A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome

Wei Guoqing, Ni Wanmao, Chiao Jen-Wei, Cai Zhen, Huang He, Liu, Liu Delong

Description

The regimen of cytarabine, aclarubicin and G-CSF (CAG) has been widely used in China and Japan for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We searched literature on CAG between 1995 and 2010 and performed a meta-analysis to determine its overall efficacy using a random-effects or fixed-effects model. Thirty five trials with a total of 1029 AML (n = 814) and MDS (n = 215) patients were included for analysis. The CR rate of AML (57.9%) was significantly higher than that of MDS (45.7%) (p < 0.01). No difference in CR was noted between the new (56.7%) and relapsed/refractory AML (60.1%) (p > 0.05). The CR rate was also significantly higher in patients with favorable (64.5%) and intermediate (69.6%) karyotypes than those with unfavorable one (29.5%) (p < 0.05). Remarkably, the CR rate of CAG was significantly higher than those of non-CAG regimens (odds ratio 2.43). CAG regimen was well tolerated, with cardiotoxicity in 2.3% and early death in 5.2% of the cases. In conclusion, CAG regimen was an effective and safe regimen for the treatment of AML, and may be more effective than non-CAG regimens. Randomized controlled trials are strongly recommended to evaluate its efficacy and safety in comparison with the current standard treatment.

Sujets

• Acute myeloid leukemia
• Myelodysplastic syndrome
• CAG
• Aclarubicin
• Meta-analysis

Informations

• Publié par: biomed
• Publié le: 01 janvier 2011
• Nombre de lectures: 9
• Langue: English

Extrait

Wei et al. Journal of Hematology & Oncology 2011, 4:46
http://www.jhoonline.org/content/4/1/46 JOURNAL OF HEMATOLOGY
& ONCOLOGY
RESEARCH Open Access
A meta-analysis of CAG (cytarabine, aclarubicin,
G-CSF) regimen for the treatment of 1029
patients with acute myeloid leukemia and
myelodysplastic syndrome
1,2* 1 2 1 1 2*Guoqing Wei , Wanmao Ni , Jen-wei Chiao , Zhen Cai , He Huang and Delong Liu
Abstract
The regimen of cytarabine, aclarubicin and G-CSF (CAG) has been widely used in China and Japan for treatment of
acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We searched literature on CAG between 1995
and 2010 and performed a meta-analysis to determine its overall efficacy using a random-effects or fixed-effects
model. Thirty five trials with a total of 1029 AML (n = 814) and MDS (n = 215) patients were included for analysis.
The CR rate of AML (57.9%) was significantly higher than that of MDS (45.7%) (p < 0.01). No difference in CR was
noted between the new (56.7%) and relapsed/refractory AML (60.1%) (p > 0.05). The CR rate was also significantly
higher in patients with favorable (64.5%) and intermediate (69.6%) karyotypes than those with unfavorable one
(29.5%) (p < 0.05). Remarkably, the CR rate of CAG was significantly higher than those of non-CAG regimens (odds
ratio 2.43). CAG regimen was well tolerated, with cardiotoxicity in 2.3% and early death in 5.2% of the cases. In
conclusion, CAG was an effective and safe regimen for the treatment of AML, and may be more effective
than non-CAG regimens. Randomized controlled trials are strongly recommended to evaluate its efficacy and safety
in comparison with the current standard treatment.
Keywords: acute myeloid leukemia, myelodysplastic syndrome, CAG, aclarubicin, meta-analysis
Introduction Aclarubicin is an oligosaccharide anthracycline, and an
Intensive chemotherapy can achieve complete remission antineoplastic antibiotic. It can intercalate into DNA
(CR) in 60% - 80% of patients with newly diagnosed de and interact with topoisomerase I and II, thereby inhi-
novo acute myeloid leukemia (AML) [1,2]. However, biting DNA replication and DNA repair [11]. This agent
current therapy is still unsatisfactory in patients with is less cardiotoxic than doxorubicin and daunorubicin
high-risk AML including elderly, relapsed, refractory, [12,13]. In 1995, a Japanese group reported a new che-
and secondary AML. Intensive chemotherapy is gener- motherapy regimen for AML treatment, which inte-
ally unsatisfactory in these patients because of drug grated granulocyte colony-stimulating factor (G-CSF)
resistance, poor performance status (PS), dysfunction of priming into the combination of low-dose cytarabine
multiple organs, and high treatment-related toxicities, (Ara-C) and aclarubicin (CAG regimen) [14]. The CAG
2regimen consists of low-dose Ara-C 10 mg/mleading to high early death (ED) rate [3-6]. Novel agents ,SQQ12
2and regimens are being developed for this group of hr on days 1-14, aclarubicin 7 mg/m , QD on days 1-8,
2patients [2,7-10]. or 14 mg/m , IV QD on days 1-4, and G-CSF 200 μg/
2m , SQ QD on days 1-14. The rationale for the regimen
includes: (1) G-CSF priming has been found to preferen-
* Correspondence: [e-mail]; [e-mail] tially potentiate Ara-C and anthracycline- mediated
1Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang
cytotoxicity on AML cells and AML progenitor cells
University School of Medicine, Hangzhou, China
2 (CFU-AML), presumably by enhancing G0 resting AMLDivision of Hematology and Oncology, New York Medical College and
Westchester Medical Center, Valhalla, New York, USA cells into the cell cycle [15]; (2) prolonged exposure to
Full list of author information is available at the end of the article
© 2011 Wei et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.Wei et al. Journal of Hematology & Oncology 2011, 4:46 Page 2 of 13
http://www.jhoonline.org/content/4/1/46
low-dose Ara-C and G-CSF can lead to preferential kill- past decades [4,23,24]. In general, the 35 studies chosen
ing of CFU-AML [16]; (3) Aclarubicin is effective for final analysis followed the standard definitions
regardless of multi-drug resistance gene status [17]; (4) described above. CR rates and side effects were carefully
CAG combination may inhibit the self-renewal capacity reviewed and compiled. Two major side effects, cardio-
of CFU-AML and leukemia stem cells [18]. Since then, toxicity and early death (ED), were chosen for further
CAG regimen has been used to treat AML and myelo- analysis since these two toxicities are generally more
dysplastic syndrome (MDS) patients widely, particularly objective. In studies which did not clearly define the cri-
for high-risk and elderly patients, in China and Japan. teria of cardiotoxicity, the toxicity was counted as being
However, the overall efficacy and safety of CAG regimen present when a study reported mortality cases due to
have not been adequately evaluated. All published stu- cardiac causes. There were different criteria for ED defi-
dies on CAG were small phase II studies with significant nition among the studies. All deaths of any cause within
variation in clinical outcomes. In this study, we per- 8 weeks of induction therapy were counted as ED in
formed a systematic review and meta-analysis to assess this meta-analysis since most of the early death reports
the overall treatment efficacy and the adverse events of in this series were within 8 weeks of induction therapy.
the CAG regimen. This would also reduce the chance of under-reporting
the toxicity. Standard age definitions were used, i.e.
Materials and methods young AML: age < = 60; Elderly AML: age >60.
Data source
The databases of PubMed, Wanfang Data, as well as Statistical analysis
American Society of Hematology (ASH) and American All statistical analyses were performed using version 2 of
Society of Clinical Oncology (ASCO) annual meeting the Comprehensive MetaAnalysis program (Biostat, Eng-
abstracts were searched for articles published in English, lewood,NJ,USA).TheCRrates of patients treated with
Chinese and Japanese languages between January 1995 CAG regimen were directly extracted from individual
and December 2010. Eligible studies were relevant clini- studies. For subgroup analysis of patients with newly
cal trials on AML and MDS patients treated with CAG diagnosed, refractory/relapsed AML, and MDS or AML
regimen. Key words used were CAG, chemotherapy, leu- transformed from MDS (MDS/t-AML) patients, numbers
kemia, and MDS. An independent search using the cita- of patients in CR were extracted from individual studies
tion database Wanfang Data (http://www.wanfangdata. and CR rates were recalculated from the derived data.
com) was also performed to identify those publications For studies with a control group, the odds ratio (OR) of
in Chinese only. CR rates was also calculated. For the meta-analysis, both
fixed-effects and random-effects models were considered.
Study selection For each meta-analysis, the Cochrane’sQstatisticwas
The publications identified were carefully screened. Pre- first calculated to assess the heterogeneity of the included
clinical studies, case reports and reviews were excluded. studies. For p values less than 0.1, the assumption of
Several reports had duplicate or overlapping informa- homogeneity was deemed invalid, and the random-effects
tion. Only the latest updated reports were included for model was used only after substantial efforts were made
meta-analysis. For two studies by Qian’s group [19,20], to explore the possible reasons for the heterogeneity.
it was impossible to decipher whether duplicate or over- Otherwise, data were assessed using both fixed-effects
lapping information was used. These were treated as and random-effects models. We used the Begg and Egger
individual studies. Efforts also were made to contact the tests to evaluate the presence of publication bias regard-
Chinese investigators to clarify study issues. We also ing the primary end point CR rates. A two-tailed p value
contacted Japanese investigators to obtain original publi- of less than 0.05 was deemed statistically significant. All
cations in with English abstracts. the statistical analyses were done by GW and DL.
Clinical endpoints Results
We extracted details on study characteristics, patient Selection of studies
characteristics, treatment information, results and fol- Using the key words, our search yielded a total of 135
low-up from the selected trials. Two investigators studies on CAG. Fifty seven studies were irrelevant to
reviewed the data independently (GW and DL). The pri- CAG regimen trials, and were excluded. Another 32 stu-
mary end point of the meta-analysis was CR rate. AML dies were eliminated due to inadequate information,
CR was defined using the criteria developed by an Inter- duplicate and/or overlap reporting. Nine case reports and
national Working Group [21]. The criteria for refractory 2 studies focus on other kinds of leukemia were also
andrelapsedAMLweredescribedpreviously[22].The excluded. A total of 35 clinical studies were eligible for
criteria for karyotype classificat