The role of donor lymphocyte infusion (DLI) in the prophylaxis of relapse has not been defined. We retrospectively analyzed the data from 88 patients with advanced-stage acute leukemia after HLA-mismatched/haploidentical hematopoietic SCT (HSCT) whose treatment did (n=61) or did not (n=27) include granulocyte CSF (GCSF)-primed PBPCs infusion (GPBPCI). The two groups were compared with respect to relapse and OS. Further, a detailed analysis of risk factors was performed. The 2-year cumulative incidence of relapse in patients receiving prophylactic GPBPCI and not receiving prophylactic GPBPCI were 36% and 55% (P=0.017), respectively. Estimated survival at 3 years was 31% for patients receiving prophylactic GPBPCI and 11% for patients not receiving prophylactic GPBPCI (P=0.001). The three-year probability of leukemia-free survival was also higher in patients who received prophylactic GPBPCI (22%) compared with patients who did not (11%) (P=0.003). Multivariate analysis for relapse showed that use of prophylactic GPBPCI after transplantation was an independent prognostic factor (P=0.025). Higher OS was associated with use of prophylactic GPBPCI (P=0.002), AML (P=0.027) and female sex (P=0.023). Our results suggest that use of prophylactic GPBPCI may increase survival of patients with advanced-stage acute leukemia who receive HLA-mismatched/haploidentical HSCT.
Hematopoietic SCT (HSCT) is one of the best options, and sometimes the only option, for the treatment of leukemia, particularly for patients with advanced-stage leukemia. Yet, the relapse rate is still very high for patients with advanced-stage leukemia who are treated by HSCT.1, 2, 3 Sierra et al.1 reported that the cumulative incidences of relapse after T-replete HSCT from unrelated donors were 44% during relapse (n=81) and 63% during primary induction failure (n=16) for AML patients. Aversa et al.2 reported a relapse incidence of 51% for 38 relapsed, acute leukemia patients who were undergoing haplo-identical HSCT. Our own data showed that the 2-yr probability of relapse in high-risk group was 51.5% for ALL patients.3
Our previous investigations have shown that infusion of granulocyte CSF (GCSF)-primed, PBPCs (GPBPCs) exhibited a comparative, or stronger, GVL effect and a comparative or lower incidence of GVHD, compared with non-primed lymphocytes.4 When GPBPC infusion (GPBPCI) was combined with short-term use of immunosuppressants for GVHD prophylaxis, the incidence of fatal GVHD complicated with GPBPCI was further reduced.5 Our initial investigation showed that use of GPBPCI combined with short-term immunosuppressant was feasible in patients with advanced leukemia to prevent relapse following HLA-mismatched HSCT.6 As randomized trials will not be available in the near future, a retrospective comparison among patients treated with or without prophylactic GPBPCI was performed to evaluate the role of GPBPCI in this setting. In addition, a detailed analysis of risk factors for relapse and survival was performed.
Materials and methods
Consecutive patients with advanced-stage acute leukemia (n=88) receiving HSCT from HLA-mismatched family donors during the same period (between January 2003 and March 2011) were enrolled in the study. A total of 61 patients were treated with prophylactic GPBPCI and 27 patients received no prophylactic treatment
Thirty-five of the 88 advanced-stage acute leukemia patients were previously enrolled in a study in 20107 and 13 of those 35 patients were previously enrolled in a second report in 2008.6 All of the patients reported before were enrolled and further followed in this study. All protocols were approved by the institutional review board of the Peking University Institute of Hematology, and all patients and their donors signed consent forms.
Patients with acute leukemia in the third CR (CR3) or beyond, or those in non-remission were classified as advanced-stage.8 Patients in the second CR (CR2) were classified as intermediate risk in most studies. Unlike our previous reports regarding high-risk leukemia,6, 7 acute leukemia in the first CR (CR1) with poor-risk cytogenetic abnormalities, such as t (9; 22) or chronic myeloid leukemia in blast phase, were not included in the current study because prophylactic imatinib or preemptive imatinib instead of prophylactic GPBPCI was used in patients with t (9; 22). In addition, patients with myelodysplastic syndrome (MDS)-transformed acute leukemia were not included in the current study. A small proportion of patients were evaluated for the Flt3 internal tandem duplication (patients undergoing HSCT after 2008), so this part of the information was not provided in the present study. The characteristics of the patients and donors are summarized in Table 1.
All donor–recipient pairs were typed at the HLA-A, B and DR loci. For each donor–recipient pair, each patient received stem cells from a family member who shared one HLA haplotype with the patient, but differed to some degree at the HLA-A, B, and D Ags of the haplotype that was not shared. In addition, HLA typing was performed on the parents and offspring of each donor–recipient pair to guarantee a true haploid genetic background among the pairs. The variability in the HLA loci among the patient–donor pairs is shown in Table 1.
Patients received conditioning therapy comprising modified BUCY2, ATG (thymoglobulin) and cytarabine (4 g/m2/d), which was given i.v. on days −10 to −9, BU (4 mg/kg/d), administered orally on days −8 to −6 before January 2008, BU (3.2 mg/kg/d), given i.v. on days −8 to −6 after January 2008, CY (1.8 g/m2/d), administered i.v. on days −5 to −4, Me-CCNU (250 mg/m2), given orally once on day −3, and ATG (thymoglobulin, 2.5 mg/kg/d; Sang Stat, Lyon, France), given i.v. on days −5 to −2.
All patients received CsA, mycophenolate mofetil and short-term MTX as a GVHD prophylactic treatment.9 MTX (15 mg/m2) was administered i.v. on day +1, followed by administration of MTX at 10 mg/m2 on days +3, +6 and +11 after HSCT. Mycophenolate mofetil was tapered from 1 to 0.5 g/day on day 30 and was discontinued over days 45–60 on the basis of the presence or absence of severe GVHD, infectious diseases and relapse risk. The dosage of CsA was adjusted to a blood concentration of 150–250 ng/mL. In case of no evidence of GVHD by day 80–90, CsA dosage was reduced gradually and discontinued around day 120. In case of occurrence of GVHD, CsA was continued.
Collection of hematopoietic cells
Donors were primed with rhG-CSF (5 μg/kg per day; Filgrastim, Kirin, Japan) and injected s.c for 5–6 consecutive days. On the fourth day, BM (granulocyte-BM) cells were harvested. The target mononuclear cell count was 2 × 108 per kg of the recipient weight. In instances of major ABO blood group incompatibility, RBCs were removed from BM cells by density gradient sedimentation with Hespan (B. Braun Medical Inc, Irvine, CA, USA) according to the manufacturer's instructions. On the fifth and sixth days, peripheral blood cells (granulocyte-PB) were collected with a COBE Blood Cell Separator (Spectra LRS, COBE BCT, Inc., Lakewood, CO, USA) at a rate of 80 mL/min from a total blood volume of 10 L. The target mononuclear cell count for transplantation was greater than 3 × 108 mononuclear cells per kg or 2 × 106 CD34+ cells per kg of the recipient weight. The surplus harvested cells were cryo-preserved in dimethyl sulfoxide in a liquid nitrogen chamber. Cryopreservation of surplus GPBPC for potential subsequent DLI is convenient for donors and cost effective. Data on the composition of grafts are shown in Table 1.
Prophylactic treatment with GPBPCI
A G-CSF-primed PBPCI was planned within 60 days post transplantation before hematologic relapse was diagnosed in patients for whom no GVHD occurred or after day 90 post HSCT in patients receiving GPBPCI, who were free of GVHD after 2 weeks off immunosuppression. Before administration of GPBPCI, serious infection had to be cleared and no serious organ failure could be present. The GPBPCI regimen comprised G-CSF-primed PBSCs instead of harvested non-primed donor lymphocytes and short-term immunosuppressive agents for prevention of GVHD after GPBPCI.6 Chimerism status was examined before and after prophylactic treatment with GPBPCI. Lymphocytes were obtained from cryo-preserved G-CSF mobilized peripheral blood. For patients receiving GPBPCI before day 90 after transplantation, original CsA was continued for another 2–4 weeks after the infusion, then tapered and stopped within 4 weeks if no GPBPCI-associated GVHD occurred. For patients receiving GPBPCI after day 90, all immunosuppressive agents should be stopped for at least 2 weeks before the infusion and no active GVHD present. These patients took oral CsA or MTX 10 mg once per week for 2–4 weeks after DLI for the prevention of DLI-associated GVHD.
Prophylactic-modified GPBPCI was administered between 28 days and 120 days (median=48 days) after transplantation in 61 patients. The median number of CD34+ cells that was infused in each patient was 0.59 (0.15–2.3) × 106/kg. The median number of CD3+ cells that was infused in each patient was 0.57 (0.4–1.6) × 108/kg.
Prophylactic GPBPCI was given to 24 out of 47 patients transplanted before July 2009 according to physicians and patients’ intension, and 7 out of these 24 patients received GPBPCI after day 90 post HSCT. On the basis of our preliminary results, physicians and patients’ confidence was increasing, therefore, prophylactic GPBPCI was given as planned before day 60 for patients transplanted after July 2009. Only 4 out of 41 patients transplanted after July 2009 did not receive prophylactic GPBPCI. The reasons for not giving prophylactic GPBPCI in the four patients were GVHD (n=3) and early relapse (n=1).
GPBPCI-mediated GVHD therapy
Methylprednisolone is the best initial therapy for treating acute GVHD after prophylactic MTX or CsA. Prednisone and CsA are considered as first-line therapies for patients with chronic GVHD. Other therapeutic options for acute or chronic GVHD are mycophenolate mofetil, tacrolimus (FK506), azathioprine, thalidomide, monoclonal antibodies directed against CD3 and CD25, and MTX.10
Definitions and assessments
Advanced-stage acute leukemia was defined in the ‘Patient eligibility’ section of the Materials and methods. Neutrophil engraftment was defined as an ANC of 0.5 × 109/L or more for 3 consecutive days and platelet engraftment was defined as 20 × 109/L or more for 7 consecutive days without transfusions. Primary engraftment failure was defined as the absence of donor-derived, myeloid cells by day 60 in patients surviving beyond day 28 after transplantation or as a second allogeneic transplant or reconstitution with autologous cells was needed. Chimerism was determined by at least two of the three following methods: DNA-based HLA typing, PCR DNA fingerprinting of STR on recipient PB cells and chromosomal FISH on recipient BM cells. Acute and chronic GVHD were defined according to published criteria;11, 12 however, GVHD was diagnosed as either acute or chronic according to the clinical features of the affected organs rather than the time that elapsed after GPBPCI treatment. Relapse was defined by morphologic evidence of disease in the peripheral blood, marrow or extramedullary sites. Leukemia-free survival (LFS) was defined as survival in continuous CR at last follow-up.
Cumulative incidences were estimated for engraftment, GVHD, non-relapse mortality (NRM) and relapse to accommodate competing risks. Competing risks for engraftment was death without engraftment; competing risks for GVHD included death without GVHD, relapse and graft rejection; relapse was a competing risk for NRM and NRM was a competing risk for relapse. The time to GVHD was defined as the time from HSCT to the onset of any grade of GVHD for all of the entire study population (with or without GPBPCI); acute GVHD was censored at day 100 after HSCT and chronic GVHD was censored at last follow-up. Furthermore, for patients with GPBPCI, the time elapsed between the onset of GVHD and GPBPCI was defined as the time from GPBPCI to the onset of any grade of GVHD.
Evaluations of any associations between GPBPCI and outcome was done using an add-on package for the R statistical software, which allows for the estimation of the semiparametric proportional hazards model for the sub distribution of a competing risk analysis as proposed by Fine and Gray.13 In addition to GPBPCI or not, the following variables were considered as covariates: recipient age, sex, disease type, time from diagnosis to transplant, number of HLA matched, mononuclear cell infused and year of transplant. When groups were compared according to continuous covariates, Mann−Whitney U tests were used. A χ2 test was used to compare categorical covariates. For continuous variables, the median was used as cutoff point. GPBPCI was studied as time-dependant variables. The probability of survival was calculated using the Kaplan–Meier method. In multivariate analysis, all factors differing in distribution between the two groups with a P<0.10 and factors found to influence outcomes in univariate analysis with a P<0.10 were included into a Cox proportional hazard model using time-dependant variables.
SAS version 8.2 (SAS Institute, Cary, NC, USA) and S Plus 2000 (Mathsoft, Seattle, WA, USA) were used for most analyses. The date of the latest follow-up was June 15, 2011, and endpoints were calculated at last contact.
Patient and donor characteristics
Characteristics of patients and donors are shown in Table 1. As shown in Table 1, GPBSCI and non-GPBSCI groups were comparable in disease characteristics (diagnosis and status before HSCT, and time from diagnosis to HSCT), extent of patient–donor pair matched (sex and HLA disparity) and graft cell count. There were several differences between the two groups. GPBSCI patients were older than patients in the non-GPBSCI group. Compared with non-GPBSCI patients, more patients in the GPBSCI group received HSCT after July 2009, but have longer follow-up time.
Analyses of chimerism indicated that all patients achieved full donor chimerism by day 30 after HSCT. Patients were engrafted to ANCs exceeding 0.5 × 109/L within a median time of 13 days (range=9–26 days). No patients had primary or secondary graft failure.
Eighty-four (95%) patients achieved platelet engraftment. The 50-day cumulative platelet engraftment probability was 91%. These platelet engraftments occurred at 16 days (range=7–74 days) after HSCT. Four patients never achieved platelet engraftment until the date of their deaths. Two of these four patients who did not receive prophylactic GPBPCI died at 47 and 132 days after HSCT, one received prophylactic GPBPCI at day 28 after HSCT and died at day 88 after HSCT, and one received prophylactic GPBPCI at day 40 after HSCT and died at day 58 after HSCT.
After treatment with prophylactic GPBPCI, 34 patients had no acute GVHD. Six patients developed acute, grade 1, GVHD, 17 developed acute, grade 2, GVHD, acute, grade 3, GVHD occurred in 5 patients and acute, grade 4 GVHD was observed in 1 patient. All cases of GVHD were subsequently controlled. Acute GVHD occurred in the 29 patients described above at a median of 22 (range=1–63) days after GPBPCI treatment. After the prophylactic GPBPCI treatment, the cumulative incidence of acute GVHD grade 2−4 (±s.d.) was 41.9±30.5%, and that of grade 3–4 was 13.2±5.1%.
After administration of prophylactic GPBPCI, chronic GVHD occurred in 24 patients and 19 of them had the extensive type of chronic GVHD. The median time of occurrence of chronic GVHD was 80 (31–171) days after GPBPCI treatment. After the prophylactic GPBPCI treatment, the 2-year cumulative incidence of cGVHD (±s.d.) was 45.4±7.0%.
At last follow-up, at a median time of 240 days (range=34–2777 days), 32 patients, including 17 who received prophylactic GPBPCI (28%) and 15 who did not (55%), experienced leukemia relapse at a median time of 106 days (range=22–804 days) after transplantation. The median time from transplantation to relapse was 75 days (range=22–455 days) in the 15 patients who relapsed without prophylactic GPBPCI; the median time from transplantation to relapse was 137 days (range=54–458 days) in the 17 patients who relapsed after prophylactic GPBPCI and the median time from prophylactic GPBPCI to the onset of relapse was 107 days (range=16–757 days). There was hematological relapse in 28 cases and extramedullary relapse in four cases. Twenty-seven of the 32 cases of relapse occurred within the first year after transplantation.
In a univariate analysis of risk factors for relapse (Table 2), use of prophylactic GPBPCI and AML were associated with lower relapse rate. The 2-year cumulative incidence of relapse (±s.d.) in patients who received prophylactic GPBPCI and patients who did not were 35.7±7.7% and 55.5±10.0% (P=0.017), respectively. In the multivariate model, use of prophylactic GPBPCI was found to be the only predictor for relapse (P=0.025; relative risk (RR)=2.40; 95% confidence interval (CI)=1.15–5.01; Table 3).
Ten out of 42 patients with AML and 7 out of 19 patients with Ph-negative ALL relapsed after prophylactic-GPBPCI treatment. Five out of 12 patients with AML and 10 out of 15 patients with Ph-negative ALL relapsed after HSCT without administration of prophylactic GPBPCI.
At the time of last follow-up, 28 patients died of relapse within a median of 59 days (range=10–456 days) after relapse.
The analyses of NRM are described in Table 4. The 2-year incidences of NRM were comparable in patients who received prophylactic GPBPCI (38%) and patients who did not (33%) (P=0.95). Five patients, including four patients who were treated with GPBPCI and one who was not treated with GPBPCI, died more than 1 year after HSCT. The four patients who were treated with GPBPCI died at days 367, 414, 529 and 690 because of infections. The other patient who did not receive GPBPCI died at day 497 from infection.
Long-term follow-up and survival
As of June 15th of 2011, 20 out of the 61 patients who received prophylactic GPBPCI were alive without disease recurrence, for which the median duration of leukemia-free survival was 318 days (range=78–2777 days) and 3 out of the 27 patients who did not receive prophylactic GPBPCI were alive without disease recurrence, for which the duration of LFS was 1000, 1227 and 1864 days. Among patients who received prophylactic GPBPCI, 21 out of the 42 patients with AML and 5 out of 19 with ALL survived without elapse; among patients not receiving prophylactic GPBPCI, 2 out of the 12 patients with AML and 1 out of 15 with ALL survived without relapse. The 3-year probability of OS was higher in patients who received prophylactic GPBPCI (30.5%) than in patients who did not (11.1%) (P=0.001, Figure 1). The 3-year probability of LFS was also higher in patients who received prophylactic GPBPCI (22%) than in patients who did not (11%) (P=0.003).
In a univariate analysis of risk factors for OS (Table 2), use of prophylactic GPBPCI, female sex and AML were associated with better outcome. Multivariate analysis identified use of prophylactic GPBPCI (P=0.002; RR=2.54; 95% CI=1.39–4.62), AML (P=0.027; RR=0.54; 95% CI=0.29–0.97) and female sex (P=0.023; RR=2.03; 95% CI=1.10–3.74) as the most significant prognostic factors (Table 3).
Patients with advanced hematologic malignancies following allogeneic HSCT have a poor prognosis because of a high rate of relapse and TRM.1, 2, 8, 14, 15, 16 Donor lymphocyte infusion (DLI) following allogeneic HSCT exhibits definite anti-leukemia effects in this group of patients.17, 18, 19, 20 Our initial results showed the feasibility of use of prophylactic GPBPCI in patients who receive HLA-mismatched HSCT without in vitro T-cell depletion.6 For the first time, our current study showed that prophylactic GPBPCI is not only safe, but can also decrease relapse and improve survival after HLA-mismatched/haploidentical HSCT.
In our previous comparative study, the prophylactic use of GPBPCI can reduce relapse rates (P=0.018) after HSCT from HLA-identical sibling donors in patients with a high risk of recurrence.21 In that study, probability of survival was not compared because of the smaller number of cases (12 patients who received prophylactic GPBPCI and 12 patients who did not). In the current study, we provided evidence that prophylactic GPBPCI can improve survival in haplo-identical HSCT settings. When the outcome of GPBPCI recipients was compared with those patients who had been treated without prophylactic GPBPCI, the use of prophylactic GPBPCI, among other established risk factors, was a significant factor for relapse and survival in a multivariate analysis.
In the current study, patients who received prophylactic GPBPCI had a higher probability of survival than those who did not. Schmid22 also reported a higher probability of survival after prophylactic DLI in a subgroup of refractory AML study population (n=17) with a 2-year OS of 87%. Comparison between Schmid’s and our results is not appropriate as Schmid’s report deals with CD3+ cell infusions and very strict inclusion criteria for pDLI (that is, being alive and in remission at day +120, without GvHD, off immunosuppressive therapy and free of severe infections) were used. The probability of survival was reported to be 37% in our own previous study in which prophylactic GPBPCI was given to patients with advanced disease who underwent the same haplo-identical transplant procedures at our institute.6 It appears that the probability of survival for patients receiving prophylactic GPBPCI in the current study was lower than that in the previous report; however, it must be noted that previously, one-thirds of the patients in the prior study had Ph-positive ALL or CML-blastic phase (BP) or MDS-transformed acute leukemia (AL) and a different definition of advanced leukemia was applied to the current report. The 30% survival probability reported here was quite acceptable considering the relatively homogenous study population and the more advanced nature of illness in the patient population that was enrolled in the current study. On the other hand, the 1-year cumulative incidence of 51% relapse in the previous report was much higher than that of our current study population who received prophylactic GPBPCI. The use of earlier infusion times may have played a role in lowering the relapse rates in the current study. Occurrence of acute GVHD in that previous report with grade 3–4 cumulative incidence of 28% was higher than that of our current population with prophylactic GPBPCI. Seventeen percent of that previous study population did not receive GVHD prophylaxis after GPBPCI.
By contrast, the outcome of advanced leukemia patients who did not receive prophylactic GPBPCI was comparable to the outcomes in many other studies in which survival has remained fairly constant at approximately 5–10%.1, 2, 8, 14, 15 Sierra et al.1 reported that the LFS of AML patients who received T-cell-replete HSCT from unrelated donors was 7% during relapse (n=81). Aversa et al.2 reported that the LFS was 4% for 38 relapsed acute leukemia patients who were undergoing haplo-identical HSCT. Doney et al.14 reported that the LFS was 9% for 95 adult patients who were in relapse from ALL after allo-HSCT. Singhal et al.15 reported that the LFS after HSCT from partially matched related donors was 14% in patients with primary refractory acute leukemia (n=19). Michallet et al.8 reported that the LFS was 9%, 13% and 11% for primary resistant, untreated relapse and refractory relapse, respectively, in AML patients who received allo-HSCT. In our recent report, the OS was 42% for high-risk, acute leukemia patients who received haplo-identical HSCT.7 Nearly half of that study population had pH-positive ALL or MDS-transformed AL, which may have contributed to the higher survival rates.
The incidence of GVHD was not increased after GPBPCI compared with non-GPBPCI group (P=0.55, data not shown). Use of GPBPCI combined with the use of short-term immunosuppressant for GVHD prophylaxis may play a role. The effect of in vivo G-CSF application on T-cell function has been extensively explored. Several reports, including our data, indicate that in vivo G-CSF application indirectly induced a decrease in T-cell proliferation and type II helper T-cell polarization of the cytokine profile. Furthermore, T-cell hyporesponsiveness induced by in vivo G-CSF may be related to a selective decrease in DC1 and the downregulation of CD28/B7 co-stimulatory signals. As compared with steady state BM, the ratio between monocyte and T-lymphocyte was significantly higher in G-CSF mobilized peripheral blood. This may contribute to the Ag-specific hyporesponsiveness of T cells in G-CSF-mobilized harvests.23, 24, 25
As a limitation to our current study, it has to be stated that the patients were not randomized on whether or not to receive GPBPCI and the control group is relatively small with only 27 patients. For patients with advanced leukemia, it is difficult to conduct prospective, controlled studies; clinicians will have to base their treatment options to a certain extent on retrospective data such as ours. The validation of the identified risk factors and the proposed strategy in a prospective study is warranted.
In conclusion, the current study shows that a lower relapse rate, a similar NRM and a higher survival probability were achieved with patients who received prophylactic GPBPCI compared with patients who did not. The results suggest that prophylaxis of relapse with use of GPBPCI may increase the survival of patients with advanced-stage acute leukemia even after HLA- mismatched T-cell-replete HSCT. Therefore, the use of prophylactic GPBPCI might be a better way to exploit the GVL efficacy. Further confirmation of these results will require the study of more cases and the participation of more SCT units. Further experimental and clinical research is required to define the role of prophylactic GPBPCI.
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This work was supported (in part) by National Natural Science Foundation of China (grant No. 30971292), National High-tech R&D Program of China (863 Program), Leading Program of Clinical Faculty accredited by the Ministry of Health of China, National Scientific Major Program-major new drug formulation (grant No. 2008zx09312-026) and Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation. We thank American Journal Experts for reviewing the paper in English. We thank every faculty member who has participated in these studies.
Author contributions: Conception and design: Huang Xiao-Jun; analysis and interpretation of the data: Huang Xiao-Jun and Wang-Yu; drafting of the article: Huang Xiao-Jun and Wang-Yu; final approval of the article: all authors; provision of study materials or patients: all authors; obtaining of funding: Huang Xiao-Jun; administrative, technical, or logistic support: Huang Xiao-Jun and Liu Kai-Yan; collection and assembly of data: Wang-Yu.
The authors declare no conflict of interest.
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Wang, Y., Liu, D., Xu, L. et al. Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis. Bone Marrow Transplant 47, 1099–1104 (2012) doi:10.1038/bmt.2011.213
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