Japanese Journal of Clinical Oncology 30:137-145 (2000)
© 2000 Foundation for Promotion of Cancer Research
Feasibility Study of Autologous Peripheral Blood Stem Cell Transplantation for the Treatment of Childhood Acute Myelogenous Leukemia
1Division of Hematology/Oncology, Shizuoka Children’s Hospital, Shizuoka, 2Department of Pediatrics, University of Tokushima, Tokushima, Saitama, 3Department of Pediatrics, Nakadori Hospital, Akita, 4National Defense Medical College, Tokorozawa, 5Tottori University, Tottori, 6National Children’s Hospital, Tokyo, 7Iwate Medical University, Morioka, 8Kurume University, Kurume, Fukuoka, 9National Okayama Hospital, Okayama, 10Kagoshima University, Kagoshima, 11Asahikawa Medical College, Asahikawa, Hokkaido, 12National Medical Center, Tokyo, 13Kanazawa University, Kanazawa, 14Aichi Medical University, Aichi-gun, Aichi, 15Children’s Cancer and Leukemia Study Group of Japan (CCLSG) and 16Haematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The primary object of this study was to identify treatment-related variables that may predict relapse of acute myelogenous leukemia (AML) after autologous peripheral blood stem cell transplantation (PBSCT), which will be critical for the development of a suitable protocol for wider application.
Methods: A total of 28 children (age 0–18 years) with AML underwent PBSCT and have had a minimum follow-up of 25 months; including 24 patients in their first complete remission (CR) and four in their second CR. The patients were divided into two cohorts according to the study phase: 16 patients were treated in an early phase pilot study and 12 patients in their first CR were treated in a prospective trial. Fifteen of the first-CR patients had any of the cited high-risk features of high WBC count (>100 x 109/l; n = 5), FAB M0/M4/M5/M7 subtypes (n = 11) or delayed achievement of CR (n = 9). Except in one patient, cytoreductive regimens did not include total body irradiation (TBI).
Results: After PBSCT, one patient died of veno-occulsive disease (VOD) and another patient relapsed early on day 43, but the remaining patients showed engraftment. Leukemic relapse was observed 1–29 months after PBSCT (median, 8 months ); in all of the 4 children treated in their second CR and in 11 of the 24 patients (46%) treated in their first CR. The remaining patients have been disease-free for 24 to 97 months (median, 53 months ). Using a multivariate analysis, the timing of apheresis was the most significant prognostic factor for those treated in their first CR (p = 0.03); 12 of the 16 patients whose PBSC were collected beyond 2.5 months of CR continue to remain in CR, while seven of the eight patients whose PBSC were harvested within 2.5 months of CR relapsed.
Conclusion: Although the small number of patients studied does not allow firm conclusions to be drawn regarding the relative effectiveness of this therapy, the results do suggest the feasibility of further studies of PBSCT for the treatment of childhood AML with high-risk features including the assessment of minimum residual disease.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The less favorable therapeutic outcome of children with acute myelogenous leukemia (AML) compared with those with acute lymphoblastic leukemia (ALL) clearly indicates the need for new approaches to this entity. Although progress has been made with the intensification of chemotherapy in conventional modality for patients with AML (1), leukemic relapse is the most frequent reason for failure when treatment consists of conventional chemotherapy. Attempts to improve the therapeutic results in AML have focused on a strategy of intensification of chemotherapy, including stem cell transplantation procedures. Although allogeneic bone marrow transplantation (BMT) has been considered an attractive option (2,3), the wide use of this procedure is obviously limited by the availability of human leukocyte antigen (HLA)-matched donors. Procedure-related toxicities (PRT), including graft-versus-host disease and interstitial pneumonitis, are the most frequent reason for failure in an allogeneic BMT cohort (3). Transplantation with compatible marrow obtained through the registry is associated with an increased risk of morbidity and mortality. Therefore, considering these limitations, a firm indication regarding whether children with high-risk AML should receive intensive conventional chemotherapy or BMT has not yet been established.
To avoid the risks associated with allogeneic BMT, an autologous stem cell rescue has been developed (4). Although autologous bone marrow transplantation (ABMT) might become more effective with the use of purged marrow cells, this is time consuming and may damage normal hematopoietic stem/progenitor cells, with a consequent delay in engraftment. In a large trial with 115 children with AML who were treated by ABMT, 15% of the patients died of complications, mostly related to slow engraftment (5). In an Italian survey, 11 of 158 children with AML (7%) died of ABMT-related toxicities (6). Therefore, the value of ABMT in the treatment of childhood AML has not yet been confirmed and the selection of patients for this marrow-ablative therapy still remains an area of debate in childhood AML. The benefits of autologous peripheral blood stem cell transplantation (PBSCT) over ABMT in pediatric patients include faster engraftment with a lower incidence of infectious morbidity (7). However, the supposed advantage of less contamination by leukemic cells compared with ABMT needs to be clarified. Although several reports have been published regarding the therapeutic effects of PBSCT in the treatment of adult patients with AML (8–10), there has been no comprehensive report for pediatric patients. The profile of the therapeutic effects in pediatric patients is completely different from that in adults and the question of which children with AML could benefit from this approach remains to be clarified. Since 1987, we have been evaluating a new program of PBSCT in children with various types of cancer. The procedures and preliminary results have been published elsewhere and the feasibility of PBSCT in terms of a stem cell rescue after marrow-ablative regimen has been established (11–13).
This is the first comprehensive PBSCT study to determine whether high-dose chemotherapy with autologous PBSCT improves the prognosis of childhood AML. Data from 28 patients were surveyed. New methods in cancer therapy should be critically evaluated before they are incorporated into routine practice. Therefore, the primary end-point of evaluation in this feasibility study was safety and the recovery of hematopoiesis. In addition, the identification of prognostic factors that affect leukemic relapse after PBSCT is of critical importance to make PBSCT effective. For this purpose, we first analyzed the data obtained in an initial pilot feasibility study and the results were then adapted to an ongoing phase III prospective study, in which the therapeutic benefits of PBSCT and conventional chemotherapy will be compared. We believe that even small-scale clinical trials could be useful for establishing guidelines for PBSCT for relatively rare childhood cancers.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
Twenty-eight children with AML underwent PBSCT from May 1989 to October 1996. The patients’ characteristics are summarized in Table 1. There were 11 males and 17 females, with a median age of 8 years (range, 0–18 years). Twenty-four of the 28 patients underwent PBSCT in their first complete remission (CR) and the remaining four patients were transplanted in their second CR. Risk factors observed at presentation in 15 first-CR patients included high WBC count (>100 x 109/l; n = 5), FAB M0/M4/M5/M7 subtypes (n = 11) and delayed achievement of CR (n = 9). Sixteen patients were treated in an early-phase pilot study conducted by the Japanese Cooperative Study Group for PBSCT (JCSG/PBSCT) and 12 patients were treated in Children’s Cancer and Leukemia Study Group (CCLSG) prospective randomized controlled trials for first-CR AML (protocols 9205 and 9411). All of the studies were approved by the respective Institutional Review Boards and informed consent was obtained from all of the patients’ guardians.
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Induction and Consolidation Treatment
Data regarding induction and consolidation chemotherapy are also summarized in Table 1. In the Childhood Working Parties of the JCSG/PBSCT pilot study, therapy was tailored to the individual patients treated at different institutes. On the other hand, the 12 patients who were treated by the recent CCLSG protocol 9205/9411 received the same induction and consolidation chemotherapy consisting of THP–adriamycin (THP–ADM; 50 mg/m2/day x 1), vincristine (VCR, 1 mg/m2/day x 1) and cytosine arabinoside (Ara-C, 160 mg/m2/day by continuous infusion for 7 days). In these protocols, all of the registered patients, who had defined high-risk factors, were assigned institutionally to (1) uninterrupted regular chemotherapy lasting for 32 weeks, (2) allogeneic BMT with a matched sibling donor at 8 weeks or (3) PBSC collection at 15 weeks after the third course of consolidation chemotherapy and subsequent transplant at 24 weeks, without follow-up. Eligible patients were automatically assigned to the PBSCT arm when they were seen in institutes which could provide the PBSCT procedure. After achievement of CR, all patients were treated uniformly as follows, before the assigned therapy was begun. The maintenance phase of therapy included cyclic administration of (1) high-dose Ara-C (2 g/m2 b.i.d. for 5 days) + VP-16 (100 mg/m2 for 3 days) and (2) THP–ADM(35 mg/m2/day ' 1), VCR (1 mg/m2/day ' 1) + Ara-C (160 mg/m2/day by continuous infusion for 5 days).
Collection and Cryopreservation of PBSC
PBSC were collected in the recovery phase of consolidation chemotherapy with a continuous-flow blood cell separator (Fenwal CS3000, Baxter Healthcare Corp., IL or Cobe Spectra Apheresis System, Cobe Laboratories Inc., Lakewood, CO), with or without recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim) or macrophage-CSF (M-CSF, Mirimostim) for mobilization of PBSC. The use of hematopoietic growth factors depended on the decision of the institution. The administration of G-CSF began from absolute granulocyte count (AGC) <0.5 x 109/l at a doses of 200 µg/m2/day intravenously. M-CSF was used from 5 days after completion of chemotherapy at a dose of 800 x 106 units/m2/day intravenously. In one patient, G-CSF at a dose of 50 µg/m2/day subcutaneously 2 days before apheresis with concomitant use of M-CSF. The apheresis was done in the recovery phase of chemotherapy when platelet (>100 x 109/l) counts were increasing rapidly. The details of these methods have been published elsewhere (14). The collected cells were then cryopreserved using the uncontrolled hydroxyethyl starch (HES)–dimethyl sulfoxide (DMSO) method as previously described (15). Frozen cells were stored in the liquid phase of liquid nitrogen or in an electric freezer (Sanyo Electric, Tokyo) at –135°C.
Cytoreductive Regimens
The pretransplant cytoreductive regimen was used at the discretion of the participating institute. The regimen used in 16 patients was a combination of busulfan (Bu, 16 mg/kg), VP-16 (50 mg/kg) and Ara-C (3 g/m2 b.i.d. for 4 days), as defined in the CCLSG protocol. The MCVAC regimen (16) was used in seven patients and consisted of MCNU (250 mg/m2 on day –8 and 200 mg/m2 on day –3), VP-16 (200 mg/m2) and Ara-C (2.0 g/m2) (each b.i.d. on days –7 through –4) and cyclophosphamide (50 mg/kg on days –2 and –1). Only one patient received a regimen that included TBI (Ara-C 2.5 g/m2 b.i.d. for 5 days + VP-16 60 mg/kg + 10 Gy TBI). In all of the protocols, children younger than 5 years received all drugs adjusted to mg/kg of body weight (1 m2 = 30 kg). In older children, the doses were determined based on the body surface calculated by the true or ideal body weight, whichever was less.
Transplant Procedure and Supportive Therapy
Thirty-six hours after completion of the cytoreductive regimen, cryopreserved cells were thawed at 37°C and promptly infused into the patient through a central venous catheter without additional post-thaw washing (day 0). The transplant procedure, including the use of G-CSF after PBSCT, differed among the participating institutes. However, all of the patients received prophylactic acyclovir 15 mg/kg/day orally or intravenously starting on the first day of the conditioning regimen and none received prophylactic antibiotics. Broad-spectrum antibiotics and amphotericin B were given only when clinically indicated. Blood products were given as needed to maintain a hemoglobin level of 8 g/dl and a platelet count of 20 x 109/l. In all cases, platelets were collected from a single donor by apheresis. In selected patients, recombinant G-CSF was administered after PBSCT once daily as a 60 min infusion for 14 days. PRT was graded according to the standard World Health Organization (WHO) system.
Statistical Analysis
The statistical analysis was conducted in April 1998. The median follow-up time was 55 months (range, 25–97 months). The following definitions of survival were used: overall survival was the time from transplant to death; disease-free survival (DFS) was the time of transplant to relapse or death; relapse-free survival (RFS) was the time from transplant to relapse (censoring at death in CR). Overall survival, DFS and RFS were determined by the Kaplan–Meier method. Different actuarial curves were compared using the log-rank test. Possible prognostic factors which may affect RFS included age and WBC count at diagnosis, FAB classification, the number of transplanted cells, the timing of apheresis and PBSCT, use of CSF for mobilization and type of conditioning regimen. Variables that potentially affected RFS were assessed in a multivariate analysis by the Cox proportional hazard model using a stepwise regression procedure. Correlation between the use of G-CSF and the numbers of mononuclear cells (MNC), CD34+ cells or colony forming unit-granulocyte/macrophage (CFU-GM) collected by apheresis were computed using the Mann–Whitney test. A univariate analysis of factors affected hematopoietic recovery was performed with the use of Kaplan–Meier analysis and the log-rank test. In this study, no analysis was attempted to compare PBSCT and conventional chemotherapy owing to the small number of patients and short follow-up.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PBSC Collection
In the pilot population, the interval from diagnosis/relapse to PBSC collection varied from 2 to 12 months (median, 4 months). On the other hand, in patients treated by the CCLSG protocols, this was from 3.2 to 7 months (median, 4.5 months). In both groups, a median of three aphereses were performed to collect PBSC and no complications related to apheresis were observed. The numbers of collected and infused mononuclear cells, CD34+ cells and CFU-GM were, respectively, 10.8 x 108/kg (range, 0.82–38.5 x 108/kg), 19.5 x 106/kg (range, 0.11–72.8 x 106/kg) and 54.6 x 104/kg (range, 1.28–288 x 104/kg), as shown in Table 2. The use of G-CSF did not significantly affect the number of CD34+ cells and CFU-GM collected.
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Toxicities and Engraftment after PBSCT
In the pilot study, the interval from diagnosis to the autograft varied from 3 to 14 months (median, 9 months), depending on the progenitor yields by apheresis (Table 2). This ranged from 7 to 13 months (median, 9 months) in those treated by the CCLSG protocol. All of the patients could be evaluated for non-hematological toxicity. Five patients showed an increase in serum levels of liver enzymes and one of these (case 18), who was a carrier of hepatitis C and was conditioned with Bu, VP-16 and Ara-C, developed clinical VOD and died of liver failure at 136 days, without evidence of leukemic recurrence. This was the only case of procedure-related death. Mild to moderate mucositis was the most frequently observed toxicity, particularly in patients conditioned by the combination of Bu, VP-16 and Ara-C. Grade 2 cardiotoxicity was seen in two patients and Grade 1 bladder toxicity was seen in two patients. Atrophic skin was observed in one patient. No cases of toxicities involving the CNS, renal or pulmonary systems were observed. No life-threatening infectious complications were observed.
Except for the the patient who died of VOD and case 24, who relapsed on day 43, all of the patients showed engraftment and a median of 23 and 69 days were required to achieve an AGC >0.5 x 109/l and a platelet count >50 x 109/l, respectively. No significant correlation was found between the number of MNC, CD34+ cells or CFU-GM and the time to achieve granulocyte engraftment, although a higher number of CFU-GM led to a faster recovery of platelet counts (p = 0.01). The post-transplant use of G-CSF led to a significantly faster recovery of both granulocyte (p < 0.01) and platelet counts (p = 0.03).
Therapeutic Results and Prognostic Factors
As of April 1998, leukemic relapse was observed in 15 patients 1–29 months after PBSCT (median, 8 months), consisting of all of the four children treated in their second CR and 11 of the 24 patients (46%) treated in their first CR. Currently, 12 patients remain disease-free at a median of 53 months (range, 24–97 months); eight patients are now beyond 4 years post-PBSCT and are presumably cured of their disease. Overall survival at 5 years in first-CR patients is 53% (95% confidence interval 41–65%) and DFS in this group is 49% (39–60%; Fig. 1). Variables that increased the probability of RFS are shown in Table 3. In a univariate analysis, the possible significant factors associated with an increased probability of RFS were the timing of apheresis (>2.5 months; p = 0.02), a Bu-based cytoreductive regimen (p = 0.04) and use of G-CSF for mobilization (p = 0.07). After a multivariate analysis, the timing of apheresis remained the only significant factor (p = 0.03): 12 of the 16 patients whose PBSC were collected more than 2.5 months after their first CR remained in CR, while seven of the eight patients treated in the early phase of the study and harvested within 2.5 months relapsed (Fig. 2). No work-up for minimum residual disease (MRD) was performed in this series of patients.
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The use of G-CSF for mobilization was evaluated for its effect on leukemic relapse; eight of the 11 patients who received G-CSF remain in RFS. Since seven of the surviving eight patients underwent cell collection beyond 2.5 months, no conclusive statements can be made. Among the patients who relapsed after PBSCT, four have experienced another remission and three of these remain in CR; two underwent allogeneic BMT using an unrelated matched donor and have been in CR 35 and 45 months after BMT, respectively. The Karnofsky score is 100% in all but two of the surviving patients, who underwent BMT with an unrelated matched donor.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This is the first study to address the role of autologous PBSCT in the treatment of children with AML, in which conventional-dose chemotherapy to induce the best remission was followed by marrow-ablative chemotherapy to achieve maximum tumor cell death. The reported DFS rate for adult patients with AML who were treated with PBSCT appeared to be the same as that observed after ABMT (8,9,10,17). However, the biological behavior of AML and the therapeutic effects of PBSCT for its treatment may be different in pediatric patients than in adults.
The primary target of this study was the identification of factors that may affect leukemic relapse after PBSCT in children with AML, which will be critical for the development of a suitable protocol for wider application and to make PBSCT more effective. The identification of pretreatment prognostic factors will allow us to select patients who will benefit the most from this treatment modality (18). The present study is limited by the small number of patients, contamination by inherent biases due to numerous variations in clinical status and treatment and the relative rarity of access to PBSCT. However, we believe that our observations may still be useful for the development of a better PBSCT program. First, our data demonstrated the relative safety of the procedure, although this series of patients was associated with rather delayed recovery of hematopoiesis after PBSCT compared with those with ALL. In our ongoing study in 51 children with first-CR ALL, the number of days to achieve an absolute granulocyte count (AGC) >0.5 x 109/l and a platelet count >20 x 109/l and >50 x 109/l after autologous PBSCT was 11, 13 and 19, respectively, with no procedure-related death (Watanabe et al., unpublished data). In patients with AML, it has been reported that the type of induction regimen affects the engraftment speed after ABMT (19,20). Our patients with AML were treated by a higher dose of Ara-C and the difference in the engraftment speed observed in our series of pediatric patients may reflect the damage to hematopoietic stem cells or the microenvironment by disease-oriented chemotherapies (21).
The improved preliminary therapeutic results in this phase III study are probably due to the benefits of intensified in vivo purging to reduce leukemic cell contamination in the graft and the leukemic burden remaining in the patient’s body at the time of PBSCT, which has also been reported in adult patients (9). It is possible that patients remaining in CR over 3 months may already have been cured by intensified chemotherapy. However, in this study, the rate of leukemic recurrence in patients who underwent early collection was unacceptably high, regardless of the timing of transplant, which is consistent with data reported by Laporte et al. (22). Thus, the present clinical data support the notion that relapse after PBSCT is partly due to the infusion of leukemic blasts contaminating the graft. This observation is inconsistent with previously published clinical and research findings (23,24) and the evaluation of minimum residual disease (MRD) by molecular techniques is currently under way in a CCLSG study. On the other hand, delaying collection to continue chemotherapy may lead to an increase in leukemia recurrence before PBSCT, since the rate of relapse in the first 6 months after achieving CR is reported to be 5% per month (25). A similar trend has been observed in adult patients with AML (26). Hence our recommendations for the timing of the collection of PBSC and subsequent transplantation are around 4 months and 4–6 months after diagnosis, respectively. For patients in subsequent remissions, our results with autologous PBSCT were disappointing, and, as in patients with delayed CR, an allograft strategy is recommended.
The application of PBSCT strikes an acceptable balance between the benefits of high-dose therapy and potential long-term toxicity. Cytoreductive regimens that include TBI are highly toxic in growing children, although a sporadic study reported its beneficial effect in terms of DFS (5). In an attempt to avoid toxicities, most of the patients in this study received a multi-drug combination chemotherapy without TBI as a conditioning regimen. With our cytoreductive regimens, particularly with the regimen using Bu, VP-16 and Ara-C, mild to moderate mucositis was the primary toxicity. Although fatal hepatic VOD was observed in one patient who was treated with this regimen, all other complications were transient and acceptable. There was no significant difference in survival between the different conditioning regimens in a multivariate analysis, although better results appeared to be obtained with the regimen consisting of Bu, VP-16 and Ara-C. Nonetheless, among patients who received the MCVAC regimen, which has been shown to be effective in patients with lymphoid malignancies (16), in most cases their cells were collected within 2.5 months. Since melphalan might be associated with less a lower probability of late adverse effects including infertility, this drug alone is also used as a preparative regimen.
Although G-CSF stimulates the growth of leukemic cells both in vitro and in vivo in adult patients with AML (27), G-CSF also reduces infectious complications and the therapeutic outcome is better in G-CSF-treated groups (28,29). Clinical trials of priming with G-CSF in the induction phase of AML did not show any clinical benefit (30). Furthermore, several published reports support the feasibility of PBSCT in AML using G-CSF-mobilized cells (9,31). In our study, seven of eight patients whose PBSC were mobilized with G-CSF beyond 2.5 months remain in their first CR and thus the possibility that G-CSF also mobilizes leukemic cells and increases leukemic relapse by increasing the frequency of contamination can apparently be rejected. The results of this study suggest that G-CSF therapy may have a beneficial effect on the enhancement of hematopoietic recovery after PBSCT, although a similar result was not seen in our prospective randomized trial in children with ALL or solid tumors or neuroblastoma (7). The current study presents numerous variations and conclusions regarding the benefit of G-CSF after PBSCT still require a disease-specified prospective randomized trial.
The present findings may permit the following conclusions. Achievement of a minimal tumor burden is critical for the prevention of both leukemic contamination of the harvested graft and subsequent leukemic relapse after PBSCT. This dose-intensive approach for children with AML is feasible, with encouraging therapeutic results to date, when PBSC are collected after intense consolidation therapy and transplants are performed in a minimum tumor burden status. Based on the observed very low procedure-related mortality, prospective randomized trials with a control group of chemotherapy-treated patients are currently under way, as part of the design demonstrated in this paper. Longer follow-up of the data obtained in this trial should be able to clarify the merit, if any, of PBSCT compared with conventional treatment.
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Acknowledgements |
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We are grateful to the many physicians and nurses who were involved in the care of these patients, and also the physicians who referred patients for treatment in our program. We also thank Dr H. Aiba, Shizuoka Children’s Hospital, for help with the statistical analysis. This work was supported by Grants-in-Aid for the Second-Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare.
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FOOTNOTES |
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+ For reprints and all correspondence: Yoichi Takaue, Department of Medical Oncology, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: ytakaue@ncc.go.jp
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Received 7 October 1999; accepted 22 November 1999.
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