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15 April 1997 | Volume 126 Issue 8 | Pages 600-607
Background: Previous studies have suggested that peripheral blood stem cell (PBC) transplantation has an advantage over autologous bone marrow transplantation.
Objective: To compare the hematologic recovery and costs associated with PBC transplantation with those associated with autologous bone marrow transplantation in patients receiving high-dose chemotherapy for solid tumors or lymphomas.
Design: Multicenter, randomized, controlled clinical trial.
Setting: French Federation of Cancer Centers, located in cancer facilities or public hospitals with transplantation units.
Patients: Children and adults with solid tumors or lymphomas who were candidates for high-dose chemotherapy.
Interventions: Bone marrow or filgrastim-mobilized PBCs.
Measurement: The major end point was the duration of thrombocytopenia (platelet count < 50 x 109/L). An economic evaluation of both types of transplantation was done prospectively to measure costs and cost-effectiveness.
Results: 129 patients entered the trial; 64 had PBC transplantation, and 65 had bone marrow transplantation. The median duration of thrombocytopenia was 16 days in the PBC group and 36 days in the bone marrow group (P < 0.001). All of the other clinical end points studied (time to last platelet transfusion, duration of granulocytopenia, number of transfusion episodes, and duration of hospitalization) favored PBC transplantation. A cost analysis showed that total cost was decreased by 17% in adults and 29% in children with PBC transplantation; thus, PBC transplantation was clearly more cost-effective than bone marrow transplantation for both platelet and granulocyte recovery.
Conclusion: Transplantation of PBCs is associated with more rapid hematologic recovery than is bone marrow transplantation after high-dose chemotherapy for solid tumors or lymphomas. Furthermore, global costs are lower and cost-effectiveness ratios are better with PBC transplantation.
Most studies have shown that the duration of granulocytopenia after autograft is shorter if PBC transplantation is used instead of bone marrow transplantation [13, 14]. In 1992, Sheridan and associates [12] found a significant reduction in the duration of thrombocytopenia after PBC and bone marrow transplantation compared with bone marrow transplantation alone. However, their study was not prospective and did not include a group that received PBC transplantation alone. Moreover, preliminary reports [15-17] suggest that autologous PBC transplantation is less costly than bone marrow transplantation.
Given these encouraging findings, in 1993 the French Federation of Cancer Centers began a randomized, controlled trial in patients who were receiving high-dose chemotherapy for a solid tumor or lymphoma. The trial compared PBC transplantation with bone marrow transplantation with respect to hematologic recovery and costs. The results of this trial are presented here.
Persons of any age and sex who had a solid tumor or lymphoma and were candidates for a first course of high-dose chemotherapy and autologous hematopoietic progenitor cell transplantation were eligible for inclusion. No grafts were collected from patients whose condition was newly diagnosed. Patients with a contraindication to cytapheresis or filgrastim, patients with a severe invasive infection, and patients who required an ex vivo purged autograft were ineligible. Written informed consent was required from all eligible adults and from the parents of eligible children. This protocol was approved by the Kremlin-Bicetre ethical committee, France.
Interventions
When a graft was planned for an eligible patient, the attending physician contacted the trial's data manager by telephone. The manager used a computer software program to randomly assign the eligible patient to receive either a PBC graft mobilized by filgrastim or a bone marrow graft. Randomization was stratified by center and, because of the particular hematotoxicity of busulfan and total-body irradiation, by the type of programmed conditioning regimen (total-body irradiation and high-dose chemotherapy with or without busulfan). Stem cells were collected within 1 month after randomization.
Collection of Peripheral Blood Stem Cells and Bone Marrow
The initial protocol included bone marrow harvest for rescue for all patients in the PBC group. However, because rescue was not used for the first 30 patients in this group, it was decided that bone marrow be harvested for rescue only when the product of leukapheresis was insufficient. Patients had to be in hematologic steady state before mobilization. Mobilization was done with 10 µg of filgrastim per kg of body weight per day, administered subcutaneously over 6 consecutive days. The PBC grafts were collected by three cytaphereses done on days 5, 6, and 7 of filgrastim administration. The minimum hemoglobin level required before collection was 10 g/L in adults and 12 g/L in children. Three cell separators were used in the different centers: Spectra (Cobe Laboratories, Lakewood, Colorado), CS 3000 (Baxter Health Care Corp., Deerfield, Michigan), or AS104 (Fresenius AG, Bad Homburg, Germany). Given the wide variations between laboratories, collection of colony-forming unit granulocyte macrophages (CFU-GM) was classified as "rich" or "poor or normal." In the main laboratory, the PBC graft was considered rich if it contained more than 30 x 104 CFU-GM/kg; this threshold was adapted for use in the other laboratories.
Bone marrow was collected from the iliac crests while patients were under general anesthesia, as described elsewhere [18]. The graft was considered rich if it contained more than 15 x 104 CFU-GM/kg.
Conditioning Regimen and Transplantation
The conditioning regimen consisted of high-dose chemotherapy with or without total-body irradiation, in accordance with current protocols developed by national tumor committees for each type of cancer (Table 1). Transplantation was to be done 1 to 2 days after the end of the conditioning regimen. ARTICLE
Peripheral Blood Stem Cell and Bone Marrow Transplantation for Solid Tumors and Lymphomas: Hematologic Recovery and Costs: A Randomized, Controlled Trial
Peripheral blood stem cells (PBCs) have recently been used to reconstitute hemopoiesis after myeloablative therapy [1, 2]. The cells can be collected in patients who are in steady state, but several leukaphereses are needed [3]. Mobilization of progenitor cells from the bone marrow to the peripheral blood can be achieved with chemotherapy, alone or in combination with hemopoietic growth factors [4-6], or with hemopoietic growth factors alone administered to patients in hematologic steady state [7-12].
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Patients
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Filgrastim (5 micro g/kg per day) was administered intravenously to all patients in both groups from day 1 after transplantation until granulocyte recovery (to a granulocyte count > 1 x 109/L) (controlled twice at 48-hour intervals). Use of all other hemopoietic growth factors was prohibited throughout the trial. Data on the side effects of filgrastim were collected.
Follow-up
Daily surveillance began on the first day of hospitalization for high-dose chemotherapy and was continued throughout the hospital stay. All patients received right atrial catheters on admission and were isolated in laminar air-flow single rooms. They received parenteral nutrition and broad-spectrum antibiotics when indicated. Platelet infusions and erythrocyte concentrates were used to maintain a platelet count greater than 20 x 109/L and a hemoglobin level greater than 70 g/L. All blood products were irradiated with a dose of 25 Gy before transfusion. All extra hematologic complications were recorded [19]. After discharge, patients were checked monthly during the first 3 months and once every 3 months thereafter.
Outcome Measures
Clinical End Points
The main clinical outcome measure was the duration of thrombocytopenia (platelet count < 50 x 109/L). Other clinical measures were the time between transplantation and the last platelet transfusion, the duration of thrombocytopenia (platelet count < 30 x 109/L and platelet count < 100 x 109/L), the duration of granulocytopenia (granulocyte count < 0.5 x 109/L), the number of febrile episodes (a febrile episode was defined as a 12-hour period during which the body temperature was >38 °C), the duration of febrile granulocytopenia, and the duration of hospitalization.
Costs
Direct medical costs were estimated by measuring the physical quantities of capital and labor consumed by each patient. Monetary values were assigned to these quantities on the basis of average 1995 prices in French francs [20]. Costs were estimated from the date on which patients were admitted to the transplantation unit until discharge and were based on patients' medical records. These costs included the "room cost," the cost of filgrastim after transplantation, the cost of collection (including the costs of filgrastim priming and cell cryopreservation), and other treatment-related costs (such as those for drugs, laboratory tests, and transfusions). Given the inherent differences between hospital charges and real costs (especially in the context of a publicly funded health care system, such as that in France), hospital charges were not used to assess room costs associated with stays in the transplantation unit. Two per diem real costs were calculated on the basis of the Institut Paoli Calmettes transplantation unit (for adults) and the Institut Gustave Roussy pediatric transplantation unit (for children). The annual expenditure for consumable supplies, cost for personnel in the unit, and depreciation of equipment were evaluated to calculate these per diem costs for each stay in the transplantation unit. The step-down method was used to add overhead costs to these per diem costs [21, 22]. An additional study was done on the basis of detailed observations made during 42 leukapheresis procedures and 141 bone marrow harvest procedures done between January 1992 and May 1993 at the Institut Paoli Calmettes to determine the average cost of the two collection procedures. These average costs were ultimately applied to the study patients.
Statistical Analysis
It was estimated [23] that at least 70 patients per group would be needed to show a minimal reduction of 10 days in the duration of thrombocytopenia in the PBC group (one-tailed test, 
= 0.05, ß = 0.10; duration of thrombocytopenia in the bone marrow group ±SD, 33 ± 20 days).
Analyses were done using the intention-to-treat principle. Differences between groups were evaluated by the chi-square test or the Fisher exact test for categorical variables and by the Student t-test or nonparametric test for continuous variables (two-sided tests). All analyses of clinical end points were adjusted for center and type of conditioning regimen.
In the life-table analysis, actuarial probabilities were estimated using the Kaplan-Meier method [24]. The curves carry 95% CIs calculated according to the method of Rothman [25]. Survival curves were compared using the log-rank test [26]. Values are the mean ±SD unless otherwise indicated.
Industry Support
Laboratoire AMGEN (Neuilly, France) provided support for this study with an agreement that the report would be submitted for publication regardless of the findings. One of the authors participated in developing the protocols and is a Laboratoire AMGEN employee.
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Table 2 shows the baseline characteristics of the two groups. High-dose chemotherapy was indicated most often for breast cancer (28%) and lymphoma (12%) in adults and for neuroblastoma and Ewing sarcoma (23%) in children. All patients had received conventional combined chemotherapy before study entry according to standard treatment protocols. They received a median of 5 drugs (range, 2 to 10 drugs) and a median of 7 courses of therapy (range, 2 to 27 courses of therapy) before graft harvest. Five patients had also received extended-field radiotherapy. As a result of previous treatment, only 45 patients (35%) were in first complete remission and 9 (7%) had progressive disease at the time of high-dose chemotherapy (Table 2). Clinical status at the time of the graft did not differ significantly between the two groups, but the proportion of patients who had transplantation while they were in partial second or subsequent remission or while they had progressive disease was higher in the PBC group (37%) than in the bone marrow group (20%). All patients received high-dose chemotherapy with (20%) or without (80%) busulfan as a conditioning regimen before transplantation (Table 2).
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In the PBC group, three leukaphereses were completed in 60 patients (94%); the clinician decided to stop collection after two cytaphereses in 1 patient, and additional cytaphereses (one in 1 patient and three in 2 patients) were required in 3 patients a few weeks later because the CFU-GM content of the graft collected during the first series of cytaphereses was considered too poor. According to the amended protocol, 3 patients for whom the CFU-GM content of the grafts was too poor received both bone marrow and PBCs. For 1 patient in the bone marrow group, the CFU-GM content of the graft was not rich enough. Three cytaphereses were done, and this patient received both bone marrow and PBCs. According to the intention-to-treat principle, all of these patients were analyzed in the groups to which they had been assigned at randomization. The mean total number of CFU-GM collected in patients in the PBC group was 92.7 x 104/kg ± 110.8 x 104/kg. Total CFU-GM collection was poor or normal in 19% of patients and rich in 81%. The number of CD34+ cells collected was determined in 47 patients in the PBC group (mean, 9.8 x 106/kg ± 9.2 x 106/kg).
Thirty-one patients (48%) received red blood cells before one or more cytaphereses were done. The median daily dose of filgrastim used for mobilization was 10 micro g/kg (range, 6 to 15 micro g/kg); the median total daily dose was 570 µg (range, 130 to 1000 micro g). The mean total CFU-GM content of the graft was significantly greater in the 47 patients (73%) whose first leukapheresis procedure was done on day 5 (106.7 x 104/kg ± 122.7 x 104/kg) than in the 11 patients (17%) whose first procedure was done on day 6 of filgrastim administration (59.8 x 104/kg ± 63.6 x 104/kg) [P = 0.014]. In the bone marrow group, the mean total number of CFU-GM collected was 19.7 x 104/kg ± 18.8 x 104/kg). Patients were classified as having a poor (24%), normal (25%), or rich (51%) collection.
As shown in Table 3, the median duration of thrombocytopenia (platelet count < 50 x 109/L) was significantly decreased in the PBC group (17.5 days [range, 1 to 145 days]) compared with the bone marrow group (36.5 days [range, 9 to 579 days]) (P < 0.001). All other end points also favored PBC transplantation: The median time between transplantation and the last platelet transfusion was decreased by 15 days, the duration of thrombocytopenia (platelet count < 30 x 109/L) was decreased by 21 days, the duration of thrombocytopenia (platelet count < 100 x 109/L) was decreased by 21 days, and the duration of granulocytopenia (granulocyte count < 0.5 x 109/L) was decreased by 4 days (P < 0.001) in the PBC group (Figure 1).
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In both groups, the duration of cytopenia decreased with the number of progenitor cells injected. In the PBC group, this decrease was significant for the duration of granulocytopenia (granulocyte count < 0.5 x 109/L) and thrombocytopenia (platelet count < 50 x 109/L). In the bone marrow group, the decrease seen was not significant. The duration of cytopenia was shorter for granulocytes and platelets when patients had received fewer than six courses of conventional chemotherapy before transplantation, although the differences were not significant in the PBC group.
All but 4 patients (3 in the PBC group and 1 in the bone marrow group) had at least one febrile episode. A microorganism was identified in 13 patients in the PBC group and 14 patients in the bone marrow group. Of these 27 patients, 20 had bacterial organisms (10 in each group), 2 had fungal organisms (1 in each group), 1 had a viral organism (in the bone marrow group), and 4 had two or more types of organisms (2 in each group). Median duration of fever and median duration of febrile granulocytopenia (Table 3) were shorter in the PBC group (P = 0.030 and P = 0.009, respectively) than in the bone marrow group. The number of severe hemorrhages was higher in the bone marrow group (n = 9) than in the PBC group (n = 3), although the difference was not significant (P = 0.07). No difference in extrahematologic complications was seen between the two groups (Table 3).
The median number of red blood cell transfusions was decreased significantly in the PBC group (2 transfusions [range, 0 to 20 transfusions]) compared with the bone marrow group (4 transfusions [range, 1 to 18 transfusions]) (P < 0.001). The proportion of patients who had more than four episodes was 8% and 37%, respectively. Similarly, the median number of platelet transfusions was significantly lower in the PBC group (3.5 transfusions [range, 1 to 25 transfusions]) compared with the bone marrow group (9 transfusions [range, 2 to 66 transfusions]) (P < 0.001). The proportion of patients who received more than nine platelet transfusions was 14% in the PBC group and 46% in the bone marrow group.
Only two patients (one in each group) did not receive filgrastim after transplantation. As expected, given the difference in the duration of neutropenia in the two groups, the median duration of filgrastim therapy after transplantation was shorter in the PBC group (10 days [range, 6 to 42 days]) than in the bone marrow group (16 days [range, 4 to 39 days]) (P < 0.001). The median duration of hospitalization was 7 days shorter in the PBC group than in the bone marrow group; the proportion of patients hospitalized for more than 4 weeks was 29% in the PBC group and 65% in the bone marrow group (P < 0.001).
As Figure 2 shows, actuarial event-free survival did not differ in the two groups (median follow-up, 20 months).
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The total cost of treatment was lower in the PBC group than in the bone marrow group (a decrease of 17% for the adults and 29% for the children) (Table 4). This decrease is largely attributable to the reduced room costs that result from shorter lengths of stay (a decrease of 12% for the adults and 33% for the children). The cost for filgrastim after transplantation was substantially lower in the PBC group than in the bone marrow group (a decrease of 32% for the adults and 33% for the children).
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Our randomized trial confirms the superiority of PBC transplantation over bone marrow transplantation with respect to speed of hematologic recovery. Schmitz and coworkers [28] published results of a study that was similar to ours but that included only patients with lymphoma. In both their study and ours, the superiority of PBC transplantation to bone marrow transplantation was shown with respect to the durations of thrombocytopenia, granulocytopenia, and hospitalization. Similarly, the consumption of blood products was significantly lower in the PBC group than in the bone marrow group in both studies. Because our trial was larger, we were also able to show differences in the durations of neutropenia and febrile neutropenia and to assess the relation between previous therapy in the bone marrow group and recovery. In addition, we studied the dose-effect relation between the CFUGM content of the graft and speed of recovery in patients who received PBCs. This dose-effect relation has previously been shown in several studies [8, 11, 29-34] but not in others [5, 7]. Another randomized study [35] compared PBC transplantation with bone marrow transplantation in patients with germ cell tumors [35]. The results of this series of 46 evaluable patients favored PBC transplantation in terms of hematologic recovery, but no benefit was seen in terms of duration of hospitalization or costs. Finally, we found that the duration of filgrastim therapy before PBC graft collection seems to be related to the concentration of progenitor cells. Sheridan and associates [12] found that collection should ideally start on the fifth day of filgrastim therapy.
In the patients who received PBCs, recovery was not transient; this is shown by the significant difference in the duration of thrombocytopenia (platelet count < 100 x 109/L). Other reports have confirmed the absence of late failures and have obtained results similar to ours [7, 29, 36]. Whether equally rapid recovery could be obtained with a filgrastim-primed bone marrow graft remains open to discussion [37, 38].
The role of therapy before harvest is also well known. It has been shown that both the duration and intensity of previous chemotherapy [39, 40] and the use of extended-field radiotherapy [8] can impair the quality of the graft obtained. In our study, the duration of cytopenia was shorter for granulocytes and platelets when patients had received fewer than six courses of conventional chemotherapy before transplantation. However, the differences were not significant in the PBC group.
Death and carcinologic events were not study end points, but rates of relapse have been similar in both groups to date. The role of tumor cells in contaminating the bone marrow graft has been shown in acute myelogenous leukemia and neuroblastoma [41, 42], and the presence of tumor cells in the PBC graft is well known and may have prognostic significance [43]. However, our follow-up was probably too short and the number of patients in our trial was probably too small to show a difference in the relapse rate between the two groups.
Economic assessments of PBC transplantation in cancer therapy have shown direct cost savings associated with a reduction in the duration of hospitalization for patients receiving PBCs compared with patients receiving bone marrow. These savings are only partly offset by the additional drug purchase costs related to PBC transplantation [16, 17]. We confirm that PBC autotransplantation seems to be less costly than bone marrow transplantation. Our cost model included the costs of cell harvesting, cell cryopreservation, and filgrastim (for both priming and stimulation after transplantation); other economic evaluations of hematopoietic stimulating factor have not included these costs and may be biased [17].
The primary limitation of our cost assessment, which favors PBC transplantation, is that because of trial constraints, only the patient costs accrued until discharge from the transplantation unit could be considered. It can be argued, however, that no evidence indicates that patient follow-up costs after discharge from the transplantation unit (including costs of transfusions, outpatient clinic visits, hospital readmissions, and drugs) could reverse our results so that they support autologous bone marrow transplantation. On the contrary, a previous retrospective study done in one of the centers participating in the trial [15] showed that the follow-up cost for PBC transplantation was less than the follow-up cost for autologous bone marrow transplantation during the first month after discharge.
In conclusion, our randomized clinical trial clearly confirms the superiority of PBC transplantation over bone marrow transplantation for solid tumors or lymphomas in terms of hematologic recovery. Peripheral blood stem cell transplantation was not associated with an increase in the incidence of visceral complications or with a compromise in the probability of event-free survival after a median of 20 months. Furthermore, the global costs of PBC transplantation were lower than those of bone marrow transplantation for both adults and children. Economic and clinical arguments favor the substitution of PBC autotransplantation for bone marrow autotransplantation in patients with solid tumors and lymphomas.
From Institut Gustave Roussy, Villejuif, France; INSERM U 379 and Institut Paoli Calmettes, Marseille, France; Institut Curie, Paris, France; Centre Leon Berard, Lyon, France; GIP Sudest Francilien, Creteil, France; Centre Rene Huguenin, Saint-Cloud, France; and Laboratoire AMGEN, Neuilly, France.
Dr. Le Corroller: Unite INSERM 379, Institut Paoli Calmettes, 232 Boulevard Sainte Marguerite, 13273 Marseille Cedex 09, France.
Dr. Blaise: Unite Fonctionnelle de Greffe, Institut Paoli Calmettes, 232 Boulevard Sainte Marguerite, 13273 Marseille Cedex 09, France.
Dr. Michon: Service de Pediatrie, Institut Curie, 26 Rue d'Ulm, 75231 Paris Cedex 05, France.
Dr. Philip: Unite de Chimiotherapie Intensive et de Greffe de Moelle, Centre Leon Berard, 28 Rue Laennec, 69373 Lyon Cedex 08, France.
Dr. Norol: CDTS du Val de Marne, Hopital Henri Mondor, 51 Avenue du Marechal de Lattre de Tassigny, 94010 Creteil Cedex, France.
Dr. Janvier: Service d'Hematologie, Centre Rene Huguenin, 35 Rue Dailly, 92211 Saint-Cloud Cedex, France.
Dr. Pico: Service Paris, Institut Gustave Roussy, 94805 Villejuif Cedex, France.
Dr. Baranzelli: Service d'Oncologie Medicale, Centre Oscar Lambret, 1 Rue Frederic Combemale, B.P. 307, 59020 Lille Cedex, France.
Dr. Rubie: Service de Medecine Infantile, CHU Purpan, Place du Dr. Baylac, 31059 Toulouse Cedex, France.
Dr. Coze: Service de Pediatrie et d'Oncologie Pediatrique, Hopital la Timone, Boulevard Jean Moulin, 13385 Marseille Cedex 5, France.
Dr. Meresse: Laboratoire Amgen, 192 Avenue Charles de Gaulle, 92200 Neuilly-sur-Seine, France.
Dr. Benhamou and Ms. Pinna: Biostatistique et Epidemiologie, Institut Gustave-Roussy, 94805 Villejuif Cedex, France.
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