6)
19 (63.3) 11 (36.7)
10 (52.6) 9 (47.4)
15 (42.9) 20 (57.1)
46 (54.8) 38 (45.2)
19 (63.3) 11 (36.7)
11 (57.9) 8 (42.1)
16 (45.7) 19 (54.3)
0.101a
Hb
