Med Oncol (2014) 31:962 DOI 10.1007/s12032-014-0962-z
ORIGINAL PAPER
Standard intensive chemotherapy is less effective and far more toxic than attenuated induction and post-induction regimen in elderly patients with acute myeloid leukemia Bin-Tao Huang • Wei-Hong Zhao • Qing-Chun Zeng Bing-Sheng Li • Rui-lin Chen
•
Received: 13 March 2014 / Accepted: 7 April 2014 / Published online: 18 April 2014 Ó Springer Science+Business Media New York 2014
Abstract The open-label, prospective study aimed to evaluate the efficacy and safety for standard intensive chemotherapy compared with attenuated therapy in elderly patients with acute myeloid leukemia (AML). A total of 297 patients between 65 and 82 years were enrolled in the study. The 141 patients received standard-dose therapy (daunorubicin 45 mg/ m2 9 3 days with cytarabine 100 mg/m2 9 7 days for induction therapy, while post-induction therapy consisted of high-dose cytarabine 1.5 g/m2 9 4 days), and the attenuated treatment (daunorubicin 30 mg/m2 9 3 days with cytarabine 75 mg/m2 9 7 days for induction therapy, while post-induction therapy consisted of attenuated high-dose Ara-C 1.0 g/ m2 9 3 days) was administered to the remaining 156 patients, based on a random number assigned. Total 168 patients (56.6 %) achieved complete remission with an incomplete blood recovery (CR)/CRi. No significant differences were observed between the two treatments (P = 0.60). Attenuated chemotherapy improved overall survival (OS) and progression-free survival (PFS) compared to standard-dose therapy;
5-year OS values for these two groups were 39 and 24 months, respectively (P \ 0.001), and the PFS values for these two groups were 35 versus 23 months (P \ 0.001). In addition, the attenuated treatment with a poor risk profile overcame the negative impact and yielded OS and PFS values similar to those of the standard-dose chemotherapy with a better-tointermediate risk profile. Five-year OS values for these two groups were 28 versus 28 months (P = 0.89), and the 5-year PFS values were 27 and 28 months, respectively (P = 0.89). The most common adverse drug effect for chemotherapy was agranulocytosis (98.3 %). There was a significant difference in early mortality between the attenuated and standard-dose treatment groups (0.64 % vs. 7.1 %, respectively, P \ 0.01). Standard intensive chemotherapy is less effective and far more toxic than attenuated induction and post-induction regimen in elderly patients with AML. Keywords Elderly patients Acute myeloid leukemia Attenuated chemotherapy
Bin-Tao Huang and Wei-Hong Zhao have equally contributed to this work. B.-T. Huang (&) Department of Hematology, The Affiliated Hospital of Inner Mongolia Medical University, 1 TongDao Avenue North, Hohhot 010059, People’s Republic of China e-mail:
[email protected] W.-H. Zhao Department of Gastroenterology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010059, People’s Republic of China
B.-S. Li Huizhou Medicine Institute, Huizhou 516003, People’s Republic of China R. Chen Department of Rheumatology and Immunology, Guangzhou Medical College, The Second Affiliated Hospital, Guangzhou 510260, People’s Republic of China
Q.-C. Zeng Department of Medicine, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, Guangdong 510515, People’s Republic of China
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Introduction The incidence of acute myeloid leukemia (AML) in individuals aged more than 60 years is about 10 times higher than in younger individuals [1]. The standard approach to intensive post-induction consolidation therapy in adults with AML differs according to cytogenetic risk. Patients with moderate or high cytogenetic risk typically receive high-dose intermittent cytarabine (HiDAC) therapy, while patients with low risk receive allogeneic stem-cell transplantation (allo-SCT) [2–4]. Though these intensive therapies have benefitted younger patients with AML, they have offered only minor improvements to elderly AML patients during the same period [5]. For elderly patients, the benefit of standard intensive induction chemotherapy treatment remains debatable due to its excessive toxicity during initial stages, short response duration, and low median overall survival (OS) rate [5]. Factors related to age, including poorer performance status (PS) and morbidity, may directly affect treatment tolerance [6–9]. Furthermore, factors related to disease biology, including frequency of prior myelodysplastic syndrome (MDS) and the unfavorable karyotype, may lower both the response rate and duration. In a large retrospective study, the outcome for elderly patients with AML reported a 2-year survival rate of 6 % [10]. Only 30 % of these patients received chemotherapy treatment within 2 years of AML diagnosis [10]. Additionally, Dombret et al. [5] showed that repeated, intensive post-remission courses are not effective in older patients. In the cancer and leukemia group B (CALGB) study, two intensive postinduction courses did not show any significant differences in survival rate when compared to four less intensive courses [11]. More recent findings have demonstrated that prolonged and attenuated treatment is preferable to intensive postinduction chemotherapy, for consolidation therapy in elderly patients with AML achieves complete remission (CR) after standard intensive remission induction [12]. There is still uncertainty concerning the attenuated induction and post-induction strategies for elderly patients with AML. Our study thus involved a multicenter study review of the OS, overall response (OR), progression-free survival (PFS), and safety of attenuated and prolonged therapy when compared to standard intensive regimens for induction and post-induction therapy in patients aged over 65 years with newly diagnosed primary or secondary AML.
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2013 (Fig. 1). All eligible patients (age C65 years) were diagnosed according to the World Health Organization (WHO) classification [13, 14]. Our study was approved by the institution review board at each of the participating centers. After all patients provided written informed consent, they were divided into two treatment cohorts standard intensive dose induction and post-induction therapy versus attenuated and prolonged therapy regimen based on a random number assigned. No enrolled elderly patients exhibited reduced intensity during allo-SCT, nor could be assigned to receive further treatment. Selection criteria There were three selection criteria. Elderly patients (age C65 years) had to exhibit de novo and post-MDS AML (excluding acute promyelocytic leukemia) or AML evolving from a prior myeloproliferative disorder according to WHO classification. All participants also needed Karnofsky performance status (KPS) scores of at least 60. Participants also had to provide written informed consent before joining the observational study. Chemotherapy protocols The standard intensive dose regimen [15] consisted DNR 45 mg/m2 daily for 3 days in combination with 100 mg/m2 of cytarabine (Ara-C) by continuous infusion daily for 7 days for induction therapy, while post-induction therapy consisted of 45 mg/m2 of DNR daily for 3 days combined with a daily dose of 100 mg/m2 for 7 days (two cycles) and Ara-C 1.5 g/m2 daily for 4 days (four cycles). The attenuated chemotherapy regimen consisted of 30 mg/m2 daily of DNR for 3 days combined with 75 mg/m2 of Ara-C by continuous infusion daily for 7 days for induction therapy), while post-induction therapy consisted of DNR 30 mg/m2 daily for 3 days combined with Ara-C 75 mg/m2 daily for 7 days (two cycles) and Ara-C 1.0 g/m2 daily for 3 days (four cycles) (Fig. 1). Supportive therapy We defined myelosuppression as a neutrophil count less than 0.5 9 109/L. A granulocyte colony stimulant was administered until the neutrophil count exceeded 1.5 9 109/L. Study endpoints
Methods Study sample Our open-label, prospective, multicenter clinical assessment study enrolled participants from October 2007 to May
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Hematology and morphology were defined according to Cheson et al. [16], while CR was defined as normocellular bone marrow with fewer than 5 % blasts, no Auer rods, and no evidence of extramedullary involvement. Patients who relapsed or died within 28 days after CR were not
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Fig. 1 Study design and patient disposition
considered to have achieved CR [17]. Patients with CR involving incomplete blood recovery (CRi) were also included. Partial remission (PR) was classified according to the standards of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in AML [16]. Progression-free survival (PFS) was defined as the time elapsed from diagnosis until progression or death from any cause [18], while OS was measured from the time of diagnosis until death from any cause. Patients still alive at the date of last contact were censored [19]. Early death was defined as that occurring prior to the completion of induction therapy [20]. Adverse events were monitored and recorded according to the Common Terminology Criteria
for Adverse Events (CTCAE) version 3.0 (National Cancer Institute, 2003).
Statistical analysis Statistical analysis was carried out using SPSS 13.0 statistical software. The comparison of the two treatment subgroups (accommodating sex, leukocyte count, advanced age, distribution of FAB subtype, and cytogenetic risk profiles), response rate for induction therapy, time to neutrophil count [1.5 9 109/L and adverse-event response were evaluated by the v2 test or Wilcoxon’s test. OS and PFS were estimated by the Kaplan–Meier method. A p value \0.05 was considered statistically significant.
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Table 1 Characteristics of elderly patients with AML
Table 2 Response to induction therapy of elderly patients with AML
Regimens
Standard-dose chemotherapy arm
Attenuated-dose chemotherapy arm
Total cases
141
156
Sex (male/female)
76/65
84/72
0.99
Age (mean, range) Advanced age (C70 years)
68.9, 65–79 47
68.6, 65–82 40
0.39
Leukocyte count,
21.1, 1.4–78.2
18.7, 1.1–68.7
P value
0.21
9
910 /L (mean, range) De novo
105
113
Secondary
36
43
M0
1
2
M1 M2
9 71
14 69
M4
27
29
M5
29
36
M6
4
5
M7
0
1
FAB subtype
Cytogenetic risk 89
59
67
Attenuateddose chemotherapy arm
n
n
(%)
141
P value
(%)
156
CR/CRi
82
58.2
86
55.1
0.60
PR
46
32.6
48
30.8
0.73
128
90.8
134
85.9
0.19
Overall response (CR/ Cri ? PR)
10
7.1
1
3
2.1
21
0.64
0.003
Not reach OR
0.77
disorder). Patients with low cytogenetic risk comprised 126 (42.4 %) of the participants. The two treatment subgroups were well balanced in terms of sex (P = 0.99), age (P = 0.37), FAB subtype (P = 0.77), and distribution of cytogenetic risk profiles (P = 0.85) at the time of therapy (Table 1).
0.85 82
Standard-dose chemotherapy arm
0.69
Results Patient characteristics After induction therapy examinations of blood and marrow aspiration smears were performed from days 21 to 28 in order to document remission status. All eligible patients received an induction treatment (i.e., standard or attenuated induction) and continued to receive rotating intensity postinduction therapy (i.e., standard or attenuated consolidation) until progression. A total of 141 patients received standard-dose induction and post-induction chemotherapy and were thus classified according to the standard-dose chemotherapy subgroup, while 156 patients received attenuated induction and post-induction regimen and were thus included in the attenuated chemotherapy subgroup (Fig. 1). Among all participants 87 (29.3 %) were aged C70 years. The leukocyte counts of 170 patients (57.2 %) exceeded 10 9 109/L at diagnosis. Meanwhile, 79 patients (26.6 %) were diagnosed with secondary AML (post-MDS AML or AML evolving from a prior myeloproliferative
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Total cases
Early death
Type of AML
Better-tointermediate risk profile Poor risk
Treatment regimen
13.5
Response to induction therapy CR/CRi after induction chemotherapy was achieved in 168 patients (56.6 %), and no significant differences were observed between the two subgroups (P = 0.60, Table 2). Of the 297 patients, 94 (31.6 %) obtained a partial response, and again, there were no significant differences between the two subgroups (P = 0.73, Table 2). Most patients (88.2 %) reached OR (CR/CRi ? PR), while patients under the standard-dose chemotherapy subgroup gained the same satisfactory OR when compared to the attenuated and prolonged chemotherapy subgroup (P = 0.19, Table 2). By contrast, 10 elderly patients died before the completion of the two standard-dose induction therapy cycles, and one patient died during two cycles of attenuated-dose induction therapy. The rate of early death between the two therapy subgroups showed a significant difference (P \ 0.01, Table 2). A total of 24 patients did not reach OR, abandoned the induction chemotherapy, or received supportive care (Fig. 1; Table 2). Overall and progression-free survival rates The Kaplan–Meier survival curve demonstrates that OS was lower in the standard-dose chemotherapy subgroup than in the attenuated and prolonged chemotherapy subgroup. Median OS at 5 years was 24 versus 39 months (P \ 0.001, Fig. 2). The attenuated treatment regimen provided more benefits for patients with better-to-
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Fig. 2 OS by treatment arms
Fig. 3 OS by treatment arms in different cytogenic risk profiles. 1 Standard-dose chemotherapy arm in better-to-intermediate risk profile. 2 Standard-dose chemotherapy arm in poor risk profile. 3 Attenuated-dose chemotherapy arm in better-to-intermediate risk profile. 4 Attenuated-dose chemotherapy arm in poor risk profile
intermediate risk profiles than patients with similar profiles in the standard-dose treatment subgroup (P = 0.001, Fig. 3), and median OS at 5 years reached 47 versus 28 months. At the same time, the negative impact was decreased by attenuated treatment in the poor risk profile subgroup, as it yielded 5-year OS results similar to those in the standard-dose subgroup under the better-to-intermediate risk profile (28 vs. 28 months, P = 0.89, Fig. 3). We furthermore analyzed PFS at 5 years for all patients who attained CR. Similarly, the attenuated treatment subgroup benefitted more than the standard-dose treatment
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Fig. 4 PFS by treatment arms
Fig. 5 PFS by treatment arms in different cytogenic risk profiles. 1 Standard-dose chemotherapy arm in better-to-intermediate risk profile. 2 Standard-dose chemotherapy arm in poor risk profile. 3 Attenuated-dose chemotherapy arm in better-to-intermediate risk profile. 4 Attenuated-dose chemotherapy arm in poor risk profile
subgroup in terms of PFS, for 5-year PFS was 35 versus 23 months (P \ 0.001, Fig. 4). Patients with a better-tointermediate risk profile gained satisfactory benefits from the attenuated treatment regiments over patients with the better-to-intermediate risk profile and standard-dose treatment subgroup (P \ 0.01, Fig. 5); PFS at 5 years reached 44 versus 28 months. As for the attenuated treatment subgroup with poor risk profiles, estimations for PFS at 5 years were similar to the standard-dose chemotherapy subgroup and better-to-intermediate risk profile (27 vs. 28 months, P = 0.89, Fig. 5).
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Table 3 Main adverse events for two regimen arms in the induction and post-induction treatment Standard-dose chemotherapy arm
Attenuateddose chemotherapy arm
n
n
(%)
(%)
Total patients
141
156
Time to neutrophil count [1.5 9 109/L (days, mean ± SE)
25.8 ± 0.44
20.5 ± 0.43
Neutrophil grade C 4
139
153
(98.6)
P value
\0.001
(98.1)
0.74
Other non-hematological grade C3 Infection
58
(41.1)
32
(20.5)
\0.001
Nausea-vomiting
6
(4.3)
7
(4.5)
0.92
Allergic reaction
3
(2.1)
8
(5.1)
0.17
Dermatology/skin
1
(0.7)
4
(2.6)
0.22
Cardiac general
2
(1.4)
0
(0)
0.14
Liver dysfunction
4
(2.8)
1
(0.6)
0.14
Renal failure
1
(0.7)
0
(0)
0.29
Chemotherapy and adverse effects of induction and post-induction therapy The most common adverse drug effect for chemotherapy was agranulocytosis (98.3 %). However, the standard-dose subgroup demonstrated better outcomes regarding neutrophil count exceeding 1.5 9 109/L than the attenuated treatment subgroup (25.8 days vs. 20.5 days, P \ 0.001). Accordingly, the standard-dose subgroup also incurred more severe infections (grades C3) than the attenuated chemotherapy subgroup (41.1 vs. 20.5 %, P \ 0.001, Table 3). Most adverse drug effects—allergies and skin conditions—stemming from induction and post-induction treatment were moderate (grades 1 or 2). Only a small number of participants receiving chemotherapy had severe multisystem adverse events (grades C3), including nausea and vomiting (4.4 %), allergic reactions (3.7 %), and dermatology/skin (1.7 %). Among the 297 participants, five (1.7 %) developed severe grade-three liver dysfunctions, one (0.3 %) developed grade-3 renal insufficiency, and two (0.7 %) developed heart failure. However, timely termination and consolidation of chemotherapy and adequate supportive care reversed and removed these complications. There were no differences in severe multisystem incidences between the two treatment regimen subgroups (Table 3).
Discussion Lo¨wenberg et al. [21] have described how the subgroup of patients aged from 60 to 65 years benefitted most from
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intensified dosages of daunorubicin (90 mg/m2), though high-dose DNR did not benefit patients aged more than 65 years. Elderly patients newly diagnosed with AML are generally less tolerant of standard intensive induction chemotherapy [15] and show prolonged myelosuppression after receiving intensive chemotherapy, which leads to a higher incidence of treatment-related mortality when compared to younger patients [11]. The results of the standard intensive chemotherapy in elderly persons with AML are generally considered unsatisfactory due to the treatment’s excessive toxicity [5, 12]. However, the attenuated intensity of post-remission consolidation chemotherapy has usually reduced the incidence of fatal complications [15]. Our study showed excellent results for elderly patients (age [65) who received attenuated chemotherapy. The attenuated treatment regimen allowed patients with a poor risk profile to overcome the negative impacts of treatment and gain the same benefits of OS and PFS of the standarddose regimen subgroup with better-to-intermediate risk. Time to neutrophil count ([1.5 9 109/L) in the attenuated and prolonged chemotherapy subgroup was briefer than the standard-dose regimen subgroup, and thus, early death rates of the attenuated and prolonged chemotherapy subgroup were significantly lower. Regarding non-hematopoietic multisystem adverse effects, the majority of patients showed only mild or moderate toxicity. There is currently no universally accepted standard for the care of older patients with AML, for the patient population is clinically heterogeneous, and currently available therapies are largely ineffective [22]. Our study showed that the attenuated intensity of induction and post-induction chemotherapy reduced the incidence of fatal complications and was tolerated by elderly patients. However, additional reasons for the dismal results in elderly patients after intensive induction therapy include the failure to achieve remission and short remission duration, not only toxicity. Above all, the results suggest that attenuated induction and post-induction chemotherapy regimens improve 5-year PFS and OS, as well as significantly reduce early mortality. Standard intensive chemotherapy is less effective and far more toxic than attenuated induction and post-induction regimen in elderly patients with AML. For the attenuated and prolonged treatment subgroups with poor risk profiles, our results demonstrate PFS and OS estimations similar to the standard-dose regimen subgroup with better-to-intermediate risk profiles. Acknowledgments We would like to thank all the patients and the clinicians from the participating sites. This work was supported by grants from the Natural Science Foundation of Inner Mongolia (2013MS1157) and The Inner Mongolia Autonomous Region Health and Family Planning health research projects (201302059). All authors discussed the results and commented on the manuscript.
Med Oncol (2014) 31:962 Conflict of interest I would like to declare on behalf of my coauthors that this work is original research that has not been published previously and is not under consideration for publication elsewhere, either in part of in whole. All the authors listed have approved the manuscript that is enclosed.
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