HLA-Mismatched Stem-Cell Microtransplantation As Postremission Therapy for Acute Myeloid Leukemia: Long-Term Follow-Up

  1. Hui-Sheng Ai⇓
  1. Mei Guo, Kai-Xun Hu, Guang-Xian Liu, Chang-Lin Yu, Jian-Hui Qiao, Qi-Yun Sun, Zheng Dong, Xue-Dong Sun, Hong-Li Zuo, Qiu-Hong Man, Zhi-Qing Liu, Tie-Qiang Liu, Li Wei, Bing Liu, and Hui-Sheng Ai,Affiliated Hospital of Academy of Military Medical Sciences; Jun-Xiao Qiao, Wan-Jun Sun, Hong-Xia Zhao, and Ya-Jing Huang, Second Artillery General Hospital, Beijing; Juan Wang, Centre Hospital of Cangzhou City, Cangzhou; and Xu-Liang Shen, Chang Zhi Medical College, Chang Zhi, China.
  1. Corresponding author: Hui-Sheng Ai, MD, Department of Hematology and Transplantation, Affiliated Hospital of the Academy of Military Medical Sciences, Dongdajie 8, Beijing 100071, China; e-mail: huishengai{at}163.com.

  1. Both M.G. and K.-X.H. contributed equally to this work.

 
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Abstract

Purpose Despite best current therapies, approximately half of patients with acute myeloid leukemia in first complete remission (AML-CR1) with no HLA-identical donors experience relapse. Whether HLA-mismatched stem-cell microtransplantation as a novel postremission therapy in these patients will improve survival and avoid graft-versus-host disease (GVHD) is still unknown.

Patients and Methods One hundred one patients with AML-CR1 (9 to 65 years old) from four treatment centers received programmed infusions of G-CSF–mobilized HLA-mismatched donor peripheral-blood stem cells after each of three cycles of high-dose cytarabine conditioning without GVHD prophylaxis. Donor chimerism and microchimerism and WT1+CD8+ T cells were analyzed.

Results The 6-year leukemia-free survival (LFS) and overall survival (OS) rates were 84.4% and 89.5%, respectively, in the low-risk group, which were similar to the rates in the intermediate-risk group (59.2% and 65.2%, respectively; P = .272 and P = .308). The 6-year LFS and OS were 76.4% and 82.1%, respectively, in patients who received a high dose of donor CD3+ T cells (≥ 1.1 × 108/kg) in each infusion, which were significantly higher than the LFS and OS in patients who received a lower dose (< 1.1 × 108/kg) of donor CD3+ T cells (49.5% and 55.3%, respectively; P = .091 and P = .041). No GVHD was observed in any of the patients. Donor microchimerism (2 to 1,020 days) was detected in 20 of the 23 female patients who were available for Y chromosome analysis. A significant increase in WT1+CD8+ T cells (from 0.2% to 4.56%) was observed in 33 of 39 patients with positive HLA-A*02:01 antigen by a pentamer analysis.

Conclusion Microtransplantation as a postremission therapy may improve outcomes and avoid GVHD in patients with AML-CR1.

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INTRODUCTION

It is still a challenge to treat patients with acute myeloid leukemia (AML) in first complete remission (CR1). High-dose cytarabine (Ara-C) and autologous stem-cell transplantation as postremission intensification therapy have long been proven effective in improving survival for patients with AML-CR1, but the relapse rate remains high.1–3 Allogeneic stem-cell transplantation (alloSCT) with intensive myeloablative conditioning results in a lower relapse rate in patients with AML-CR1, but also in higher severe graft-versus-host disease (GVHD) and transplantation-related mortality.4,5 Nonmyeloablative stem-cell transplantation based on reduced-intensity conditioning may improve survival and reduce toxicity of conditioning,5–8 but GVHD is still significant. HLA-mismatched stem-cell transplantation can increase available donors but also has significant mortality.9–12

Recently, several studies have revealed that granulocyte colony-stimulating factor (G-CSF) –mobilized donor peripheral-blood stem cells (GPBSCs) based on alloSCT can be effective in mediating graft-versus-leukemia (GVL) effects and promote hematologic recovery without amplification of acute GVHD.13,14 More recently, our randomized clinical study with a small cohort of elderly patients with AML demonstrated that infusion of HLA-mismatched GPBSC combined with chemotherapy improves patient outcome and avoids GVHD when compared with only chemotherapy.15 On the basis of these observations, we designed a stem-cell microtransplantation as a new postremission therapy for patients with AML-CR1 in intermediate- and low-risk groups in which patients received programmed infusions of HLA-mismatched GPBSCs after intensive Ara-C chemotherapy without GVHD prophylaxis with the intention to form a transit or durable donor microchimerism and to induce specific antileukemia effects and avoid GVHD.

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PATIENTS AND METHODS

Eligible patients were between 9 and 65 years of age with de novo AML between May 2004 and February 2011 (Table 1). Diagnosis was confirmed according to the French-American-British classification and WHO criteria (except for patients with acute promyelocytic leukemia). Cytogenetic studies on pretreated bone marrow samples were performed at diagnosis using a standard banding technique and classified according to the International System of Human Cytogenetic Nomenclature.16,17 Molecular markers such as ETO, PML/RARa, NPM1, and FLT3-ITD were analyzed after October 2008. Patients with t(8;21), ETO, and/or NPM1 without FLT3-ITD were defined as low risk, whereas patients with complex karyotypes, unfavorable cytogenetics, FLT3-ITD gene expression, secondary AML, and initial leukocytes more than 100 × 109/L were defined as high risk. The other patients were classified as intermediate risk.2,3,16,17

View this table:
Table 1.

Demographics and Clinical Characteristics of Patients With AML-CR1

The protocol was approved by the Human Ethics Committees of the Affiliated Hospital of the Academy of Military Medical Sciences, Beijing; the Second Artillery General Hospital, Beijing; the Central Hospital of Cangzhou City, Hebei Province; and Chang Zhi Medical College, Shanxi Province, China. This protocol was conducted in accordance with the Declaration of Helsinki. All patients and donors gave written informed consent before enrollment onto the study.

Before transplantation, donor and recipient HLA-A, -B, -C, -DRB1, and -DQB1 loci were typed at intermediate resolution by a polymerase chain reaction (PCR) with sequence-specific primer method. Of the 101 patient/donor pairs, 32 were mismatched in four of 10, 61 were mismatched in five of 10, six were mismatched in six of 10, and two were mismatched in eight of 10 HLA alleles. The median donor age was 36 years old, and donors included 27 brothers, 13 sisters, 15 sons, 14 daughters, 16 fathers, 10 mothers, three uncles, one nephew, and two cousins.

Treatment Design

Remission induction chemotherapy consisted of intravenous infusion of Ara-C 150 mg/m2 daily for 7 days and either mitoxantrone (10 mg/m2) or daunorubicin (45 mg/m2) daily for 3 days. To assess patient response, a mandatory bone marrow aspirate was performed on day 7 and at the time of bone marrow recovery or at day 28 after the start of chemotherapy. If residual leukemia was present, a second cycle of the same induction therapy was permitted. Patients who did not achieve a complete remission (CR) after two cycles of induction therapy were removed from the study.

Patients who achieved CR1 in the high-risk group were assigned to receive alloSCT and were excluded. Low- and intermediate-risk patients who had available HLA-matched related donor and were assigned to receive alloSCT were also excluded from this study. Only patients who were defined as low or intermediate risk and lacked HLA-matched donors were enrolled onto this study.

The microtransplantation regimen consisted of three cycles of high-dose Ara-C chemotherapy (Ara-C 2.5 g/m2 per 12 hours intravenously on days 1, 2, and 3) followed by infusion of GPBSCs 24 hours after each completion of Ara-C therapy with a 3-month interval between the courses. The dose of Ara-C was decreased to 2.0 g/m2 for six dosages if patients were older than age 55 years. Otherwise, the regimen with intermediate-dose Ara-C chemotherapy (Ara-C 1.5 g/m2) was terminated in November 2006, based on a previous small randomized study that showed that intermediate-dose Ara-C with microtransplantation (n = 20) had better outcome than intermediate-dose Ara-C chemotherapy only (n = 19) in such patients. No further therapy was given after final microtransplantation. Prophylaxes for GVHD, cytomegalovirus, and Pneumocystis jiroveci were not used before and after the microtransplantation.

Mobilization and Apheresis of Donor Peripheral Mononuclear Cells

Apheresis of donor peripheral mononuclear cells was performed using a CS-3000S cell separator (Baxter, Deerfield, IL) after the donors were subcutaneously injected with G-CSF 5 μg/kg twice a day for 5 days. The apheresed donor cells were aliquoted and cryopreserved in liquid nitrogen, but fresh donor cells were used for the first course. The median numbers of mononuclear, CD34+, CD3+, and natural killer (NK) cells infused per course were 2.8 × 108/kg (range, 1.2 to 5.6 × 108/kg), 1.8 × 106/kg (range, 0.7 to 5.2 × 106/kg), 1.1 × 108/kg (range, 0.4 to 2.4 × 108/kg), and 0.18 × 108/kg (range, 0.023 to 0.684 × 108/kg), respectively.

Analysis of WT1/HLA-A*02:01+CD8+ T Cells

Only 39 of 101 patients who and/or whose donor had HLA-A*02:01 were monitored for WT1/HLA-A*02:01+CD8+ T cells from peripheral blood before and after microtransplantation, as previously described.18 Briefly, at least 1 × 106 freshly isolated peripheral-blood mononuclear cells were labeled with CD3 and CD8 antibodies and a phycoerythrin-conjugated WT1/HLA-A*02:01 pentamer (RMFPNAPYL; Proimmune, Oxford, United Kingdom). A corresponding IgG2a isotype of CD3 and CD8 antibodies and pentamer of an irrelevant peptide (SLYNTVATL; Proimmune) were used as negative controls. WT1/HLA-A*02:01+CD8+ T cells were reported as a percentage of pentamer-positive T cells among the total CD8+ T-cell population.

Detection of Donor Chimerism and Donor Microchimerism

Chimerism detection.

Both peripheral-blood cells and bone marrow cells from all 101 patients were tested for hematopoietic donor chimerism by a standard cytogenetic analysis and a semiquantitative PCR-based analysis of the short tandem repeats with a sensitivity of 1% as previously described.12

Microchimerism detection.

Only 23 female patients who had a male donor were consecutively monitored for donor microchimerism (donor cells < 1%) using peripheral-blood cells and bone marrow cells in a real-time quantitative PCR method for the detection of the sex-determining region of the Y chromosome with a sensitivity of 10−6 cells as previously described.15

Response Criteria and Outcome Evaluation

Responses were determined according to the revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia.1,16,17 Relapse was defined as marrow infiltration of more than 5% leukemia cells in a patient with a previous CR or with evidence of extramedullary leukemia. Leukemia-free survival (LFS) was measured as the length of time from CR to relapse. Overall survival (OS) was defined as the time from diagnosis to death or to the last date of follow-up until October 2011.

The recovery time of neutrophils and platelets was defined as the first of 3 consecutive days on which the absolute neutrophil count and platelet count exceeded 0.5 × 109/L and 30 × 109/L, respectively. Acute GVHD and chronic GVHD were defined according to published criteria.19

Statistical Analysis

SPSS 9.0 software (SPSS, Chicago, IL) was used for all the statistical analyses. Survival data were analyzed by means of the log-rank test, and the survival curves were made using the Kaplan-Meier method. The t test or Wilcoxon rank sum test and Cox proportional hazards models were applied to identify significantly independent factors for LFS and OS, respectively. Statistical significance was defined as P < .05.

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RESULTS

Of 265 patients, 220 achieved CR (83%), of whom 138 patients received one induction course and 82 patients required a second course. Of the 220 patients who achieved CR, 101 patients who were in the low- or intermediate-risk group and were lacking HLA-matched related donors were enrolled onto this study. The 119 patients who were not enrolled onto the study included 51 patients who received HLA-matched alloSCT, 18 patients who received HLA-mismatched (n = 15) or unrelated (n = 3) alloSCT, 17 patients with early relapse, 10 patient who refused participation, 10 patients who received other nonprotocol treatments, five patients with withdrawal by physician, three patients with early death, and five patients with unknown reason for nonparticipation.

Of the 101 patients, 93 patients (92.1%) finished all therapy courses. The other eight patients, who terminated the second (n = 2) or third course (n = 6) because of either leukemia relapse (n = 7) or severe infection (n = 1), were included in the final data analyses (Fig 1).

Fig 1.
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Fig 1.

Flow chart of microtransplantation. Allo-SCT, allogeneic stem-cell transplantation; AML, acute myeloid leukemia; CR, complete remission; CR1, first complete remission; CR2, second complete remission; MST, micro stem-cell transplantation; NR, no response.

LFS and OS

The median follow-up period was 51 months (range, 8 to 72 months), and no patient was lost during the follow-up period. During follow-up, 24 patients (23.8%) experienced relapse. The 6-year LFS rates were 84.4% and 59.2% in the low-risk and intermediate-risk groups, respectively (P = .272; Fig 2A). The 6-year OS rates were 89.5% and 65.2% in the low-risk and intermediate-risk groups, respectively (P = .308; Fig 2B). By multivariate analysis, among the factors influencing LFS and OS (eg, sex; the numbers of mononuclear, CD34+, CD3+, and NK cells infused; and killer-cell immunoglobulin-like receptor profile of NK cells), only the dose of donor T cells infused was identified as a positive prognostic parameter; patients who received high-dose donor CD3+ T cells (≥ 1.1 × 108/kg) in each course had much higher 6-year LFS and OS rates (76.4% and 82.1%, respectively) than patients receiving low-dose donor CD3+ T cells (< 1.1 × 108/kg; 49.5% and 55.3%, respectively; P = .091 and P = .041; Figs 2C and 2D). There were no significant differences in the 6-year LFS and OS rates between patients who received a higher dose (≥ 0.3 × 108/L) versus a lower dose (< 0.3 × 108/L) of infused NK cells (74.4% and 86.3% v 63.1% and 67.9%, respectively; P = .753 and P = .41).

Fig 2.
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Fig 2.

(A) The 6-year leukemia-free survival (LFS) rate was not significantly different (P = .272) between the low-risk group (84.4%) and intermediate-risk group (59.2%). (B) The 6-year overall survival (OS) rates were 89.5% and 65.2% in the low-risk and intermediate-risk groups, respectively (P = .308). The 6-year (C) LFS and (D) OS rates were 76.4% and 82.1%, respectively, in patients with a high dose of donor T cells (≥ 1.1 × 108/kg) for each course, which were significantly higher than the rates in patients with a lower dose of donor T cells (49.5% and 55.3%, respectively; P = .091 and P = .041).

Hematopoietic Recovery

The median time to neutrophil recovery was 8 days (range, 5 to 16 days), 9 days (range, 2 to 15 days), and 12 days (range, 7 to 19 days) after courses 1, 2, and 3, respectively. The median time to platelet recovery was 11 days (range, 5 to 36 days), 12 days (range, 1 to 36 days), and 14 days (range, 7 to 36 days) after courses 1, 2, and 3, respectively. Three patients had delayed recovery of neutrophils and platelets, and one of these patients died of severe fungus infection after the second course.

GVHD and Infections

No acute or chronic GVHD was observed in any of the patients during the entire treatment and follow-up periods. Three patients developed slight skin rash on the second day after the first (n = 2) or second (n = 1) course of the therapy, which disappeared within 12 hours after antiallergic therapy. Of the 101 patients, 22.3%, 19.4%, and 21.3% developed severe fungal and/or bacterial infections after courses 1, 2, and 3, respectively. Cytomegalovirus and Pneumocystis jiroveci pneumonia were not observed in any of the patients.

Detection of WT1+CD8+ T Cells

Of 39 patients with positive HLA-A*02:01, 33 patients (84.6%) had significantly increased WT1+CD8+ T cell responses, with frequencies of WT1+CD8+ T cells between 0.2% and 4.56% of the CD8+ population from 11 to 1,462 days after transplantation (Fig 3). Kinetic monitoring of WT1+CD8+ T cells showed that increases of WT1+CD8+ T cells emerged on day 10 to 14 and remained at higher levels between 28 and 360 days after the microtransplantation. Of the 33 patients with increased WT1+CD8+ T cells, 24 patient/donor pairs were both HLA-A*02:01 positive, whereas three donors only and six patients only were HLA-A*02:01 positive. WT1+CD8+ T cells were not detected in the other six patients with positive HLA-A*02:01. Patients with increased WT1+CD8+ T cells had higher LFS and OS rates (65.7% and 70.1%, respectively) than patients without increased WT1+CD8+ T cells (33.3% and 50%, respectively), but the difference was not statistically significant (P = .078 and P = .08, respectively).

Fig 3.
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Fig 3.

Kinetic monitoring of WT1+CD8+ T cells after microtransplantation. (A) Normal data; (B) (log)10 of data in part A. Of 39 patients with positive HLA-A*02:01, 33 patients had a significant increase in WT1+CD8+ T-cell response, with frequencies of WT1+CD8+ T cells between 0.2% and 4.56% of the CD8+ population from 11 to 1,462 days (48.73 months) after transplantation. MST, micro stem-cell transplantation.

Donor Chimerism and Microchimerism

Chimerism detection.

Of the 101 patients, only four patients had a transient (< 2 weeks) and low percentage (15% to 31%) of mixed donor chimerism (MC); the other 97 patients had no MC or full donor chimerism (FDC) after microtransplantation.

Microchimerism detection.

Of the 23 female patients with available SRY gene, 20 patients (86.9%) had detectable donor microchimerism, with a range of 0.00000697 to 0.46 copies of gene expression compared with the inner control gene β-globin (1.0 copy). Kinetic analysis showed that donor microchimerism emerged on day 2 and peaked on day 7 to 14 after microtransplantation. Persistent times of donor microchimerism were 34 months (n = 1), 15 months (n = 3), 12 months (n = 1), 8 months (n = 3), 6 months (n = 3), 4 months (n = 2), 1 month (n = 2), and 2 weeks (n = 5) after microtransplantation (Fig 4). Donor microchimerism was not detected in the other three assessable female patients and all of the specimens before transplantation. In the 20 patients with detectable donor microchimerism, 10 patients and/or their donors were HLA-A*02:01 positive, and all 10 patients had increased WT1+CD8+ T cells after transplantation. There was no positive correlation between the emergence and persistent time of donor microchimerism and number of CD3+, CD34+, and mononuclear cells infused.

Fig 4.
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Fig 4.

The kinetics of donor microchimerism after the microtransplantation. (A) Normal data; (B) (log)10 of data in part A. Donor microchimerism was detected in 20 of 23 patients (range, 0.00000697 to 0.46 gene expression copies compared with the internal control gene β-globin [1.0 copy]). The kinetics of donor microchimerism showed that microchimerism emerged on day 2 and reached its peak on days 7 through 14 after microtransplantation. The longest persistent time of donor microchimerism was 1,020 days. MST, micro stem-cell transplantation.

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DISCUSSION

The optimal postremission therapy can significantly improve the outcome of patients with AML. The aim of this study was to test whether microtransplantation as a new treatment method for patients with AML can produce significant antileukemia effects and reduce treatment-related toxicities to improve long-term outcome in a large cohort, based on our previously published observations in older patients with AML, which showed that GPBSCs with chemotherapy significantly improved outcome compared with chemotherapy alone.15 The results showed that 101 patients with AML-CR1 in the low-risk or intermediate-risk group who received microtransplantation therapy achieved higher 6-year LFS and OS rates (84.4% and 89.5%, respectively, in low-risk group; 59.2% and 65.2%, respectively, in intermediate-risk group) compared with rates previously reported in the literature with high- or intermediate-dose Ara-C as postremission chemotherapy (5-year LFS and OS: approximately 61% and 66% in low-risk group and 41% and 50% in intermediate-risk group).1–5,6,7,20,21 Notably, no acute or chronic GVHD was observed in any of the patients. These results suggest that the microtransplantation as a postremission therapy is effective in improving LFS and avoids transplantation-related complications such as GVHD.

The main goal of alloSCT is to achieve durable donor cell engraftment and maximize GVL effects.4–7 In the present study, FDC was not found in any of patients, and transient MC was only observed in four patients, whereas donor microchimerism was detected in 20 of the 23 female patients who had available SRY gene data, suggesting that the donor cells infused (at least a small population) may remain long term as a microchimerism within the recipients.

Several studies have reported that antitumor response still remained despite loss of donor chimerism in some patients with cancer or leukemia who received alloSCT.17,22,23 Other studies have demonstrated that the detection of WT1+CD8+ T cells using tetramer or pentamer analysis might provide indirect evidence for GVL and recipient-versus-leukemia effects after donor lymphocyte infusion in patients with leukemia.17,24,25 In this study, significant increases in WT1+CD8+ T cells were observed in 33 of 39 patients with positive HLA-A*02:01, including all 10 patients with detectable donor microchimerism, suggesting the existence of a specific antileukemia effect mediated by the microtransplantation that may be independent of FDC or MC. We further identified the cell origin of the WT1+CD8+ T cells in 33 patients using an HLA-A*02:01 pentamer; 24 patient/donor pairs were both HLA-A*02:01 positive, whereas three donors only and six patients only were HLA-A*02:01 positive. These results revealed that the microtransplantation mediated specific antileukemia effects, not only GVL effects but also recipient-versus-leukemia effects, through direct activity or interaction with the recipient's immune system after donor cell infusions and rejections.18,24,25 More importantly, the clinical results showed that patients receiving a high dose of CD3+ cells had significantly higher 6-year OS compared with patients receiving a lower dose. Although not statistically relevant, a trend toward better LFS and OS was observed when comparing patients with increased WT1+CD8+ T cells versus patients without increased WT1+CD8+ T cells, indicating that the infused donor cells, including T cells, NK cells, and other immune elements, may play an important role in inducing specific antileukemia effects and thus in improving clinical outcome.14–16,26

Severe GVHD frequently occurs after alloSCT with HLA-matched or -mismatched donors.4–9 However, no acute or chronic GVHD was observed in any of the 101 patients after microtransplantation in this study, despite the infusion of a high dose of HLA-mismatched donor CD3+ cells (up to 2.4 × 108/kg) and lack of GVHD prophylaxis. The exact mechanism of the successful avoidance of GVHD after microtransplantation remains unclear. Recently, it has been suggested that donor leukocyte microchimerism may help avoid graft rejection or severe GVHD in patients with renal or liver transplantation.27,28 In the present study, donor microchimerism was observed in 20 of the 23 detectable patients, implying a potential link between microchimerism and lack of GVHD. Furthermore, other studies have shown that the degree of host immune suppression plays a role in induction of chimerism and occurrence of GVHD. One study reported that all four patients who received autologous stem-cell transplantation before donor lymphocyte infusion experienced acute GVHD, whereas the other 12 patients without immune-suppressive treatment did not develop GVHD.29,30 In our study, none of the patients had received strong immunosuppressive treatment before microtransplantation, preserving considerable immune functions of the recipients, which may be important in preventing GVHD. In addition, GPBSC contains a large number of stem cells, progenitor cells, and regulatory T lymphocytes and NK cells, which may be helpful in regulating the TH1/TH2 balance, thus alleviating or attenuating GVHD.13,14

Another important finding of this study is that microtransplantation decreased time to hematologic recovery, although only a donor microchimerism was observed. We speculate that this finding may be linked to the fact that GPBSC contains large numbers of hematopoietic stem and progenitor cells, which facilitated recipients' hematopoietic recovery. Another possible reason may be related to GPBSC promoting hematopoietic recovery in cooperation with G-CSF. Other benefits of the microtransplantation were relatively few severe infections and low financial cost of the treatment.

In conclusion, microtransplantation can improve outcome but avoid GVHD and is associated with donor microchimerism and potential antileukemia effects, which may provide a safe and effective postremission therapy for patients with AML-CR1. Further studies on large cohorts of patients are needed.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

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AUTHOR CONTRIBUTIONS

Conception and design: Mei Guo, Kai-Xun Hu, Guang-Xian Liu, Chang-Lin Yu, Jian-Hui Qiao, Zheng Dong, Hui-Sheng Ai

Financial support: Hui-Sheng Ai

Administrative support: Mei Guo, Kai-Xun Hu, Guang-Xian Liu, Chang-Lin Yu, Jian-Hui Qiao, Qi-Yun Sun, Zheng Dong, Hui-Sheng Ai

Provision of study materials or patients: Mei Guo, Kai-Xun Hu, Guang-Xian Liu, Chang-Lin Yu, Jian-Hui Qiao, Jun-Xiao Qiao, Zheng Dong, Wan-Jun Sun, Xue-Dong Sun, Juan Wang, Xu-Liang Shen, Hui-Sheng Ai

Collection and assembly of data: Mei Guo, Kai-Xun Hu, Jian-Hui Qiao, Jun-Xiao Qiao, Zheng Dong, Wan-Jun Sun, Xue-Dong Sun, Hong-Li Zuo, Qiu-Hong Man, Zhi-Qing Liu, Tie-Qiang Liu, Hong-Xia Zhao, Ya-Jing Huang, Li Wei, Bing Liu, Juan Wang, Xu-Liang Shen, Hui-Sheng Ai

Data analysis and interpretation: Hui-Sheng Ai, Mei Guo, Kai-Xun Hu, Jian-Hui Qiao, Qi-Yun Sun, Jun-Xiao Qiao, Zheng Dong

Manuscript writing: All authors

Final approval of manuscript: All authors

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Affiliations

Mei Guo, Kai-Xun Hu, Guang-Xian Liu, Chang-Lin Yu, Jian-Hui Qiao, Qi-Yun Sun, Zheng Dong, Xue-Dong Sun, Hong-Li Zuo, Qiu-Hong Man, Zhi-Qing Liu, Tie-Qiang Liu, Li Wei, Bing Liu, and Hui-Sheng Ai, Affiliated Hospital of Academy of Military Medical Sciences; Jun-Xiao Qiao, Wan-Jun Sun, Hong-Xia Zhao, and Ya-Jing Huang, Second Artillery General Hospital, Beijing; Juan Wang, Centre Hospital of Cangzhou City, Cangzhou; and Xu-Liang Shen, Chang Zhi Medical College, Chang Zhi, China.

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Footnotes

  • Author affiliations appear at the end of this article.

  • See accompanying editorial on page 4051

  • Supported by Grant No. 81130054 from the National Natural Foundation of China and Grants No. 2010CB529404, 2011C13964803, and 2012C13966904 from the National Basic Research Program of China (973 Program).

  • H.-S.A., as principal investigator, had full access to all of the data in this study and takes responsibility for integrity of the data and accuracy of data analysis. The funding agencies/sponsors had no role in data collection, analysis, manuscript preparation, or authorization for publication.

  • Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Received January 25, 2012.
  • Accepted August 22, 2012.
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  1. Published online before print October 8, 2012, doi: 10.1200/JCO.2012.42.0281 JCO vol. 30 no. 33 4084-4090
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