Japanese Journal of Clinical Oncology 32:135-139 (2002)
© 2002 Foundation for Promotion of Cancer Research
Infusion of a High Number of CD34+ Cells Provides a Rapid Hematopoietic Recovery and Cost Savings in Autologous Peripheral Blood Stem Cell Transplantation
1 Second Department of Medicine and 2 Department of Clinical Laboratory and Medicine, Kyoto Prefectural University of Medicine, Kyoto and 3 Department of Medicine, Shakaihoken Kyoto Hospital, Kyoto, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The objectives of this study were to evaluate the effect of the number of infused CD34+ cells on hematopoietic recovery and on the cost in autologous peripheral blood stem cell transplantation (PBSCT).
Methods: Sixty-nine patients who received autologous PBSCT (ABSCT) were divided into three groups defined by the number of infused CD34+ cells. The number of days until 0.5 x 109/l neutrophils and 50 x 109/l platelets, the number of transfused blood products, the febrile days, the duration of parenteral antibiotics and the cost of additional supportive care (transfusions of blood products and parenteral antibiotics) were analyzed.
Results: Twenty-three patients received <2.5 x 106/kg of CD34+ cells (group A), 25 patients received 
2.5 to 5 x 106/kg of CD34+ cells (group B) and 21 patients received 5 x 106/kg of CD34+ cells (group C). Patients in group C had rapid neutrophil (p < 0.01) and platelet (p < 0.05) recovery and required less platelet transfusions (p < 0.05) than patients in other groups. Transfusions of red blood cell concentrates, the duration of febrile days or parenteral antibiotics were not statistically different between the two groups. The patients in group C required significantly lower costs for platelet concentrates and additional supportive care (p < 0.05).
Conclusion: Infusion of 5 x 106/kg of CD34+ cells in ABSCT shortens hematopoietic recovery and reduces costs for additional supportive care.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Autologous peripheral blood stem cell transplantation (PBSCT) has been used following high-dose chemotherapy as an alternative to bone marrow transplantation (BMT) for hematological malignancies or chemosensitive solid tumors (1–3). One of the most important benefits of PBSCT compared with BMT is rapid hematopoietic recovery (4–7) and it is reported that PBSCT represents significant cost savings compared with BMT (6,7). For autologous PBSCT (ABSCT), it is accepted that infusion of at least 2.0 or 2.5 x 106/kg of CD34+ cells ensures a threshold effect for a rapid hematopoietic recovery (8,9) and there are several reports that infusion of higher CD34+ cell numbers reduces the cost of ABSCT (10–12). However, there has been no report on economic evaluation after ABSCT in Japan. Here we evaluate the effect of infused CD34+ cell dose on hematopoietic recovery and on costs in ABSCT.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
Sixty-nine patients with advanced malignancy who received ABSCT following high-dose chemotherapy or total body irradiation were consecutively enrolled in this study (Table 1). The study included 43 men and 26 women, their ages ranging from 18 to 67 years with a median of 50 years. Five patients had acute myelogenous leukemia (AML), three had acute lymphoblastic leukemia (ALL), 29 had non-Hodgkin’s lymphoma (NHL), six had multiple myeloma (MM), two had Hodgkin’s disease (HD), one had myelodysplastic syndrome (MDS), 19 had small cell lung cancer (SCLC), three had invasive thymoma and one had rhabdomyosarcoma. After several courses of conventional chemotherapy, the patients were enrolled in various protocols evaluating mobilization of PBSCs. High-dose cytarabine (CA) 12 g/m2, high-dose etoposide (ETP) 1.5 g/m2 or high-dose cyclophosphamide (CPM) 2 g/m2 was administered for mobilization of PBSC (1,13,14). Recombinant human (rh) G-CSF (Kirin Brewery, Tokyo, Japan) was administered by s.c. injection at a dose of 50 mg/m2 beginning on the second day after completion of high-dose chemotherapy and continued until the collection of PBSC was completed. The details of cryopreservation were described previously (1) and patients received myeloablative chemotherapy or radiation therapy followed by ABSCT. Five patients with AML, three patients with ALL and one patient with MDS were treated with busulfan (16 mg/kg) and CPM (120 mg/kg) and/or total body irradiation (TBI, 6 Gy). Twenty-nine patients with NHL and two patients with HD were treated with MCNU (400 mg/m2), CPM (100 mg/kg), ETP (1500 mg/m2) and calboplatin (CBDCA, 1200 mg/m2). Six patients with MM were treated with melphalan (140 mg/m2), ETP (750 mg/m2) and TBI (10 Gy) or MCNU (250 mg/m2). Nineteen patients with SCLC and three patients with invasive thymoma were treated with ifosphamide (6 g/m2), ETP (1000 mg/m2) and CBDCA (1200 mg/m2) and one patient with rhabdomyosarcoma was treated with cisplatin (25 mg/m2), ETP (500 mg/m2), CPM (1200 mg/m2) and pirarubicin (40 mg/m2). The cryopreserved PBSC was thawed and infused on day 0 and rh G-CSF was injected s.c. at a dose of 50 mg/m2 from day +1 until the day when the neutrophil count exceeded 5 x 109/l (15,16).
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CFU-GM Assays and Flow Cytometric Analysis
Colony-forming unit of granulocyte-macrophage (CFU-GM) assay and flow cytometric analysis of CD34+ cells in leukapheresis products were carried out using the standard method as described previously (17).
Supportive Care
We evaluated additional costs for transfusion and parenteral antibiotics after ABSCT. Transfusion of packed red blood cell concentrate (RC-MAP) was performed as required to maintain a hematocrit of >20% and that of packed platelet concentrate (PC) was performed to maintain a platelet count >20 x 109/l. One unit of RC-MAP is produced from 200 ml of total blood cells by blood donation. The additional costs for transfusion were estimated as 12 149 yen per 2 units of RC-MAP and 74 378 yen per 10 units of PC. All patients received prophylactic oral antibiotics (ofloxacin) and antifungal therapy (amphotericin B). Patients developing a temperature 38°C during the neutropenic period received broad-spectrum i.v. antibiotics [piperacillin sodium (PIPC) and sulbactum sodium/cefoperazon sodium (SBT/CPZ)], typically stopped after five consecutive afebrile days during continued neutropenia or sooner if neutrophil recovery had occurred. The cost of the additional antibiotics, PIPC and SBT/CPZ, was estimated as 10 168 yen per day.
Statistical Analysis
Data are expressed as mean ± SE except as indicated. The log-rank test was used to evaluate the hematopoietic recovery. An unpaired t-test was used to evaluate the units of transfused blood products, the duration of febrile days and parenteral antibiotics and the cost of transfusion and antibiotics. A value of p < 0.05 was regarded as statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Number of CD34+ Cells and Infused CFU-GM
The 69 patients were divided into three groups defined by the number of infused CD34+ cells. Twenty-three patients received <2.5 x 106/kg of CD34+ cells (group A), 25 patients received
2.5 to 5 x 106/kg of CD34+ cells (group B) and 21 patients received 5 x 106/kg of CD34+ cells (group C). In group A, the median number (range) of CD34+ cells and CFU-GM infused were 1.6 (0.74–2.4) x 106/kg and 2.57 (0.38–8.8) x 105/kg, respectively, the median number (range) of CD34+ cells and CFU-GM infused in group B were 3.4 (2.5–4.9) x 106/kg and 3.2 (0.86–14.6) x 105/kg, respectively, and the median number (range) of CD34+ cells and CFU-GM infused in group C were 9.8 (5.2–38.6) x 106/kg and 6.46 (2.0–20.8) x 105/kg, respectively. The median number of the apheresis to harvest the infused CD34+ cells was one in each group and the ranges of numbers of aphereses were 1–6 in group A, 1–3 in group B and 1 in group C.
Hematopoietic Recovery
No patients died from the complication of ABSCT. The probabilities of achieving 0.5 x 109/l neutrophils and 50 x 109/l platelets are shown in Fig. 1. The neutrophil count reached 0.5 x 109/l in all patients and no patients died from the complication of ABSCT. The median period to reach 0.5 x 109/l neutrophils was 11 days in groups A and B and 9 days in group C, and was significantly shorter in group C than in group A or B (Table 2) (p < 0.01). The median period to reach 50 x 109/l platelets was 18 days in group A, 17 days in group B and 14 days in group C, and also was significantly shorter in group C than in group A or B (Table 2) (p < 0.05). In six patients of group A, the platelet count did not reach 50 x 109/l, but reached 20 x 109/l. The transfusion of PC was not needed after the achievement of a platelet count >20 x 109/l.
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Transfusion Units of Blood Products
Eleven of 23 patients (47.8%) in group A, 11 of 25 patients (44%) in group B and seven of 21 patients in group C (33.3%) received RC-MAP transfusion. There was no significant difference between any two of the three groups.
All patients received PC transfusion after ABSCT. The median units of transfused PC were 40 in groups A and B and 25 in group C, and the patients in group C received significantly fewer PC transfusions than those in group A or B (p < 0.05).
Duration of Febrile Period and Parenteral Antibiotics
Nineteen patients (27.5%) experienced no febrile episodes and 30 patients (43.5%) had 1–3 days of fever 38°C. Seventeen patients (73.9%) in group A, 18 patients (72%) in group B and 14 patients in group C (66.7%) had no febrile episodes or less than 3 days of fever. The medians of febrile days were one in groups A and C and two in group B. The median days when the parenteral antibiotics were given were seven in group A, 11 in group B and eight in group C. There was no significant difference between any two of the three groups (data not shown).
Costs of Transfusions and Parenteral Antibiotics
The costs of transfusion of blood products and parenteral antibiotics were estimated as those for additional supportive care produced by the difference of infused CD34+ cell doses (Table 2). The costs for RC-MAP transfusion were not different between any two of the three groups. The costs for PC transfusion were 633 800 ± 162 900 yen in group A, 365 900 ± 64 400 yen in group B and 214 300 ± 26 900 yen in group C, and was significantly lower in group C than in group A or B (p < 0.05). The costs for parenteral antibiotics were 111 400 ± 25 100 yen in group A, 145 600 ± 21 800 yen in group B and 93 000 ± 16 300 yen in group C, and there was no significant difference between any two of the three groups. The total costs for transfusion of blood products and parenteral antibiotics were 778 500 ± 194 200 yen in group A, 524 700 ± 82 100 yen in group B and 314 800 ± 38 700 yen in group C, and was significantly lower in group C than in group A or B (p < 0.05). The infusion of 5.0 x 106 CD34+ cells/kg in ABSCT provides significant cost savings in the administration of blood products and parenteral antibiotics (p < 0.05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although it has been shown that 2 x 106 CD34+ cells/kg is a minimum threshold for rapid engraftment (8,9), the infusion of more CD34+ cells leads to a rapid hematopoietic recovery, as reported previously (18–21). Kiss et al. (18) and Weaver et al. (19) demonstrated that infusion of
5.0 x 106 CD34+ cells/kg appears to be optimal for ensuring rapid neutrophil and platelet recovery. Remes et al. (20) documented that infusion of 4.0 x 106 CD34+ cells/kg produced less units of blood product for transfusion and a shorter duration of hospitalization than infusion of <4.0 x 106 CD34+ cells/kg. In this study we demonstrated that a significantly rapid engraftment was obtained at a stem cell dose of 5.0 x 106 CD34+ cells/kg in ABSCT.
We evaluated only the costs of additional transfusion and parenteral antibiotics; the cost of rh G-CSF after ABSCT and the cost on hospital days were not included. The units of RC-MAP required was not significantly different between any two of the three groups, whereas the PC transfusions required were significantly less in group C (p < 0.05). This observation suggests that a rapid hematopoietic recovery was obtained and less transfusions of PC were required in the patients who were infused 5.0 x 106/kg CD34+ cells. The number of whole CD34+ cells or megakaryocytic subtype of CD34+ cells infused was correlated with platelet recovery after ABSCT (17–21). The infusion of a higher CD34+ cell dose induced a more rapid platelet recovery.
Although the achievement of 0.5 x 109/l neutrophils was more rapid in the group with infusion of 5.0 x 106/kg CD34+ cells than in the other two groups, there was no significant difference in the duration of febrile days or parenteral antibiotics between any two of the three groups. Scheid et al. (10) demonstrated that infusion of 5.0 x 106 CD34+ cells/kg significantly reduced infectious complications and the use of parenteral antibiotics.
The cost of additional supportive care was significantly less in the group with infusion of 5.0 x 106 CD34+ cells/kg than in the other two groups. Schulman et al. (11) assessed CD34+ cell dose and resource utilization in patients undergoing ABSCT and demonstrated that the cost saving induced by the infusion of 5.0 x 106/kg CD34+ cells was US $9134 (28.2% decrease) in univariate analysis. The cost saving in group C was 463 700 yen (59.6% decrease) compared with that in group A and was 209 900 yen (40.0% decrease) compared with that in the group B. There was no difference in the cost of RC-MAP or parenteral antibiotics, but a significant difference was observed in the cost of PC transfusions. The reduction in the cost of PC transfusions, which is due to rapid platelet recovery, reflects that of the cost of additional supportive care. It has been demonstrated that infusion of 5.0 x 106 CD34+ cells/kg significantly reduces hospital days (10). We did not include the cost of hospitalization in this analysis, but the duration of stay in the sterile unit during the neutropenia of <1 x 109/l after ABSCT was shorter in the group with infusion of 5.0 x 106 CD34+ cells/kg than in the other groups because of the rapid neutrophil recovery in the former group (data not shown).
It is known that the regimen of myeloablative chemotherapy or radiation therapy affects hematopoietic recovery and cost savings after ABSCT. Weaver et al. (19) analyzed the engraftment kinetics in 692 patients after ABSCT and demonstrated that patients receiving thiotepa (500 mg/m2), CPM (6 g/m2) and CBDCA (800 mg/m2) recovered platelets significantly faster than other patients. Schulman et al. (11) demonstrated in an analysis of 1317 patients that the cost of transplantation was lower for patients receiving thiotepa (500 mg/m2), CPM (6 g/m2) and CBDCA (800 mg/m2) or carmustine (300 mg/m2), ETP (1200 mg/m2), cytarabine (800 mg/m2) and CPM (140 mg/kg) (11). We do not discuss this issue here because the number of patients enrolled in our study was not so large as that in the studies mentioned. However, it is necessary to analyze this issue in a large-scale study in Japan.
In conclusion, these observations indicate that infusion of 5 x 106/kg CD34+ cells in ABSCT shortens the period to hematopoietic recovery and reduces the cost of additional supportive care and in addition the infusion of high CD34+ cells enables us to perform ABSCT safely and cost-effectively.
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FOOTNOTES |
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+ For reprints and all correspondence: Eishi Ashihara, Second Department of Medicine, Kyoto University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Abbreviations: PBSCT, peripheral blood stem cell transplantation; ABSCT, autologous PBSCT; BMT, bone marrow transplantation; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin’s lymphoma; MM, multiple myeloma; HD, Hodgkin’s disease; SCLC, small cell lung cancer; CA, cytarabine; ETP, etoposide; CPM cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; CBDCA, calboplatin; TBI, total body irradiation; CFU-GM, colony-forming unit of granulocyte macrophage; RC-MAP, red blood cell concentrates; PC, platelet concentrates; PIPC, piperacillin sodium; SBT/CPZ, sulbactum sodium/cefoperazon sodium; SE, standard error
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19
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21
Dercksen MW, Rodenhuis S, Dirkson MK, Schaasberg WP, Baars JW, van der Wall E, et al. Subsets of CD34+ cells and rapid hematopoietic recovery after peripheral-blood stem-cell transplantation. J Clin Oncol 1995;13:1922–32.
Received November 5, 2001; accepted January 17, 2002
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