Int J Hematol (2014) 100:141–151 DOI 10.1007/s12185-014-1617-8
ORIGINAL ARTICLE
Role of induction and consolidation chemotherapy in elderly acute myeloid leukemia patients Soo-Jeong Kim • June-Won Cheong • Dae-Young Kim • Je-Hwan Lee • Kyoo-Hyung Lee Yeo-Kyeoung Kim • Hyeong-Joon Kim • Ik-Chan Song • Deog-Yeon Jo • Jeong-Ok Lee • Soo-Mee Bang • Jinny Park • Jae Hoon Lee • Won-Sik Lee • Young-Don Joo • Chi Hoon Maeng • Hwi-Joong Yoon • Na-Ri Lee • Jae-Yong Kwak • Kyoung Ha Kim • Jong-Ho Won • Bo Ram Han • Dae Young Zang • Joon Ho Moon • Sang Kyun Sohn • Sung Hwa Bae • Hun Mo Ryoo • Sung-Yong Kim • Mark Hong Lee • Yoo Hong Min • The Korean Society of Hematology AML/MDS Working Party
•
Received: 12 January 2014 / Revised: 9 June 2014 / Accepted: 10 June 2014 / Published online: 5 July 2014 Ó The Japanese Society of Hematology 2014
Abstract The present study sought to elucidate the role of induction and consolidation therapy in elderly patients. We retrospectively collected data of 477 patients who were aged over 60 years at the time of acute myeloid leukemia (AML) diagnosis. The median overall survival (OS) was 339 days in the induction group (n = 266) and 86 days in the best supportive care group (n = 211) (P \ 0.001). In the induction group, the complete remission (CR) rate was 58.3 %, and treatment-related death was 15.4 %. Successful induction was related to good performance [Eastern
Cooperative Oncology Group (ECOG \2)] [hazard ratio (HR) 3.215; P = 0.002]. Mortality correlated with failure to achieve CR (HR 4.059; P \ 0.001) and poor performance status (ECOG [2) (HR 2.731; P = 0.035). In CR patients, poor karyotype and absence of consolidation (HR 2.313; P = 0.003) correlated with mortality. More than one cycle of consolidation was associated with better OS (P \ 0.001). Lack of salvage therapy was associated with mortality in patients who did not achieve CR (HR 3.223; P = 0.005). Intensive induction in patients with good performance and [1 cycle of consolidation after CR may
S.-J. Kim J.-W. Cheong Y. H. Min (&) Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea e-mail:
[email protected]
W.-S. Lee Y.-D. Joo Department of Hemato/Oncology, College of Medicine, Inje University, Busan, Republic of Korea
D.-Y. Kim J.-H. Lee K.-H. Lee Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Y.-K. Kim H.-J. Kim Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea I.-C. Song D.-Y. Jo Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea J.-O. Lee S.-M. Bang Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea J. Park J. H. Lee Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea
C. H. Maeng H.-J. Yoon Department of Hematology-Oncology, College of Medicine, Kyung Hee University Seoul, Seoul, Republic of Korea N.-R. Lee J.-Y. Kwak Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea K. H. Kim J.-H. Won Division of Hematology-Oncology, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea B. R. Han D. Y. Zang Division of Hematology-Oncology, Hallym University Medical Center, Hallym University College of Medicine, Seoul, Republic of Korea J. H. Moon S. K. Sohn Department of Hematology and Medical Oncology, Kyungpook National University Hospital, Daegu, Republic of Korea
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be the best strategy for improving OS in elderly AML patients. Keywords
Elderly AML Induction Consolidation
retrospective study, we aimed to identify prognostic factors associated with OS in elderly AML patients who were treated with intensive induction treatment or best supportive care, and also to verify the role of induction and consolidation treatment in this patient population.
Introduction Materials and methods The incidence of acute myeloid leukemia (AML) increases with age. Reports from the Surveillance, Epidemiology, and End Results database show a rapid increase in the incidence of AML among patients aged over 60 years [1], and the median age of AML diagnosis is 72 years in the Swedish Acute Leukemia Registry [2]. There are several key differences between elderly and younger AML patients. First, a poor-risk karyotype is more frequently observed in elderly AML patients compared with younger patients, and it is closely related with worse clinical outcomes [3]. The expression of genes related to poor drug response, such as the multidrug resistance-1 gene, is also increased in elderly patients [4, 5]. In addition, old age itself is one of the most important prognostic factors. Elderly people usually have poor performance status and a high incidence of medical co-morbidities [6, 7], and these factors may be related to poor outcomes in elderly AML patients. Only one randomized clinical trial and several retrospective studies have shown an advantage of intensive induction treatment over supportive care in elderly AML patients. These reports demonstrated that intensive induction treatment could result in complete remission (CR) and improve overall survival (OS) in elderly AML patients aged 75–80 years [2, 8]. However, the most important limitation of intensive induction treatment for elderly AML patients was the high incidence of treatment-related death, which was reported to be as high as 20 % [9, 10]. Therefore, when determining treatment strategies for elderly patients, it is necessary to carefully select the patients most likely to benefit from intensive induction treatment. White blood cell (WBC) count, cytogenetics, age, AML type, and performance status at the time of diagnosis of AML have been reported as prognostic factors affecting OS [11–13]. However, the studies that led to the identification of these prognostic factors did not include patients who received best supportive care, and there were no additional analyses on patients who failed induction treatment. In this S. H. Bae H. M. Ryoo Department of Hematology-Oncology, Deagu Catholic Medical Center, Catholic University of Daegu School of Medicine, Deagu, Korea S.-Y. Kim M. H. Lee Division of Hematology-Oncology, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
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Patients and data collection The data were collected by questionnaires distributed to hematology physicians of 14 hospitals in Korea from the Korean AML/Myelodysplastic Syndrome (MDS) Working Party. The data of elderly patients (aged C60) who were diagnosed with AML between January 2001 and December 2007 were collected, and their medical records were selected for review. The questionnaire included data about demographics, information at diagnosis [date of diagnosis, type of AML (de novo or secondary), French American British classification, World Health Organization classification, previous cytotoxic therapy, previous radiation therapy, Eastern Cooperative Oncology Group (ECOG) performance status, extramedullary involvement, laboratory results, serum lactate dehydrogenase (LDH) levels, bone marrow (BM) blasts, peripheral blood blasts, karyotype, AML1/ETO rearrangement, PML/RARa rearrangement, CBF/MYH11 rearrangement, FLT3/ITD mutation, immunophenotyping results], treatment (induction therapy regimen, result of induction therapy, consolidation therapy regimen, salvage therapy regimen, relapse, stem cell transplant), and final outcome. The classification of karyotype risk groups followed the definition of the Southwest Oncology Group [14]. In addition, availability of information on overall survival, remission, and induction therapy was required for patient inclusion in the analysis. Patients were excluded if they were diagnosed with acute promyelocytic leukemia (APL) or underwent autologous or allogeneic hematopoietic stem cell transplant (HSCT). This study was approved by the institutional review board and the patients were not required to give informed consent because of the retrospective design of the study. Definitions The induction group included patients who received intensive induction treatment and the best supportive care (BSC) group included patients who received conservative care or low-intensity therapy, such as low-dose cytarabine, hydroxyurea, or thioguanine monotherapy. The definition of complete remission, relapse, disease-free survival (DFS), and OS followed the criteria of the International Working Group [15]. Early death was defined as mortality
Induction and consolidation in elderly AML
occurring within 30 days after initiation of induction treatment. Induction therapy protocols Administration of induction treatment to patients was determined according to the individual strategies and protocols of the 14 hospitals. In the induction group, patients were treated with cytarabine ? idarubicin in a 7 ? 3 regimen (cytarabine 100 mg/m2 continuous infusion days 1–7, idarubicin 12 mg/m2 intravenous injection days 1–3), cytarabine ? daunorubicin in a 7 ? 3 regimen (cytarabine 100 mg/m2 continuous infusion days 1–7, daunorubicin 45 mg/m2 days 1–3), or various regimens with similar intensity to the cytarabine ? idarubicin 7 ? 3 regimen.
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Statistical analysis Categorical variables were compared using the Chi-square test, and continuous variables were evaluated by the Student’s t test. DFS and OS were calculated according to the Kaplan–Meier method, and parameters were compared by the log-rank method. The Cox proportional hazard model was used in the multivariate analysis of prognostic factors. P values lower than 0.05 were considered statistically significant. Statistical analysis was performed using SPSS software version 18.0 (IBM, Armonk, NY, USA).
Results Patient characteristics
Consolidation therapy protocols Administration of consolidation treatment and selection of protocol was decided by individual strategies of participating hospitals. Applied consolidation protocols were cytarabine ? idarubicin 7 ? 3 regimen, cytarabine ? idarubicin 5 ? 2 regimen (cytarabine 100 mg/m2 continuous infusion days 1–5 idarubicin 12 mg/m2 intravenous injection days 1–2), high-dose cytarabine (cytarabine 3000 mg/m2 twice for day 1, 3, 5), cytarabine ? etoposide ? idarubicin regimen (MEC regimen; cytarabine 1000 mg/m2 twice day 1–4, etoposide 100 mg/m2 day 1–3, idarubicin 12 mg/m2 day 1–2), FLAI-5 (fludarabine 30 mg/m2 day 1–5, cytarabine 2000 mg/m2 day 1–5, idarubicin 5 mg/m2 day 1, 3, 5), FLAI-12 (fludarabine 30 mg/m2 day 1–5, cytarabine 2000 mg/m2 day 1–5, idarubicin 12 mg/m2 day 1, 3, 5).
Data from a total of 528 patients were initially collected. After excluding APL and HSCT patients, data from 477 patients were analyzed (Fig. 1). The characteristics of patients are summarized in Table 1. The induction group included 266 patients (55.8 %), and the BSC group included 211 patients (44.2 %). The age of included patients ranged from 60 to 101 years (median 68 years). The median age of the induction group was significantly lower than that of the BSC group (66 vs. 72 years, P \ 0.001), and the induction group also had a better performance status than the BSC group (P \ 0.001). Secondary AML was more frequently observed in the BSC group (8.3 vs. 15.2 %, P = 0.011), and the median platelet count was higher in the BSC group. There was no statistical difference in the distribution of karyotype risk groups (P = 0.494).
Fig. 1 Flow diagram of patients, treatments, and result. APL acute promyelocytic leukemia, HSCT hematopoietic stem cell transplantation, BSC best supportive care, CR complete remission, Tx treatment
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Table 1 Patient characteristics
Induction group (n = 266)
BSC group (n = 211)
Male:female
152:114
122:89
Median age, years, n (range)
66 (60–86)
72 (60–101)
60–65
132
30
66–70
82
55
71–75
40
65
76–
12
61
P value 0.478 \0.001
Secondary AML
22 (8.3 %)
32 (15.2 %)
0.011
Median WBC, 9109/L (range)
7.68 (0.15–333.40)
9.13 (0.72–349.18)
0.380
Median Hb, g/dL (range)
8.1 (3.8–13.8)
7.9 (4.0–12.8)
0.151
Median PLT, 9109/L (range)
46 (1–776)
58 (2–534)
0.024
Median BM blast, % (range)
60 (8–99.9)
60 (10.2–100)
0.754
Median PB blast, % (range)
26 (0–98)
19 (0–98)
0.247
Median LDH, IU/L (range)
575 (38–11794)
571 (40–6487)
0.932 \0.001
ECOG, n (%) 0 1
12 (4.5) 110 (41.4)
2 (0.9) 53 (25.1)
2
46 (17.3)
56 (26.5)
3
9 (3.4)
18 (8.5)
4
0
3 ((1.4)
Favorable
12 (4.5)
7 (3.3)
Intermediate
163 (61.3)
115 (54.5)
Poor
55 (20.7)
44 (20.9)
Unknown
36 (13.5)
45 (21.3)
Karyotype risk group, n (%)
0.494
Molecular abnormalities (positive/negative) BSC best supportive care, AML acute myeloid leukemia, WBC white blood cell, Hb hemoglobin, PLT platelet, BM bone marrow, PB peripheral blood, LDH lactate dehydrogenase, ECOG Eastern Cooperative Oncology Group
CBFb/MYH11 rearrangement
0/37
1/42
0.116
AML1/ETO rearrangement
13/125
7/95
0.065
FLT3/ITD mutation
14/65
5/31
0.001
MLL/AF4 rearrangement
6/51
1/44
0.228
dupMLL
13/28
19/17
0.668
17
23
0.076
Myelofibrosis, any grade
Treatment result The characteristics of treatment for induction, consolidation, and best supportive care were listed in Table 2. In the induction group, most of the patients (91.6 %) received the standard 7 ? 3 regimen consisting of idarubicin or daunorubicin. Other regimens included fludarabine ? cytarabine ? granulocyte colony-stimulating factor (FLAG)based regimens or high-dose cytarabine-based regimens. The CR rate was 58.3 % (n = 155), and the early death rate was 15.4 % (n = 41). Among 155 patients who successfully achieved CR, consolidation treatments were administered to 81.3 % (n = 126). Forty-two patients (33.3 %) received 1 cycle of consolidation, 59 patients (46.8 %) 2 cycles, 16 patients (12.7 %) 3 cycles, 7 patients (5.6 %) 4 cycles and 2 patients more than 5 with a median
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of 2 cycles (range 1–6). For consolidation therapy regimens, high-dose cytarabine (cytarabine 3 mg/m2 every 12 h for days 1, 3, 5) was used in 19.8 % (n = 25) of cases, a repeated course of the standard 7 ? 3 regimen was used in 13.5 % (n = 17), 5 ? 2 regimen was used in 16.7 % (n = 21), and 2.4 % (n = 3) received a fludarabine ? cytarabine ? idarubicin regimen. Among the rest of 126 patients, 49 patients received various consolidation regimens, and 11 patients did not provide information about the regimen. The 29 patients who did not receive consolidation therapy were older (median age 67.9 vs. 65.7 years, P = 0.002) and had a poorer performance status (P = 0.013) than patients that did receive consolidation therapy, but the distribution of karyotype risk groups and WBC counts were not statistically different between these 2 groups. Relapse was observed in 79 patients
Induction and consolidation in elderly AML
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Table 2 Characteristics in treatments for induction, consolidation, and best supportive care Treatment
Regimen
No. of patients
%
Induction (n = 266)
Ara-C?idarubicin 7,3
173
65.5
69
26.1
FLAG-Ida FLAG
9 2
3.4 0.8
Ara-C mono
4
1.5
Ara-C?mitoxantrone
1
0.4
Modified AIDA
1
0.4
Others
5
1.9
Unknown
2
0.8
12
5.7
Ara-C?daunorubicin 7,3
BSC (n = 211)
Low-dose cytarabine Azacytidine Others Conservative care
Consolidation (n = 126)
1
0.4
36
17.1
162
76.8
Ara-C?idarubicin 7,3
17
13.5
Ara-C?idarubicin 5,2
21
16.7
FLAI(5)
1
0.8
FLAI(12)
2
1.6
High-dose Ara-C Others
25 49
19.8 38.9
Unknown
11
8.7
BSC best supportive care, Ara-C cytarabine, FLAG fludarabine ? cytarabine ? granulocyte colony-stimulating factor, Ida idarubicin, AIDA ATRA ? idarubicin
(51.0 %) who achieved CR after a course of induction treatment. Among patients who failed to achieve CR after the first induction course, 15 patients began a salvage treatment, and 4 of these patients achieved CR (salvage CR rate 26.7 %). The FLAG regimen was used for salvage treatment in 9 patients. In the BSC group, 12 patients received low-dose cytarabine (LDAC), 1 patient received azacytidine, and 36 patients received various oral cytoreductive agents (Table 2). One patient in the BSC group who received LDAC achieved CR. None of the patients in the BSC group began any kind of salvage treatment. OS according to clinical factors in the induction and BSC groups The median OS was 339 days [95 % confidence interval (CI), 275–403 days] in the induction group and 86 days (95 % CI, 54–118 days) in the BSC group (P \ 0.001). The OS of the patients were compared in each age group of 5-year intervals. In ages up to 75 years, the induction group showed a longer OS compared to the BSC group; however, no difference was found in ages over 75 (median 78 days in induction group vs. 83 days in BSC
group, P = 0.094) (Table 3). The patients with good performance status (ECOG \3) had a longer OS in the induction group than in the BSC group; however, there was no difference in OS in patients with poor performance status (ECOG 3 or 4) when compared between the induction and BSC group. The induction group also exhibited a longer OS in all karyotype risk groups. Among de novo AML patients, the induction group showed prolonged OS (median 244 vs. 94 days, P \ 0.001). On univariate analysis of OS in the induction group, performance status, karyotype risk groups, WBC count, and serum LDH level were statistically significant predictors of OS. In the BSC group, performance status, karyotype risk group, BM blast, and LDH level showed a statistical correlation with OS. As the reference value of LDH varied among the 14 hospitals, the effect of LDH was not analyzed by multivariate analysis. Prognostic factors related to achievement of CR Prognostic factors associated with CR were analyzed in the induction group. In the univariate analysis, good performance status (ECOG\2) (63.9 vs. 38.2 %, P = 0.002) and low LDH levels (69.5 vs. 48.6 %, P = 0.001) were associated with increased CR rates. Age (\65 years), favorable karyotype risk group, and de novo AML resulted in marginal significance. When these factors were analyzed for achievement of CR by logistic regression, good performance status [ECOG \2, Hazard ratio (HR) 3.215; 95 % CI, 1.508–6.853; P = 0.002] was the only factor associated with achievement of CR (Table 4). Prognostic factors related to mortality according to treatment and response In the multivariate analysis of factors predictive of mortality, poor performance status (ECOG [2; HR 2.731; 95 % CI, 1.073–6.949; P = 0.035) and failure to achieve CR (HR 4.059; 95 % CI, 2.398–6.949; P \ 0.001) were significantly associated with increased mortality, but karyotype risk group was not significantly associated with mortality in the induction group. In the BSC group, poor karyotype risk group (HR 3.729; 95 % CI, 0.822–16.912; P = 0.004) and BM blasts (C50 %) (HR 2.010; 95 % CI, 1.075–3.756; P = 0.029) were associated with increased mortality. Among patients who achieved CR after the first induction treatment, poor karyotype risk group (HR 1.767; 95 % CI, 1.018–3.067, P = 0.043) and lack of consolidation treatment (HR 2.313; 95 % CI, 1.333–4.011; P = 0.003) were associated with mortality. For those who failed to achieve CR, lack of salvage treatment (HR 3.223; 95 % CI, 1.426–7.285; P = 0.005) was associated with poor OS (Table 5).
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146 Table 3 OS in the BSC group and induction group
S.-J. Kim et al.
Variables
No.
BSC group (n = 211)
56 (20.8–91.2)
132
346 (222.8–469.2)
\0.001
0.313 30
66–70
55
67 (13.8–120.2)
82
316 (209.1–422.9)
\0.001
65
116 (44.2–187.8)
40
332 (138.9–525.1)
0.042
76–
61
83 (35.5–130.5)
12
78 (0–610.4)
12 110
308 (0–697.8) 427 (310.9–543.1)
\0.001 \0.001
85 (4.7–165.3)
46
332 (196.1–467.9)
0.007
62 (20.6–103.4)
9
22 (0–63.6)
0.721
18
0
–
NA
2 53
7 116 (48.7–183.3)
2
56
3
18
4
3
Intermediate Poor
0.004
de novo
7
190 (27.8–352.2)
12
NR
0.016
101 (48.4–153.6)
163
392 (297.6–486.4)
\0.001
55
239 (118.2–359.8)
44
45 (23.9–66.1) 0.846
174
94 (62–126)
\0.001 0.143
244
339 (227.7–403.3)
\0.001 0.123
62 (44.8–79.2)
\50
76
136 (51.8–220.2)
104
367 (236.9–497.0)
\0.001
C50
111
71 (44.2–97.8)
149
316 (238.8–393.2)
\0.001
93
471 (263.9–678.0)
18
366 (212.4–519.6)
Myelofibrosis Absent Present (any grade)
22
186 (1.6–370.5)
32
BM blasts (%)
0.010
0.306
0.087 72
116 (62.8–169.2)
23
53 (39.7–66.3)
WBC, 9109/L (range)
0.185
0.344
\100,000
183
C100,000
25
101 (63.4–138.6) 52 (19.2–84.8)
LDH (IU/L)
\0.001 \0.001 0.049
233
346 (297.3–394.7)
30
225 (94.4–355.6)
0.048
\0.001 0.008 0.038
\600
91
126 (49.1–202.9)
130
392 (290.9–493.0)
\0.001
C600
81
67 (37.3–96.7)
114
250 (147.7–352.3)
\0.001
\8.0
161
88 (24.5–151.5)
117
339 (248.3–429.6)
\0.001
C8.0
47
83 (39.2–126.8)
146
332 (203.0–460.9)
\0.001
Hb (g/dL)
0.661
PLT, 9109/L (range)
0.509
0.087
\100
161
C100
47
74 (49.8–98.2) 144 (112.0–175.9)
Overall survival according to treatment We then evaluated OS according to receipt of induction, consolidation, and salvage chemotherapy. The median OS of CR patients who received consolidation was 629 days, while the median OS for those who did not receive consolidation was 339 days (95 % CI, 462.0–795.9 vs. 132.1–545.8; P = 0.006). In patients who failed to achieve CR (non-CR), the median OS was 332 days for patients who received salvage treatment and 62 days for those who did not receive salvage treatment (95 % CI, 231.3–412.8
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0.033
115
Type of AML 2nd
0.094 \0.001
0.036
0 1
Favorable
Levels of significance for univariate analysis on variables in induction group or BSC group
0.823
71–75
Karyotype risk group
à
Pà
Induction group (n = 266)
ECOG
BSC best supportive care, AML acute myeloid leukemia, WBC white blood cell, Hb hemoglobin, PLT platelet, BM bone marrow, OS overall survival, LDH lactate dehydrogenase, ECOG Eastern Cooperative Oncology Group Levels of significance for difference between induction and BSC group for each variables
Pà
No.
Age 60–65
P
Survival, median days (95 % CI)
0.289 216
339 (277.2–400.8)
\0.001
46
322 (231.5–412.5)
0.012
vs. 40.3–83.7; P \ 0.001). In the BSC group, patients who received LDAC had a median OS of 131 days, and patients with conservative care only had a median OS of 83 days; this difference was not statistically significant (95 % CI, 66.1–195.9 vs. 49.5–116.5; P = 0.285) (Fig. 2a). In nonpoor-risk karyotype patients who achieved CR, administration of consolidation treatment resulted in improved OS (consolidation vs. no consolidation: median 609 vs. 392 days; 95 % CI, 320.6–897.3 vs. 148.3–635.6; P = 0.038), and this was also true for poor-risk karyotype patients who achieved CR (consolidation vs. no
Induction and consolidation in elderly AML
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Table 4 Prognostic factors related to achievement of CR in induction group Univariate Variables
Multivariate No.
No. (%)
Age
P
Variables
0.077
ECOG
HR
95 % CI
1.508–6.853
0.002
60–65
132
84 (64.6)
0, 1
3.215
66–
134
70 (52.2)
2–4
1
0.002
P
Type
0.603
ECOG 0, 1
122
78 (63.9)
2–4
55
21 (38.2) 0.090
de novo
1.356
2nd
1
0.430–4.271
Cytogenetics
0.078
Karyotype risk group Favorable Non-favorable
12
10 (83.3)
212
127 (59.9) 0.056
Type of AML de novo 2nd
244
145 (60.9)
22
9 (40.9)
Favorable
7.774
Non-favorable
1
0.794–76.100
Age
0.061
60–65
1.960
66
1
0.971–3.957
0.147 BM blasts (%) \50
104
66/102 (64.7)
C50
149
83/145 (57.2) 0.395
Myelofibrosis Absent Present (any grade)
93 18
53/92 (57.6) 11/17 (64.7) 0.261
WBC, 9109/L (range) \100,000
233
137/229 (59.8)
C100,000
30
15/29 (51.7) 0.001
LDH (IU/L) \600
130
89/128 (69.5)
C600
114
54/111 (48.6) 0.375
Hb (g/dL) \8.0
117
66/115 (57.4)
C8.0
146
86/143 (60.6) 0.364
PLT, 9109/L (range) \100
216
123/212 (58.0)
C100
46
28/45 (62.2)
Hazard ratios show the probabilities of achievement of complete remission AML acute myeloid leukemia, BM bone marrow, WBC white blood cell, LDH lactate dehydrogenase, Hb hemoglobin, PLT platelet, CR complete remission, ECOG Eastern Cooperative Oncology Group
consolidation: median 387 vs. 53 days; 95 % CI, 114.4–659.5 vs. 0–160.8; P = 0.001) (Fig. 2b, c). When patients were divided by the number of cycles of consolidation treatment (1 vs.[1 cycle), the patients who received more than 1 cycle showed prolonged OS (1 vs. [1 cycle: median 471 vs. 847 days; 95 % CI 316.4–625.5 vs. 368.1–1325.8; P \ 0.001) (Fig. 2d).
Discussion We analyzed the effect of induction and consolidation treatment on OS using retrospective data of 477 patients collected from 14 hospitals in Korea. Although this study was retrospective, the follow-up duration of all patients exceeded 3 years from diagnosis, and the majority of cases
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1.333–4.011 2.313 No
1
4.059
Yes
No
2.398–6.949
0.463–3.226 C100,000
\100,000
WBC
2.731 3, 4
1.073–6.949 1 0-2
Hazard ratios show the probabilities of mortality
C50 \0.001 1.223
1 \50
0.685
BM blast
1
2.010
1.075–3.756
0.029 0.715–3.327 1
1.543 3, 4
0–2
ECOG 0.035 ECOG
CR achievement
1 Yes 0.269 0.822–16.912
0.304–5.474 1.291
3.729 Poor
Intermediate
1.833 Poor
0.419–8.021
0.232–4.098 0.974 Intermediate
CR complete remission, BM bone marrow, OS overall survival, HR hazard ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, WBC white blood cell
1.426–7.285 3.223 No
Yes
1
2.054 3,4 1.018–3.067 1.767 Poor
Consolidation
1 Non-poor
Karyotype risk group 0.004
1 Favorable
Karyotype risk group 0.080
1 Favorable
Karyotype risk group
95 % CI HR
123
Salvage 0.003
0-2
0.043
ECOG
1
HR Variable Variable HR Variable Variable
P
BSC group Induction group
Table 5 Prognostic factors for OS in subgroups of treatment and result
95 % CI
P
CR patients
HR
95 % CI
P
Non-CR patients
95 % CI
0.789–5.350
0.140
0.005
S.-J. Kim et al.
P
148
had information available for important clinical factors, such as karyotype, performance status, and treatment history, regardless of the treatment group. In addition, our data analyzed prognostic factors for patients who received only best supportive care, which makes this study unique in comparison with other reports on elderly AML patients. In our study, we demonstrated a clear benefit of intensive induction and consolidation treatment in elderly AML patients. We also found that successful achievement of CR is the strongest prognostic factor for improved OS. Furthermore, although the data were limited to a small number of patients, we observed a benefit of salvage treatment when given to patient refractory to the first induction treatment. Deciding on treatment strategies for elderly AML patients is quite difficult because there is no sufficient evidence on the benefits of an intensive treatment regimen in this patient population, and a randomized clinical trial addressing this issue is difficult to design. Therefore, most of the available data addressing treatment options in elderly patients have resulted from retrospective analyses. There is only 1 randomized clinical trial with a small patient number that shows the benefit of induction treatment [16]. In several retrospective studies, the results on the benefit of induction treatment are contradictory [13, 17–20]. Our study shows a clear advantage of induction treatment in elderly AML patients aged up to 75 years, but the upper age limit eligible for induction treatment has not yet been determined. In a Swedish report, 80 years was suggested as the upper limit, and in a report by MD Anderson Cancer Center, 70–75 years was suggested as the limit [2, 20]. Performance status is also accepted as one of most important prognostic factors in elderly patients by many studies. We confirmed that performance status is associated with survival in patients treated with induction therapy, but not in the BSC group or non-CR patients. This may be due to the close relationship of early death during induction treatment and poor performance status. Among patients who received induction treatment, successful achievement of CR was the strongest factor associated with OS. Therefore, appropriate selection of patients eligible for intensive treatment should focus on the probability of CR achievement. The most commonly reviewed prognostic factors for CR in many other studies were karyotype, performance status, leukocytosis, and age [13, 21–23]. In our study, karyotype, performance status, and type of AML correlated with achievement of CR in the univariate analysis. However, karyotype failed to show statistical significance in the multivariate analysis. Although karyotype is an important factor regardless of age, the evidence that normal karyotype elderly AML patients showed more genetic alterations by single-nucleotide polymorphism array than younger patients supports
Induction and consolidation in elderly AML
149
Fig. 2 Overall survival probability of patients according to a achievement of CR and application of consolidation or salvage treatment, b administration of consolidation in non-poor karyotype
patients, c administration of consolidation in poor karyotype patients, and d consolidation cycle number
the hypothesis that additional biologic factors may be related to achievement of CR rather than karyotype alone [24]. There are no concrete data on the optimal induction regimen for elderly patients. In this study, the majority of patients used standard 7 ? 3 regimens, and there were no statistical differences between induction regimens (data not shown). Reports on the factors related to survival in conservatively treated patients are rare. In our analysis, OS of the BSC group was related to karyotype and BM blasts. In the BSC group, patients who lived longer than the median survival of their group (86 days) had several outstanding clinical characteristics, including fewer BM blasts and lower WBC count. When the patient who has all these factors received low-dose cytarabine treatment, survival
was prolonged over 1 year, regardless of whether complete remission was achieved. This finding suggests that even in patients who are not suitable for intensive induction therapy, a portion of selected patients may benefit from lowdose treatment. Therefore, further studies are warranted in this patient population, perhaps using hypomethylating agents or newer drugs of low intensity. After successful achievement of CR, application of consolidation treatment was associated with improved OS. There are only a few randomized clinical trials that have shown a benefit from any schedule or intensity of consolidation therapy in elderly patients. Several prospective trials included consolidation treatment in their protocols, but the effect of consolidation dose or cycle was not thoroughly analyzed [25, 26]. In our analysis, the patients
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150
who received consolidation treatment were younger and had better performance status than patients who did not receive consolidation treatment. However, after correcting for age and performance status, consolidation therapy still had a significant relationship with improved OS. Because our study was not randomized, we were cautious in analyzing the benefit of multiple consolidation courses. However, there were no differences in clinical factors between patients who received different consolidation cycle numbers. There were certain limitations to our study given its retrospective design and multicenter data collection. Accordingly, approximately 15 % of data on karyotype and performance status were missing, and the regimens used for induction and consolidation were not uniform. However, the treatments used were commonly administered regimens in clinics, and all had similar intensities. Although there are limitations with retrospective data, we found several important factors affecting treatment decisions of elderly AML patients. Based on our analysis, the best survival outcome of elderly patients can be achieved by induction treatment followed by multiple consolidation treatments. As the clinical factors are currently insufficient for selection of suitable patients for induction treatment, biomarkers for successful CR should be further investigated. Conflict of interest All authors have no financial conflict of interest with company for this investigation to declare.
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